Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

Interferons are a family of cytokines first identified in the 1950s on the basis of their antiviral function (1). Since their discovery, IFNs have been divided into three types based on their respective cell surface receptors. The type I IFNs are by far the largest family and consist of >20 individual members, such as IFN-α, -β, -ε, -κ, and -δ (2). These cytokines bind to cell surface IFN-α receptor (IFNAR) that is composed of two subunits: IFNAR1 and IFNAR2 (3, 4). Type I IFNs are produced in large quantities following viral infection and are regarded as the archetypal antiviral cytokine. The essential host-protective role for type I IFNs in controlling viral infection is exemplified by the observation that type I IFNR-deficient (Ifnar1−/−) mice quickly succumb to a variety of viral infections compared with wild-type (WT) mice (48).

The sole type II IFN, IFN-γ, signals through the IFN-γ receptor (IFNGR) complex comprising IFNGR1 and IFNGR2 subunits (9). IFN-γ is produced predominantly by activated T and NK cells and plays a major role in activating immune cells during infection with intracellular pathogens (reviewed in Ref. 9). Deficiency in IFN-γ production or signaling leads to loss of resistance to Mycobacteria (10), Listeria (11), and Leishmania (12). Furthermore, hereditary loss-of-function mutations in the IFN-γ or IL-12 signaling pathways in humans, known as Mendelian susceptibility to mycobacterial diseases, results in increased susceptibility to infection with mycobacteria (1316), establishing the critical function for the IFN-γ/IL-12 axis in immunity to intracellular infection.

The more recently identified type III IFNs include IFN-λ1, IFN-λ2, and IFN-λ3. The receptor for type III IFNs contains two subunits, the unique IFN-λ receptor (IFNLR1) and the shared IL-10R2 subunit that is involved in IL-10, IL-22, and IL-26 signaling (17, 18). Interestingly, despite using different cell surface receptors, type III IFNs exhibit similar biological activities to type I IFNs because both types of IFNs activate the same intracellular signaling pathways (reviewed in Ref. 19). However, the magnitude of STAT activation and subsequent biological activities induced by type I IFNs are often greater than those induced by type III IFNs (19). In addition, unlike the type I IFNR, which is expressed almost ubiquitously on all cells, IFNLR1 is expressed predominantly on epithelial cells (20). Therefore, the biological role of type III IFNs is believed to be much more restricted than that of type I IFNs.

It is perceived that type I and type III IFNs are quintessential mediators of antiviral immunity, and IFN-γ is required for resistance to intracellular bacterial and parasitic infections. However, although originally discovered based on their antimicrobial activities, type I IFNs are now known to exhibit other functions, such as antiproliferative and immunoregulatory properties (reviewed in Ref. 21). Some of the classically described immunoregulatory activities are the ability to upregulate MHC class I expression, promote NK cell cytotoxicity, and affect maturation and recruitment of myeloid cell populations (reviewed in Ref. 22). Importantly, recent studies demonstrated that type I IFNs can play a negative role in the control of a diverse range of pathogens. This review summarizes the biological effects of type I IFNs on host resistance to infections, with a focus on the mechanisms underlying the induction and detrimental function of the cytokines in infection.

Induction of type I IFNs has been studied extensively over the last two decades, initially in viral infections and more recently in intracellular bacterial infections. Three distinct pathways were shown to be critical in the induction of these cytokines. TLRs (reviewed in Ref. 23), the retinoic acid–inducible gene (RIG)-like helicases (reviewed in Ref. 24), and the more recently discovered cytoplasmic DNA sensors (2529).

The TLRs are membrane-bound pathogen recognition receptors (PRRs) expressed either on the cell surface (TLR1, 2, 4, 5, and 10) or in endosomes (TLR3, 7, 8, and 9) (23). TLR2, 3, 4, 7, 8, and 9 were shown to induce type I IFNs via recognition of their respective pathogen-associated molecular pattern ligands (30). With the exception of TLR3 and TLR4, MyD88 is the adaptor molecule that mediates type I IFN production for all TLRs. TLR3 and TLR4 induce IFN-β production via the adaptor molecule TRIF (23). Activation of either the MyD88-dependent or -independent pathway leads to activation of members of the IFN regulatory factor (IRF) family, most notably IRF3 and IRF7 (31). IRF3 and IRF7 bind to the promoters of type I IFN genes and initiate their transcription.

The RIG-I like family of helicases contains the members RIG-I and melanoma differentiation-associated protein 5, which recognize cytoplasmic RNA and interact with the mitochondrial membrane-bound IFN-β promoter stimulator 1 (24). This, in turn, interacts with tank-binding kinase 1 (TBK1) to activate IRF3 and IRF7, leading to transcription of IFN genes.

In addition, cytoplasmic DNA sensors, such as IFN-γ–inducible protein 16 (IFI16) (27), DNA-dependent activator of IRFs (26), and cyclic GMP–AMP synthase (cGAS) (25, 28), can bind dsDNA and trigger endoplasmic reticulum–associated adaptor molecule stimulator of IFN genes (STING) (32), TBK1, and IRF3-dependent type I IFN induction (31).

The IFN signaling cascade is initiated by the binding of the cytokines to the high-affinity receptor subunit IFNAR2, followed by binding of the binary complex to IFNAR1 (reviewed in Refs. 3, 33). This receptor engagement induces phosphorylation of the intracellular receptor-associated JAK kinases JAK1 and TYK2, which leads to phosphorylation, dimerization, and nuclear translocation of STAT transcription factors. In addition to inducing STAT homo- and heterodimers (34), type I IFNR engagement results in the formation of the well-studied signaling molecule IFN-stimulated gene factor 3, a complex composed of STAT1:STAT2 and IRF9 (35). In addition to STAT1:STAT2, other STAT homodimers and heterodimers can be induced by type I IFNs in some cell types. Activated STATs translocate to the nucleus where they bind to the promoters of IFN-regulated genes (IRGs) to induce their transcription. Differential combinations of STAT homo- and heterodimers are believed to trigger functionally distinct genes, although the mechanisms governing such associations are poorly understood. Finally, other signaling mechanisms, such as PI3K and MAPK pathways, also contribute to the generation of type I IFN signaling (36). The signaling of type I IFNs via different intracellular signaling mechanisms is postulated to be responsible for cell-type specific functions of IFNs (reviewed in Ref. 37).

Hundreds of IRGs have been reported. Bioinformatic approaches have led to the identification of IFN-inducible gene signatures (3840), although the precise function of individual IRGs in an immune response is still being elucidated (39). This IFN gene signature is traditionally referred to as the “antiviral state” (41) and forms the basis by which type I IFNs confer their antiviral effector functions. Among the most characterized IRGs are antiviral proteins, such as Mx proteins, protein kinase R (PKR), and 2′5′-oligoadenylate synthase (2′5′OAS) (reviewed in Ref. 42), which suppress viral replication by binding to viral polymerases and ribonucleoproteins (as in the case of Mx) (43), inhibiting gene translation (PKR) (44), or cleaving viral ssRNA (2′5′OAS) (45).

Although the host-protective functions of type I IFNs have been well established in viral infection, their role in the host response to other microorganisms has been recognized only recently (reviewed in Refs. 33, 4648). As discussed below, type I IFNs are now known to play a pivotal role in regulating the outcome of many infections. This review summarizes their detrimental function in immunity against a group of highly diverse pathogens, with the aim of understanding the cytokines’ biological functions in infection. Because the role of type I IFNs in bacterial infections has been comprehensively discussed recently (49), only some bacterial pathogens are discussed below.

Listeria monocytogenes is a Gram-positive bacterium known to cause disease when ingested (50), and cell-mediated immunity is essential for host control of the infection. L. monocytogenes is initially phagocytosed by macrophages and dendritic cells and then escapes from the phagosome into the cytosol by secreting the listeriolysin O (LLO) toxin (51). Critically, LLO and subsequent bacterial escape into the cytoplasm are required for type I IFN production because LLO-deficient Listeria strains do not induce type I IFNs (51). Pathogenicity of LLO is further exemplified by the observation that Bacillus subtilis engineered to express LLO also escapes into the cytoplasm and induces IFN-β production and a subsequent IFN-dependent gene signature (51).

Once in the cytosol, L. monocytogenes produce cyclic diadenosine monophosphate that induces type I IFN in an IRF3-dependent, MyD88-independent manner (5254). Interestingly, a recent study demonstrated that, in human cells, Listeria-derived DNA, rather than cyclic diadenosine monophosphate, triggers IFN-β production via cytosolic DNA sensors IFI16 and cGAS (55). This occurs, in part, because murine cells are more responsive to bacterial cyclic dinucleotides than human cells (28, 56).

Intravenous or i.p. infection with the bacteria induces type I IFN expression in mice (52, 57), and Ifnar1−/− mice are more resistant to infection compared with WT mice (53, 58, 59). In addition, pretreatment of mice with polyinosinic-polycytidylic acid (poly I:C), an inducer of type I IFNs, increases their susceptibility to L. monocytogenes infection (53). Considerable work has been performed to define the mechanisms by which type I IFNs enhance host susceptibility to infection. Type I IFNs were shown to increase lymphocyte apoptosis (53, 59, 60), enhance macrophage cell death (61, 62), antagonize IFN-γ signaling by downregulating the IFNGR on APCs (63), inhibit neutrophil migration (64), and reduce the production of protective IL-12 and TNF-α (58, 59). Together, these findings suggest that the bacterium-induced type I IFNs can modulate multiple protective mechanisms to impair survival of the infected host.

A recent study discovered that type I IFNs suppress the immune system via induction of 25-hydroxycholesterol, an oxysterol that is produced by the IFN-inducible gene cholesterol 25-hydroxylase (Ch25h) (65). Mice deficient in Ch25h exhibit increased inflammasome-dependent IL-1β release, IL-17 production, and neutrophil recruitment. Importantly, L. monocytogenes–infected Ch25h-deficient mice display reduced bacterial numbers in spleens and livers compared with WT mice (65), implicating a role for 25-hydroxycholesterol in the type I IFN–dependent suppression of immunity to the infection. Nevertheless, it remains to be determined whether this pathway represents a common mechanism mediating type I IFN–dependent immune suppression.

Mycobacteria are slow-growing intracellular bacteria. Mycobacterium tuberculosis is the causative organism for tuberculosis (TB) and is responsible for 1.3 million deaths annually (66). Approximately 10% of infected individuals eventually develop active disease. In both humans and mice, host control of M. tuberculosis depends on Th1 cell-mediated immunity. IFN-γ is essential for activating macrophages to contain intracellular infection (reviewed in Ref. 67). Although avirulent mycobacteria are effectively eliminated by host immunity, virulent mycobacteria deploy multiple strategies to evade the host antimicrobial machinery, allowing their survival within host macrophages.

Recent evidence suggests that type I IFNs may play a previously unappreciated role in M. tuberculosis persistence and TB pathogenesis. In both human and mouse macrophages, type I IFNs are induced following infection with virulent M. tuberculosis but not avirulent vaccine strains, such as M. bovis BCG (68, 69). Interestingly, the mycobacterial virulence factor ESX-1, which is absent in BCG (70), is required for type I IFN production (68, 69). ESX-1 was shown to permeabilize the phagosomal membrane and thus, allow phagosomal mycobacterial products to access cytoplasmic innate recognition machinery (71, 72). Indeed, mycobacterial extracellular DNA was shown to activate IRF3 to induce IFN-β production in a STING/TBK1-dependent manner (71).

The induction of a large number of IFN-related genes was observed in M. tuberculosis–infected mice, as well as M. bovis–infected cattle (69, 7375). In humans, a comparable IFN-inducible gene signature was observed in the blood of TB patients, as well as in 10–25% of latently infected individuals (76). Further analysis revealed that 86 transcripts can distinguish active TB from other types of inflammatory conditions, such as systemic lupus erythematosus (76), which is known to be associated with an enhanced type I IFN gene signature. This finding suggests that the whole-blood IFN signature could be useful in identifying active TB disease. However, recent studies reported that a similar set of IFN-inducible genes can be detected in other inflammatory diseases, such as melioidosis (77) and sarcoidosis (78), arguing that the clinical potential for the IFN-inducible gene signature in TB diagnosis needs to be evaluated more carefully.

Because avirulent mycobacteria do not induce type I IFNs, it is hypothesized that type I IFN production is associated with mycobacterial virulence and increased host susceptibility. Indeed, infection of mice with hypervirulent clinical isolates results in higher type I IFN production compared with less virulent laboratory strains, and the increased type I IFN levels are associated with reduced expression of Th1 cytokines TNF-α and IL-12 (7981). Importantly, Ifnar1−/− mice and Irf3−/− mice (unable to induce IFN-β) demonstrate lower bacterial burden compared with WT animals (71, 79, 81). Furthermore, intranasal treatment of mice with the type I IFN inducer poly I:C exacerbated pulmonary TB in WT, but not Ifnar1−/−, mice (82).

Although the exact mechanisms by which type I IFNs exacerbate TB infection are currently being investigated, recent works revealed a number of modes of action. For instance, exogenous or M. tuberculosis–induced type I IFNs were shown to suppress expression of the IL1B gene in human macrophages (68). A separate study found that blockade of IFN-β–induced IL-10 signaling partially restored IL1B expression, indicating that type I IFNs may act indirectly to confer their negative effects via IL-10 (83). Because IL-10 has been known to exacerbate murine mycobacterial infections under some circumstances (84), IL-10 induction by type I IFNs could be one mechanism by which type I IFNs impair resistance to mycobacterial infection (8587). Interestingly, a recent study suggests that M. tuberculosis–induced type I IFN production can be regulated by IL-1β through PGE2 (88). PGE2 administration suppresses type I IFN production and increases survival in treated mice, suggesting a cross-regulation between the IL-1β and type I IFN pathways and that antagonism of type I IFN production via PGE2 could be used as a potential therapy for active TB.

In addition, type I IFNs can suppress IFN-γ signaling by downregulating IFNGR1 expression (63, 82, 89), suggesting that their detrimental effect directly involves the antagonism of type II IFN signaling. Interestingly, Desvignes et al. (90) found that, in the absence of IFN-γ signaling, type I IFNs play a host-protective role during M. tuberculosis infection, because mice deficient in both type I and type II IFNR components have worse pathology and increased mortality compared with single type II IFNR–deficient animals. This finding suggests that type I IFNs are detrimental only when IFN-γ–dependent immune mechanisms are activated. In line with this work, M. tuberculosis strains known to trigger high levels of type I IFN also induce increased levels of the negative regulator of IFN signaling, suppressor of cytokine signaling 1 (SOCS1) (81). Moreover, Ifnar1−/− mouse macrophages express lower levels of Socs1 during mycobacterial infection, and IFN-γ–activated Socs1−/− macrophages have lower intracellular bacteria as a result of the increased IFN-γ signaling (91). These experimental findings, together with the clinical observation that increased SOCS protein expression correlates with increased disease severity (92, 93), hint that a detrimental role for type I IFNs in M. tuberculosis infection is to antagonize host-protective functions of IFN-γ.

TB is not the only mycobacterial disease associated with type I IFN induction. Self-healing tuberculoid leprosy is traditionally associated with the development of a Th1 response, whereas disseminated lepromatous leprosy is characterized by a Th2 response. Interestingly, this historical view was revised recently by placing type I IFN as a central regulator determining the outcome of M. leprae infection. Lepromatous leprosy is associated with the development of an IFN-β–inducible gene signature in the blood (94). Importantly, type I IFNs are shown to increase bacterial burden and tissue pathology by limiting IFN-γ–dependent antimicrobial activity through production of the immunosuppressive cytokine IL-10 (94).

Franciscella tularensis is the causative bacterium for the highly lethal disease tularemia (reviewed in Ref. 95). Although human disease is shown to occur via zoonotic transmission from arthropods or other infected animals, F. tularensis has gained increasing attention because of its potential use in bioterrorism (96). Host control of F. tularensis infection is dependent on cell-mediated immunity (reviewed in Refs. 97, 98). F. tularensis infects macrophages, neutrophils, and dendritic cells and establishes a replicative niche in macrophages by inhibiting acidification of the phagosome and escaping into the cytoplasm (99101). Interestingly, induction of IFN-β during F. tularensis infection is dependent on access of the bacterium to the cytoplasm (102). This cytokine induction appears to be IRF3 dependent but TLR independent (102, 103). Although the PRR responsible for type I IFN induction during F. tularensis infection remains to be identified, IFN-β expression is greatly reduced in STING-deficient cells (104), suggesting a possible involvement of DNA-sensing receptors, such as cGAS and IFI16, in the process (105). Furthermore, cytosolic bacterial nucleic acids from F. tularensis (103) were shown to induce absent in melanoma 2 inflammasome complex formation and secretion of the proinflammatory cytokines IL-1β and IL-18 (102, 104, 106, 107), providing further evidence that bacterial DNA is able to access cytoplasmic PRRs.

The role of type I IFNs in F. tularensis infection is poorly understood. Although type I IFN production is critical for activation of the host-protective absent in melanoma 2 inflammasome during F. tularensis infection (102104), type I IFNR–deficient mice were shown to be more resistant to intradermal infection than WT animals (108). This latter study suggests that type I IFNs can negatively regulate the accumulation of IL-17–producing cells, thereby impairing neutrophil accumulation and resistance to F. tularensis infection (108, 109). However, other mechanisms may exist. As reviewed by Furuya et al. (109), neutrophil recruitment following pulmonary F. tularensis infection is independent of IL-17, suggesting that the mechanism of action of type I IFNs operating in intradermal infection (108) is different from that in intranasal infection (110).

Salmonella are Gram-negative bacteria. Salmonella enterica serovar Typhi (S. typhi) and S. paratyphi are causative organisms for the disease typhoid fever. Host control of infection is dependent on macrophages and neutrophils, as well as the production of IL-6, IL-1β, IL-18, IFN-γ, and TNF-α (reviewed in Ref. 111). Because S. typhi is an exclusively human pathogen, studies in mice use the nontyphoidal S. enterica serovar Typhimurium (S. typhimurium) strain. Although Salmonella-derived LPS is known to induce IFN-β production in macrophages in a TLR4/TRIF-dependent manner (112), a more recent study demonstrated that S. typhimurium RNA also triggers IFN-β production in fibroblasts via a RIG-I/MAVS–dependent pathway (113).

A role for type I IFN in Salmonella infection in vivo was recognized only recently. Following i.v. infection with S. typhimurium, Ifnar1−/− mice show reduced mortality associated with increased macrophage numbers compared with WT mice (114). Type I IFNs are responsible for the S. typhimurium–induced cell loss by triggering RIP1- and RIP3-dependent necroptosis, an inflammatory form of cell death. Interestingly, type I IFNs also can promote necroptosis in mice administered LPS and TNF-α (115), suggesting that this mechanism could play a role in other infection and/or inflammation settings in which the host response is mediated by macrophages.

Chlamydia trachomatis is an intracellular bacterium and the causative organism of the sexually transmitted infection Chlamydia that is responsible for reproductive morbidity in females. Host control of Chlamydia infection is predominantly dependent on IFN-γ, although other unidentified mechanisms have been investigated (reviewed in Ref. 116).

The role of type I IFNs in Chlamydia infection is not as well defined as in other intracellular bacterial-infection models. C. trachomatis and the murine pathogen C. muridarum infect and replicate in epithelial cells and were found to induce IFN-β in a TLR3/TRIF- (117, 118) or cGAS/STING-dependent manner (119121). Ifnar1-deficient mice exhibit reduced bacterial burden compared with WT mice following genital (122) and respiratory (123) infection with C. muridarum, revealing a detrimental role for type I IFNs in regulating mucosal immunity to this intracellular pathogen. However, type I IFNs do not appear to interfere with the development of a Th1 response to C. trachomatis because IL-12, TNF-α, and IFN-γ expression were unaffected in both studies (122, 123). Instead, the increased resistance of Ifnar1−/− mice was found to be associated with reduced macrophage apoptosis, suggesting that type I IFNs impair host immunity by inducing the death of host-protective effector cells.

Interestingly, in contrast to these studies, mice deficient in the mucosal tissue–specific IFN-ε demonstrate increased bacillary burden and disease symptoms compared with WT mice (124). Although the IFN-ε–protective mechanisms are still under investigation, it appears that different members of the type I IFN family may have distinct functions in this infection model.

Staphylococcus aureus is a Gram-positive bacterium and is responsible for significant morbidity and mortality in infection with antibiotic-resistant strains (125). Innate myeloid cells, such as neutrophils and macrophages, play an essential role in the clearance of S. aureus (126, 127). This extracellular bacterium was unexpectedly shown to induce type I IFN production. At least three distinct innate-sensing mechanisms have been proposed: (1) the short sequence-repeat region of S. aureus surfactant protein A triggers IFN-β production in human and mouse airway epithelial cells in vitro (128); although the molecular pathway has yet to be defined, the observation that the cytokine induction requires internalization of surfactant protein A hints at a possible involvement of an intracellular recognition mechanism in the process; (2) S. aureus DNA activates mouse dendritic cells to produce IFN-β in a TLR9-dependent manner (129); and (3) microbial products, such as peptidoglycan, released during bacterial autolysis can activate the NOD2/IRF5-dependent pathway to produce IFN-β in mouse dendritic cells (130).

Interestingly, a recent study demonstrated that a hypervirulent strain of S. aureus induces a higher level of IFN-β production and causes greater mortality compared with its less virulent counterparts (130), suggesting an association between type I IFN and bacterial virulence. Type I IFNs appear to enhance pathology in S. aureus infection by increasing TNF-α and IL-6 production (128130), as well as neutrophil recruitment (128, 130). Therefore, although neutrophils are essential for the clearance of S. aureus, their excessive recruitment causes tissue inflammation, leading to reduced resistance in this setting. Indeed, Ifnar1−/− mice are protected against lethal S. aureus pneumonia (128). Similarly, Tlr9−/− mice, which are unable to produce IFN-β in response to the infection, demonstrate reduced mortality, suggesting that the TLR9 signaling pathway contributes to IFN-β induction and mortality in vivo (129).

In contrast to resistance to intracellular pathogen infection, Th1-dependent cell-mediated immunity plays a lesser role in controlling extracellular bacteria. Therefore, these findings on S. aureus infection provide interesting insights into the negative role of type I IFNs in infection and indicate that type I IFNs play a broader role in host susceptibility to infection beyond suppressing IFN-γ−induced antimicrobial effector mechanisms.

Candida albicans, a fungus residing predominantly on mucosal surfaces, can cause opportunistic infections and presents a significant burden to immunocompromised individuals (reviewed in Ref. 131). Neutrophils and monocytes/macrophages, through the production of NADPH and myeloperoxidase, play a critical role in the host control of the fungal infection (reviewed in Ref. 132).

Induction of IFN-β by Candida spp. in dendritic cells was shown to depend on an active phagocytosis process and requires C-type lectin and TLR7 (133). Macrophages stimulated in vitro with poly I:C exhibit reduced phagocytic potential and impaired killing of phagocytosed C. albicans (134). Addition of anti–IFN-α/-β– or anti–IFN-β–neutralizing Abs restored the candidacidal activity of macrophages (134). In a mouse model of disseminated candidiasis with C. glabrata, deficiency in type I IFN signaling results in enhanced tissue pathogen clearance compared with control animals (133). Similarly, C. albicans–infected Ifnar1−/− mice show increased survival compared with their WT counterparts that is due to reduced recruitment and activation of inflammatory monocytes and neutrophils (135). In addition, treatment of mice with poly I:C increases Candida disease severity in a type I IFN–dependent manner (134, 136, 137). Therefore, these data suggest a model in which type I IFNs regulate the outcome of infection through their regulatory role on monocytes and neutrophils.

Trypanosoma are parasites that are usually transmitted by insect vectors. Control of T. cruzi infection is critically dependent on IFN-γ produced by activated NK cells and T cells (138). Although the induction of type I IFNs by T. cruzi and T. equiperdum has been observed for decades (139, 140), only recently has work addressed the significance of the cytokines in the resistance to the parasite. Studies performed using infected murine bone marrow–derived dendritic cells and macrophages indicate that T. cruzi–induced IFN-β is predominantly produced in a TRIF-dependent manner (141), although it is not known whether TLR3, TLR4, or both are responsible for type I IFN induction.

Importantly, the level of IFN-β induction in T. cruzi–infected mice correlates with disease severity, suggesting an association between type I IFNs and worsened disease outcome (142). Recently, Chessler et al. (143) reported that Ifnar1−/− mice show improved survival following lethal T. cruzi challenge, which is associated with a reduction in IFN-γ expression in the splenocytes of WT mice compared with Ifnar1−/− animals; this suggests that inhibition of IFN-γ production or signaling might be one of the mechanisms by which type I IFNs enhance host susceptibility to the infection (143). Indeed, Lopez et al. (144) found that mice deficient in a negative regulator of type I IFN signaling were unable to control infection because of significantly reduced IFN-γ induction.

Leishmania is a genus of parasites that infect human hosts via sandfly bites and cause leishmaniasis (reviewed in Ref. 145). Resistance to Leishmania is dependent on Th1 cell responses, whereas susceptibility to infection is associated with Th2 responses (reviewed in Ref. 146). Although early studies suggested that type I IFNs enhance resistance to L. major (147, 148), possibly by promoting the expression of NOS2, IL-12p40, and IFN-γ (147, 149), recent reports showed that type I IFNs are detrimental for control of other Leishmania spp.

Type I IFNs were shown to prevent parasite clearance in parasite-infected macrophages and mice. Incubation of L. amazonensis– and L. braziliensis–infected macrophages with exogenous IFN-β increases parasite burden as a result of reduced superoxide production (150). Moreover, macrophages deficient in the type I IFN–inducible dsRNA-dependent kinase PKR clear L. amazonensis more efficiently and exhibit reduced IL-10 production compared with WT macrophages (151). Treatment of infected human macrophages with poly I:C promotes parasite replication in a PKR-dependent manner, although the role of type I IFN was not formally established. In vivo, L. amazonensis–infected Ifnar1−/− mice show reduced parasite load, as well as decreased pathology, compared with WT mice (152). The increased resistance is associated with enhanced recruitment of neutrophils. In this case, neutrophils are believed to mediate pathogen killing by releasing enzymes, such as elastase and myeloperoxidase (152).

Interestingly, the negative roles of type I IFN in Leishmania infection are mainly reported in infections with L. amazonensis and L. braziliensis, which form the New World species of Leishmania that are predominant in the western hemisphere. It is possible that the beneficial or detrimental role of type I IFN in the infection is dependent on the particular species of Leishmania present. Interestingly, the frequently metastasizing L. braziliensis and L. guyanensis contain the dsRNA virus Leishmania RNA virus (LRV)1 (153155). Mice infected with L. guyanensis containing this virus produce IFN-β in a TLR3-dependent manner, and TLR3−/− mice display reduced footpad swelling (156). Although an isolate of L. major was found to contain LRV2, the effect of the virus on the outcome of L. major infection was not investigated (157). It is possible that the detrimental role of type I IFNs in Leishmania infection is due to the presence of LRV1 or other Leishmania viruses.

Plasmodium are zoonotic parasites that are able to infect humans and cause malaria (158) and are responsible for ∼1 million deaths annually. Host control of the parasite is believed to be dependent on T lymphocytes, the cytokines IFN-γ and TNF-α, and Abs (reviewed in Ref. 159). Multiple innate-sensing pathways were shown to mediate type I IFN induction by the parasite. In addition to TLR7/TLR9-dependent mechanisms (160, 161), type I IFNs can be induced in a STING, TBK1, IRF3/IRF7–dependent manner via AT-rich stem-loop DNA (162). P. berghei–derived RNA also can trigger IFN-β production in a melanoma differentiation-associated protein 5/MAVS-dependent manner (163). However, it is unknown how these pathogen products gain access to the cytosol.

Although it is evident that type I IFNs can be produced by malaria parasite–infected cells in vitro, the cytokines’ function during infection in vivo is less clear. Type I IFNs were shown to mediate protection against blood-stage (164) and liver-stage (163, 165) malaria in infected animals. However, recent studies revealed that type I IFNs increase host susceptibility to cerebral malaria (162, 166).

Following P. berghei ANKA infection, parasitemia and clinical scores are significantly lower in Ifnar1−/− mice compared with WT animals (167). Interestingly, the enhanced resistance is associated with increased numbers of IFN-γ–secreting CD4+ T cells (167). In a follow-up study, type I IFNs were shown to act directly on splenic conventional dendritic cells to impair their ability to phagocytose parasites and prime Th1 cells (168). In addition, deficiency in type I IFN signaling results in an increase in MHC class II expression. Importantly, Ab blockade of type I IFNR prevents disease progression and the death of infected mice. Together, these findings reveal that type I IFNs regulate parasite control by suppressing IFN-γ production and suggest that blockade of type I IFN signaling during severe malaria infection may provide a novel adjunct therapy (168).

Lymphocytic choriomeningitis virus (LCMV), a member of the Arenaviridae family, is rodent borne but can be transmitted to humans in rare cases (169). It has been used extensively in laboratory research to study immune responses to viral infection owing to the fact that different isolates of the virus can lead to either acute or persistent infection (170). For example, infection of mice with LCMV Armstrong or Clone 13 leads to acute (171) and persistent (172) infection, respectively. Unlike acute infection, in which viral control is CD8+ T cell dependent (173175), clearance of persistent infection is dependent on CD4+ T cells and IFN-γ (173, 176, 177).

The requirement for type I IFNs for host survival following acute LCMV infection is well established, because mice deficient in the type I IFNR are susceptible to the viral infection as a result of uncontrollable viral replication (5, 178180). Although persistent LCMV infection is known to result from functional T cell exhaustion (reviewed in Ref. 181) associated with elevated PD-1 expression on T cells (182), as well as IL-10 and PD-L1 expression in infected mice (183, 184), a role for type I IFNs in this process was poorly understood until recently.

Two recent studies demonstrated that, during chronic infection, the significantly elevated levels of PD-L1 and IL-10, as well as viral loads, are significantly reduced in Ifnar1−/− mice or WT animals treated therapeutically with a blocking Ab to the receptor (176, 177). Thus, it appears that failure to control chronic LCMV infection is due, in part, to the induction of the immunosuppressive molecules PD-L1 and IL-10 by type I IFNs. Although the exact molecular pathways by which type I IFNs modulate the expression of these immune-suppressive molecules are unknown, the above findings establish that, although type I IFNs mediate resistance to LCMV early during infection, they impair viral clearance during chronic infection.

In addition to viral strains and the stages of infection, mouse strains dictate the role of type I IFNs in LCMV infection. Although New Zealand Black mice clear the Armstrong infection efficiently, they succumb rapidly to Clone 13 challenge (185). Vascular leakage, inflammatory cell infiltration, and endothelial cell loss all contribute to the death of animals. The heightened susceptibility to Clone 13 infection is dependent on type I IFN signaling because cytokine receptor blockade prevents mortality of the infected mice (185). Interestingly, IFN-α concentrations are comparable in bronchoalveolar lavage fluid of Armstrong- and Clone 13–infected mice, suggesting that the elevated type I IFN signaling, rather than production, underlies the lethal type I IFN–mediated immunopathology in this model. It would be interesting to re-evaluate the role of type I IFNs in viral infection using other mouse strains, because there clearly are differences among different laboratory strains.

HIV infection can lead to AIDS as the result of destruction of CD4+ T cells (186). Type I IFNs are induced during HIV infection, predominantly by plasmacytoid dendritic cells (187). Although type I IFNs are known to mediate antiviral immunity, there has always been caution toward a detrimental role of type I IFNs during HIV/AIDS because of their proinflammatory nature (reviewed in Refs. 188, 189). Indeed, HIV disease progression is associated with increased IFN-α expression (190), and one clinical trial indicates that treatment with anti–IFN-α–neutralizing Abs delays disease progression (191).

Sustained type I IFN stimulation can negatively affect T cell function and survival. High levels of IFN-α inhibit T cell proliferation, as well as chemokine release, in vitro (192). Furthermore, type I IFNs promote apoptosis of CD4+ T cells by inducing TRAIL (193), and patients with progressive HIV disease have higher expression levels of TRAIL and type I IFNs in lymphoid tissue (194). In addition to this proapoptotic pathway, type I IFNs were found to increase the expression of the proapoptotic protein Bak in CD4+ and CD8+ T cells, and T lymphocytes from HIV+ patients express significantly higher levels of Bak than do those from HIV individuals (195). Importantly, small interfering RNA-mediated knockdown of Bak inhibited CD95/Fas-mediated death of T cells, suggesting that targeting this pathway could provide a novel therapy for limiting CD4+ T cell loss in HIV-infected individuals. Therefore, type I IFN signaling is associated with increased T cell apoptosis and disease progression in HIV infection.

In addition, persistent type I IFN exposure can modulate IFN signaling in HIV. Although rhesus macaques treated with type I IFNs are more resistant to SIV infection, chronic type I IFN stimulation during infection renders cells refractory to further type I IFN stimulation by inducing negative regulators of type I IFN signaling, which leads to increased virus loads in treated animals compared with placebo controls (196). In a murine model of lymphopenia, chronic type I IFN exposure leads to CD4+ T cell depletion and CD8+ T cell expansion (197). Therefore, these findings suggest that type I IFNs promote CD4+ T cell depletion independently of the effects of HIV and explain how neutralizing IFN-α may delay AIDS disease progression (191). Together, these data suggest that, although type I IFNs produced during the early phases of HIV infection are protective, persistent type I IFN signaling during chronic HIV infection is detrimental to the eradication of the virus and survival of the host cells.

Epidemiological studies indicate that concurrent infection by bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, and S. aureus, contributes significantly to the mortality caused by influenza A virus (IAV) infection (198). Protection against the extracellular bacteria requires efficient recruitment of neutrophils and macrophages to the site of infection (199, 200). Recent research established a role for type I IFNs in interfering with this innate defense mechanism.

In experimental models of IAV/bacterial coinfection, in contrast to WT mice, which succumb to secondary bacterial infection rapidly, Ifnar1−/− mice are highly resistant to secondary bacterial pneumonia (201). The enhanced bacterial clearance in Ifnar1−/− mice is due to increased neutrophil influx resulting from the upregulation of chemokines KC and Mip2, as well as elevated production of IL-17 (202, 203). S. pneumoniae–superinfected Ifnar1−/− mice show increased IL-17A production by pulmonary γδ T cells (203). IL-17 is a potent regulator of neutrophil recruitment through induction of KC, Mip2, and other inflammatory mediators (204). In addition to their major inhibitory role in neutrophil recruitment, production of type I IFNs during IAV and S. pneumoniae coinfection was reported to suppress macrophage influx due to downregulation of Ccl2 (205).

In addition to extracellular bacteria, type I IFNs may play a role in regulating host resistance to superinfection with intracellular bacteria. IAV and mycobacteria coinfection leads to reduced Ag-specific T cell responses associated with decreased MHC class II expression on dendritic cells (206). Moreover, IAV was shown to impair control of M. tuberculosis in a type I IFN–dependent manner (207). The mechanisms underlying the regulatory function of type I IFNs in superinfection with intracellular bacteria remain to be elucidated.

Although type I IFNs are essential for defense against viral infections, they are now shown to impair resistance to a diverse range of pathogens. The beneficial or detrimental function of these cytokines in an infection is complex and is likely to be dependent on the type of host response triggered, as well as the combinations of host and pathogen factors, such as mouse background and pathogen species. For example, although, in many infections reviewed in this article, the main detrimental function for type I IFNs is to interfere with IFN-γ–dependent pathogen clearance programs, this clearly is not the only mechanism by which the cytokines impair host immunity. In addition, because type I IFNs can be produced by, and signal in, hematopoietic and nonhematopoietic cells, their functions in vivo also will be determined by the tissue sites and stages of infection. Although the effects of type I IFNs on immune cell functions have been the focus of recent studies (summarized in Fig. 1), the role of the cytokines in regulating the response of nonhematopoietic cells to infection should be examined carefully in future investigations. Identification of the pathways mediating the inhibitory function of type I IFNs will lead to a better understanding of the mechanisms underlying persistent infection and assist in developing novel therapeutics.

FIGURE 1.

Type I IFNs modulate immune cell functions to impair host resistance to infection. Type I IFNs suppress cytokine production and survival of lymphocytes. Type I IFN signaling in macrophages and dendritic cells inhibits IFN-γ–dependent MHC class II expression and intracellular pathogen killing. Type I IFNs also promote the expression of immunosuppressive molecules (SOCS1, PDL-1, and IL-10) and the death of macrophages. In addition, type I IFNs prevent neutrophils from migrating into the site of infection, thereby contributing to increased susceptibility to bacterial pathogens following viral infection.

FIGURE 1.

Type I IFNs modulate immune cell functions to impair host resistance to infection. Type I IFNs suppress cytokine production and survival of lymphocytes. Type I IFN signaling in macrophages and dendritic cells inhibits IFN-γ–dependent MHC class II expression and intracellular pathogen killing. Type I IFNs also promote the expression of immunosuppressive molecules (SOCS1, PDL-1, and IL-10) and the death of macrophages. In addition, type I IFNs prevent neutrophils from migrating into the site of infection, thereby contributing to increased susceptibility to bacterial pathogens following viral infection.

Close modal

We apologize to those in the field whose important work was not cited in this article because of space limitations.

This work was supported by the National Health and Medical Research Council of Australia (Project Grant APP1051742).

Abbreviations used in this article:

     
  • cGAS

    cyclic GMP–AMP

  •  
  • Ch25h

    cholesterol 25-hydroxylase

  •  
  • IAV

    influenza A virus

  •  
  • IFI16

    IFN-γ–inducible protein 16

  •  
  • IFNAR

    IFN-α receptor

  •  
  • IFNGR

    IFN-γ receptor

  •  
  • IRF

    IFN regulatory factor

  •  
  • IRG

    IFN-regulated gene

  •  
  • LCMV

    lymphocytic choriomeningitis virus

  •  
  • LLO

    listeriolysin O

  •  
  • LRV

    Leishmania RNA virus

  •  
  • 2′5′OAS

    2′5′-oligoadenylate synthase

  •  
  • PKR

    protein kinase R

  •  
  • poly I:C

    polyinosinic-polycytidylic acid

  •  
  • PRR

    pattern recognition receptor

  •  
  • RIG

    retinoic acid–inducible gene

  •  
  • SOCS1

    suppressor of cytokine signaling 1

  •  
  • STING

    stimulator of IFN gene

  •  
  • TB

    tuberculosis

  •  
  • TBK1

    tank-binding kinase 1

  •  
  • WT

    wild-type.

1
Isaacs
A.
,
Lindenmann
J.
.
1957
.
Virus interference. I. The interferon.
Proc. R. Soc. Lond. B Biol. Sci.
147
:
258
267
.
2
Pestka
S.
,
Krause
C. D.
,
Walter
M. R.
.
2004
.
Interferons, interferon-like cytokines, and their receptors.
Immunol. Rev.
202
:
8
32
.
3
de Weerd
N. A.
,
Nguyen
T.
.
2012
.
The interferons and their receptors—distribution and regulation.
Immunol. Cell Biol.
90
:
483
491
.
4
Hwang
S. Y.
,
Hertzog
P. J.
,
Holland
K. A.
,
Sumarsono
S. H.
,
Tymms
M. J.
,
Hamilton
J. A.
,
Whitty
G.
,
Bertoncello
I.
,
Kola
I.
.
1995
.
A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.
Proc. Natl. Acad. Sci. USA
92
:
11284
11288
.
5
Müller
U.
,
Steinhoff
U.
,
Reis
L. F.
,
Hemmi
S.
,
Pavlovic
J.
,
Zinkernagel
R. M.
,
Aguet
M.
.
1994
.
Functional role of type I and type II interferons in antiviral defense.
Science
264
:
1918
1921
.
6
Seo
S. U.
,
Kwon
H. J.
,
Ko
H. J.
,
Byun
Y. H.
,
Seong
B. L.
,
Uematsu
S.
,
Akira
S.
,
Kweon
M. N.
.
2011
.
Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice.
PLoS Pathog.
7
:
e1001304
.
7
Schilte
C.
,
Buckwalter
M. R.
,
Laird
M. E.
,
Diamond
M. S.
,
Schwartz
O.
,
Albert
M. L.
.
2012
.
Cutting edge: independent roles for IRF-3 and IRF-7 in hematopoietic and nonhematopoietic cells during host response to Chikungunya infection.
J. Immunol.
188
:
2967
2971
.
8
Lazear
H. M.
,
Lancaster
A.
,
Wilkins
C.
,
Suthar
M. S.
,
Huang
A.
,
Vick
S. C.
,
Clepper
L.
,
Thackray
L.
,
Brassil
M. M.
,
Virgin
H. W.
, et al
.
2013
.
IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.
PLoS Pathog.
9
:
e1003118
.
9
Schroder
K.
,
Hertzog
P. J.
,
Ravasi
T.
,
Hume
D. A.
.
2004
.
Interferon-gamma: an overview of signals, mechanisms and functions.
J. Leukoc. Biol.
75
:
163
189
.
10
Cooper
A. M.
,
Dalton
D. K.
,
Stewart
T. A.
,
Griffin
J. P.
,
Russell
D. G.
,
Orme
I. M.
.
1993
.
Disseminated tuberculosis in interferon gamma gene-disrupted mice.
J. Exp. Med.
178
:
2243
2247
.
11
Harty
J. T.
,
Bevan
M. J.
.
1995
.
Specific immunity to Listeria monocytogenes in the absence of IFN gamma.
Immunity
3
:
109
117
.
12
Taylor
A. P.
,
Murray
H. W.
.
1997
.
Intracellular antimicrobial activity in the absence of interferon-gamma: effect of interleukin-12 in experimental visceral leishmaniasis in interferon-gamma gene-disrupted mice.
J. Exp. Med.
185
:
1231
1239
.
13
de Jong
R.
,
Altare
F.
,
Haagen
I. A.
,
Elferink
D. G.
,
Boer
T.
,
van Breda Vriesman
P. J.
,
Kabel
P. J.
,
Draaisma
J. M.
,
van Dissel
J. T.
,
Kroon
F. P.
, et al
.
1998
.
Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients.
Science
280
:
1435
1438
.
14
Altare
F.
,
Durandy
A.
,
Lammas
D.
,
Emile
J. F.
,
Lamhamedi
S.
,
Le Deist
F.
,
Drysdale
P.
,
Jouanguy
E.
,
Döffinger
R.
,
Bernaudin
F.
, et al
.
1998
.
Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.
Science
280
:
1432
1435
.
15
Jouanguy
E.
,
Altare
F.
,
Lamhamedi
S.
,
Revy
P.
,
Emile
J. F.
,
Newport
M.
,
Levin
M.
,
Blanche
S.
,
Seboun
E.
,
Fischer
A.
,
Casanova
J. L.
.
1996
.
Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection.
N. Engl. J. Med.
335
:
1956
1961
.
16
Newport
M. J.
,
Huxley
C. M.
,
Huston
S.
,
Hawrylowicz
C. M.
,
Oostra
B. A.
,
Williamson
R.
,
Levin
M.
.
1996
.
A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.
N. Engl. J. Med.
335
:
1941
1949
.
17
Kotenko
S. V.
,
Gallagher
G.
,
Baurin
V. V.
,
Lewis-Antes
A.
,
Shen
M.
,
Shah
N. K.
,
Langer
J. A.
,
Sheikh
F.
,
Dickensheets
H.
,
Donnelly
R. P.
.
2003
.
IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.
Nat. Immunol.
4
:
69
77
.
18
Sheppard
P.
,
Kindsvogel
W.
,
Xu
W.
,
Henderson
K.
,
Schlutsmeyer
S.
,
Whitmore
T. E.
,
Kuestner
R.
,
Garrigues
U.
,
Birks
C.
,
Roraback
J.
, et al
.
2003
.
IL-28, IL-29 and their class II cytokine receptor IL-28R.
Nat. Immunol.
4
:
63
68
.
19
Kotenko
S. V.
2011
.
IFN-λs.
Curr. Opin. Immunol.
23
:
583
590
.
20
Sommereyns
C.
,
Paul
S.
,
Staeheli
P.
,
Michiels
T.
.
2008
.
IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo.
PLoS Pathog.
4
:
e1000017
.
21
Stark
G. R.
,
Kerr
I. M.
,
Williams
B. R.
,
Silverman
R. H.
,
Schreiber
R. D.
.
1998
.
How cells respond to interferons.
Annu. Rev. Biochem.
67
:
227
264
.
22
Hervas-Stubbs
S.
,
Perez-Gracia
J. L.
,
Rouzaut
A.
,
Sanmamed
M. F.
,
Le Bon
A.
,
Melero
I.
.
2011
.
Direct effects of type I interferons on cells of the immune system.
Clin. Cancer Res.
17
:
2619
2627
.
23
Kawai
T.
,
Akira
S.
.
2010
.
The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.
Nat. Immunol.
11
:
373
384
.
24
Yoneyama
M.
,
Fujita
T.
.
2007
.
Function of RIG-I-like receptors in antiviral innate immunity.
J. Biol. Chem.
282
:
15315
15318
.
25
Sun
L.
,
Wu
J.
,
Du
F.
,
Chen
X.
,
Chen
Z. J.
.
2013
.
Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.
Science
339
:
786
791
.
26
Takaoka
A.
,
Wang
Z.
,
Choi
M. K.
,
Yanai
H.
,
Negishi
H.
,
Ban
T.
,
Lu
Y.
,
Miyagishi
M.
,
Kodama
T.
,
Honda
K.
, et al
.
2007
.
DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response.
Nature
448
:
501
505
.
27
Unterholzner
L.
,
Keating
S. E.
,
Baran
M.
,
Horan
K. A.
,
Jensen
S. B.
,
Sharma
S.
,
Sirois
C. M.
,
Jin
T.
,
Latz
E.
,
Xiao
T. S.
, et al
.
2010
.
IFI16 is an innate immune sensor for intracellular DNA.
Nat. Immunol.
11
:
997
1004
.
28
Ablasser
A.
,
Goldeck
M.
,
Cavlar
T.
,
Deimling
T.
,
Witte
G.
,
Röhl
I.
,
Hopfner
K. P.
,
Ludwig
J.
,
Hornung
V.
.
2013
.
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING.
Nature
498
:
380
384
.
29
Ishikawa
H.
,
Ma
Z.
,
Barber
G. N.
.
2009
.
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
Nature
461
:
788
792
.
30
Kawai
T.
,
Akira
S.
.
2011
.
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.
Immunity
34
:
637
650
.
31
Honda
K.
,
Taniguchi
T.
.
2006
.
IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors.
Nat. Rev. Immunol.
6
:
644
658
.
32
Ishikawa
H.
,
Barber
G. N.
.
2008
.
STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling.
Nature
455
:
674
678
.
33
Ivashkiv
L. B.
,
Donlin
L. T.
.
2014
.
Regulation of type I interferon responses.
Nat. Rev. Immunol.
14
:
36
49
.
34
Schindler
C.
,
Levy
D. E.
,
Decker
T.
.
2007
.
JAK-STAT signaling: from interferons to cytokines.
J. Biol. Chem.
282
:
20059
20063
.
35
Fu
X. Y.
,
Kessler
D. S.
,
Veals
S. A.
,
Levy
D. E.
,
Darnell
J. E.
 Jr.
1990
.
ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains.
Proc. Natl. Acad. Sci. USA
87
:
8555
8559
.
36
Platanias
L. C.
2005
.
Mechanisms of type-I- and type-II-interferon-mediated signalling.
Nat. Rev. Immunol.
5
:
375
386
.
37
van Boxel-Dezaire
A. H.
,
Rani
M. R.
,
Stark
G. R.
.
2006
.
Complex modulation of cell type-specific signaling in response to type I interferons.
Immunity
25
:
361
372
.
38
de Veer
M. J.
,
Holko
M.
,
Frevel
M.
,
Walker
E.
,
Der
S.
,
Paranjape
J. M.
,
Silverman
R. H.
,
Williams
B. R.
.
2001
.
Functional classification of interferon-stimulated genes identified using microarrays.
J. Leukoc. Biol.
69
:
912
920
.
39
Schoggins
J. W.
,
Wilson
S. J.
,
Panis
M.
,
Murphy
M. Y.
,
Jones
C. T.
,
Bieniasz
P.
,
Rice
C. M.
.
2011
.
A diverse range of gene products are effectors of the type I interferon antiviral response.
Nature
472
:
481
485
.
40
Rusinova
I.
,
Forster
S.
,
Yu
S.
,
Kannan
A.
,
Masse
M.
,
Cumming
H.
,
Chapman
R.
,
Hertzog
P. J.
.
2013
.
Interferome v2.0: an updated database of annotated interferon-regulated genes.
Nucleic Acids Res.
41
:
D1040
D1046
.
41
Levy
D. E.
,
García-Sastre
A.
.
2001
.
The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion.
Cytokine Growth Factor Rev.
12
:
143
156
.
42
Sadler
A. J.
,
Williams
B. R.
.
2008
.
Interferon-inducible antiviral effectors.
Nat. Rev. Immunol.
8
:
559
568
.
43
Haller
O.
,
Kochs
G.
.
2002
.
Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity.
Traffic
3
:
710
717
.
44
Meurs
E. F.
,
Watanabe
Y.
,
Kadereit
S.
,
Barber
G. N.
,
Katze
M. G.
,
Chong
K.
,
Williams
B. R.
,
Hovanessian
A. G.
.
1992
.
Constitutive expression of human double-stranded RNA-activated p68 kinase in murine cells mediates phosphorylation of eukaryotic initiation factor 2 and partial resistance to encephalomyocarditis virus growth.
J. Virol.
66
:
5805
5814
.
45
Rebouillat
D.
,
Hovanessian
A. G.
.
1999
.
The human 2′,5′-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties.
J. Interferon Cytokine Res.
19
:
295
308
.
46
Decker
T.
,
Müller
M.
,
Stockinger
S.
.
2005
.
The yin and yang of type I interferon activity in bacterial infection.
Nat. Rev. Immunol.
5
:
675
687
.
47
Trinchieri
G.
2010
.
Type I interferon: friend or foe?
J. Exp. Med.
207
:
2053
2063
.
48
Parker
D.
,
Prince
A.
.
2011
.
Type I interferon response to extracellular bacteria in the airway epithelium.
Trends Immunol.
32
:
582
588
.
49
Parker
D.
, ed.
2014
.
Bacterial Activation of Type I Interferons.
Springer International Publishing
,
Cham, Switzerland
.
50
Vivant
A. L.
,
Garmyn
D.
,
Piveteau
P.
.
2013
.
Listeria monocytogenes, a down-to-earth pathogen.
Front Cell Infect Microbiol
3
:
87
.
51
McCaffrey
R. L.
,
Fawcett
P.
,
O’Riordan
M.
,
Lee
K. D.
,
Havell
E. A.
,
Brown
P. O.
,
Portnoy
D. A.
.
2004
.
A specific gene expression program triggered by Gram-positive bacteria in the cytosol.
Proc. Natl. Acad. Sci. USA
101
:
11386
11391
.
52
Stockinger
S.
,
Kastner
R.
,
Kernbauer
E.
,
Pilz
A.
,
Westermayer
S.
,
Reutterer
B.
,
Soulat
D.
,
Stengl
G.
,
Vogl
C.
,
Frenz
T.
, et al
.
2009
.
Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes.
PLoS Pathog.
5
:
e1000355
.
53
O’Connell
R. M.
,
Saha
S. K.
,
Vaidya
S. A.
,
Bruhn
K. W.
,
Miranda
G. A.
,
Zarnegar
B.
,
Perry
A. K.
,
Nguyen
B. O.
,
Lane
T. F.
,
Taniguchi
T.
, et al
.
2004
.
Type I interferon production enhances susceptibility to Listeria monocytogenes infection.
J. Exp. Med.
200
:
437
445
.
54
Woodward
J. J.
,
Iavarone
A. T.
,
Portnoy
D. A.
.
2010
.
c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response.
Science
328
:
1703
1705
.
55
Hansen
K.
,
Prabakaran
T.
,
Laustsen
A.
,
Jørgensen
S. E.
,
Rahbæk
S. H.
,
Jensen
S. B.
,
Nielsen
R.
,
Leber
J. H.
,
Decker
T.
,
Horan
K. A.
, et al
.
2014
.
Listeria monocytogenes induces IFNβ expression through an IFI16-, cGAS- and STING-dependent pathway.
EMBO J.
33
:
1654
1666
.
56
Conlon
J.
,
Burdette
D. L.
,
Sharma
S.
,
Bhat
N.
,
Thompson
M.
,
Jiang
Z.
,
Rathinam
V. A.
,
Monks
B.
,
Jin
T.
,
Xiao
T. S.
, et al
.
2013
.
Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid.
J. Immunol.
190
:
5216
5225
.
57
Havell
E. A.
1986
.
Augmented induction of interferons during Listeria monocytogenes infection.
J. Infect. Dis.
153
:
960
969
.
58
Auerbuch
V.
,
Brockstedt
D. G.
,
Meyer-Morse
N.
,
O’Riordan
M.
,
Portnoy
D. A.
.
2004
.
Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes.
J. Exp. Med.
200
:
527
533
.
59
Carrero
J. A.
,
Calderon
B.
,
Unanue
E. R.
.
2004
.
Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection.
J. Exp. Med.
200
:
535
540
.
60
Carrero
J. A.
,
Calderon
B.
,
Unanue
E. R.
.
2006
.
Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes.
J. Exp. Med.
203
:
933
940
.
61
Stockinger
S.
,
Materna
T.
,
Stoiber
D.
,
Bayr
L.
,
Steinborn
R.
,
Kolbe
T.
,
Unger
H.
,
Chakraborty
T.
,
Levy
D. E.
,
Müller
M.
,
Decker
T.
.
2002
.
Production of type I IFN sensitizes macrophages to cell death induced by Listeria monocytogenes.
J. Immunol.
169
:
6522
6529
.
62
Zwaferink
H.
,
Stockinger
S.
,
Hazemi
P.
,
Lemmens-Gruber
R.
,
Decker
T.
.
2008
.
IFN-beta increases listeriolysin O-induced membrane permeabilization and death of macrophages.
J. Immunol.
180
:
4116
4123
.
63
Rayamajhi
M.
,
Humann
J.
,
Penheiter
K.
,
Andreasen
K.
,
Lenz
L. L.
.
2010
.
Induction of IFN-alphabeta enables Listeria monocytogenes to suppress macrophage activation by IFN-gamma.
J. Exp. Med.
207
:
327
337
.
64
Brzoza-Lewis
K. L.
,
Hoth
J. J.
,
Hiltbold
E. M.
.
2012
.
Type I interferon signaling regulates the composition of inflammatory infiltrates upon infection with Listeria monocytogenes.
Cell. Immunol.
273
:
41
51
.
65
Reboldi
A.
,
Dang
E. V.
,
McDonald
J. G.
,
Liang
G.
,
Russell
D. W.
,
Cyster
J. G.
.
2014
.
Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.
Science
345
:
679
684
.
66
World Health Organization. Global Tuberculosis Report 2014. Available at: http://www.who.int/tb/publications/global_report/en/. Accessed: October 22, 2014
.
67
North
R. J.
,
Jung
Y. J.
.
2004
.
Immunity to tuberculosis.
Annu. Rev. Immunol.
22
:
599
623
.
68
Novikov
A.
,
Cardone
M.
,
Thompson
R.
,
Shenderov
K.
,
Kirschman
K. D.
,
Mayer-Barber
K. D.
,
Myers
T. G.
,
Rabin
R. L.
,
Trinchieri
G.
,
Sher
A.
,
Feng
C. G.
.
2011
.
Mycobacterium tuberculosis triggers host type I IFN signaling to regulate IL-1β production in human macrophages.
J. Immunol.
187
:
2540
2547
.
69
Stanley
S. A.
,
Johndrow
J. E.
,
Manzanillo
P.
,
Cox
J. S.
.
2007
.
The Type I IFN response to infection with Mycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis.
J. Immunol.
178
:
3143
3152
.
70
Mahairas
G. G.
,
Sabo
P. J.
,
Hickey
M. J.
,
Singh
D. C.
,
Stover
C. K.
.
1996
.
Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis.
J. Bacteriol.
178
:
1274
1282
.
71
Manzanillo
P. S.
,
Shiloh
M. U.
,
Portnoy
D. A.
,
Cox
J. S.
.
2012
.
Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages.
Cell Host Microbe
11
:
469
480
.
72
Simeone
R.
,
Bobard
A.
,
Lippmann
J.
,
Bitter
W.
,
Majlessi
L.
,
Brosch
R.
,
Enninga
J.
.
2012
.
Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death.
PLoS Pathog.
8
:
e1002507
.
73
Ottenhoff
T. H.
,
Dass
R. H.
,
Yang
N.
,
Zhang
M. M.
,
Wong
H. E.
,
Sahiratmadja
E.
,
Khor
C. C.
,
Alisjahbana
B.
,
van Crevel
R.
,
Marzuki
S.
, et al
.
2012
.
Genome-wide expression profiling identifies type 1 interferon response pathways in active tuberculosis.
PLoS ONE
7
:
e45839
.
74
Wu
K.
,
Dong
D.
,
Fang
H.
,
Levillain
F.
,
Jin
W.
,
Mei
J.
,
Gicquel
B.
,
Du
Y.
,
Wang
K.
,
Gao
Q.
, et al
.
2012
.
An interferon-related signature in the transcriptional core response of human macrophages to Mycobacterium tuberculosis infection.
PLoS ONE
7
:
e38367
.
75
Wang
J.
,
Zhou
X.
,
Pan
B.
,
Wang
H.
,
Shi
F.
,
Gan
W.
,
Yang
L.
,
Yin
X.
,
Xu
B.
,
Zhao
D.
.
2013
.
Expression pattern of interferon-inducible transcriptional genes in neutrophils during bovine tuberculosis infection.
DNA Cell Biol.
32
:
480
486
.
76
Berry
M. P.
,
Graham
C. M.
,
McNab
F. W.
,
Xu
Z.
,
Bloch
S. A.
,
Oni
T.
,
Wilkinson
K. A.
,
Banchereau
R.
,
Skinner
J.
,
Wilkinson
R. J.
, et al
.
2010
.
An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.
Nature
466
:
973
977
.
77
Koh
G. C.
,
Schreiber
M. F.
,
Bautista
R.
,
Maude
R. R.
,
Dunachie
S.
,
Limmathurotsakul
D.
,
Day
N. P.
,
Dougan
G.
,
Peacock
S. J.
.
2013
.
Host responses to melioidosis and tuberculosis are both dominated by interferon-mediated signaling.
PLoS ONE
8
:
e54961
.
78
Maertzdorf
J.
,
Weiner
J.
 III
,
Mollenkopf
H. J.
,
Bauer
T.
,
Prasse
A.
,
Müller-Quernheim
J.
,
Kaufmann
S. H.
,
Kaufmann
S. H.
TBornotTB Network
.
2012
.
Common patterns and disease-related signatures in tuberculosis and sarcoidosis.
Proc. Natl. Acad. Sci. USA
109
:
7853
7858
.
79
Ordway
D.
,
Henao-Tamayo
M.
,
Harton
M.
,
Palanisamy
G.
,
Troudt
J.
,
Shanley
C.
,
Basaraba
R. J.
,
Orme
I. M.
.
2007
.
The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation.
J. Immunol.
179
:
522
531
.
80
Manca
C.
,
Tsenova
L.
,
Bergtold
A.
,
Freeman
S.
,
Tovey
M.
,
Musser
J. M.
,
Barry
C. E.
 III
,
Freedman
V. H.
,
Kaplan
G.
.
2001
.
Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha /beta.
Proc. Natl. Acad. Sci. USA
98
:
5752
5757
.
81
Manca
C.
,
Tsenova
L.
,
Freeman
S.
,
Barczak
A. K.
,
Tovey
M.
,
Murray
P. J.
,
Barry
C.
,
Kaplan
G.
.
2005
.
Hypervirulent M. tuberculosis W/Beijing strains upregulate type I IFNs and increase expression of negative regulators of the Jak-Stat pathway.
J. Interferon Cytokine Res.
25
:
694
701
.
82
Antonelli
L. R.
,
Gigliotti Rothfuchs
A.
,
Gonçalves
R.
,
Roffê
E.
,
Cheever
A. W.
,
Bafica
A.
,
Salazar
A. M.
,
Feng
C. G.
,
Sher
A.
.
2010
.
Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population.
J. Clin. Invest.
120
:
1674
1682
.
83
Mayer-Barber
K. D.
,
Andrade
B. B.
,
Barber
D. L.
,
Hieny
S.
,
Feng
C. G.
,
Caspar
P.
,
Oland
S.
,
Gordon
S.
,
Sher
A.
.
2011
.
Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection.
Immunity
35
:
1023
1034
.
84
Redford
P. S.
,
Murray
P. J.
,
O’Garra
A.
.
2011
.
The role of IL-10 in immune regulation during M. tuberculosis infection.
Mucosal Immunol.
4
:
261
270
.
85
Redford
P. S.
,
Boonstra
A.
,
Read
S.
,
Pitt
J.
,
Graham
C.
,
Stavropoulos
E.
,
Bancroft
G. J.
,
O’Garra
A.
.
2010
.
Enhanced protection to Mycobacterium tuberculosis infection in IL-10-deficient mice is accompanied by early and enhanced Th1 responses in the lung.
Eur. J. Immunol.
40
:
2200
2210
.
86
McNab
F. W.
,
Ewbank
J.
,
Howes
A.
,
Moreira-Teixeira
L.
,
Martirosyan
A.
,
Ghilardi
N.
,
Saraiva
M.
,
O’Garra
A.
.
2014
.
Type I IFN induces IL-10 production in an IL-27-independent manner and blocks responsiveness to IFN-γ for production of IL-12 and bacterial killing in Mycobacterium tuberculosis-infected macrophages.
J. Immunol.
193
:
3600
3612
.
87
Beamer
G. L.
,
Flaherty
D. K.
,
Assogba
B. D.
,
Stromberg
P.
,
Gonzalez-Juarrero
M.
,
de Waal Malefyt
R.
,
Vesosky
B.
,
Turner
J.
.
2008
.
Interleukin-10 promotes Mycobacterium tuberculosis disease progression in CBA/J mice.
J. Immunol.
181
:
5545
5550
.
88
Mayer-Barber
K. D.
,
Andrade
B. B.
,
Oland
S. D.
,
Amaral
E. P.
,
Barber
D. L.
,
Gonzales
J.
,
Derrick
S. C.
,
Shi
R.
,
Kumar
N. P.
,
Wei
W.
, et al
.
2014
.
Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk.
Nature
511
:
99
103
.
89
Kearney
S. J.
,
Delgado
C.
,
Eshleman
E. M.
,
Hill
K. K.
,
O’Connor
B. P.
,
Lenz
L. L.
.
2013
.
Type I IFNs downregulate myeloid cell IFN-γ receptor by inducing recruitment of an early growth response 3/NGFI-A binding protein 1 complex that silences ifngr1 transcription.
J. Immunol.
191
:
3384
3392
.
90
Desvignes
L.
,
Wolf
A. J.
,
Ernst
J. D.
.
2012
.
Dynamic roles of type I and type II IFNs in early infection with Mycobacterium tuberculosis.
J. Immunol.
188
:
6205
6215
.
91
Carow
B.
,
Ye
Xq.
,
Gavier-Widén
D.
,
Bhuju
S.
,
Oehlmann
W.
,
Singh
M.
,
Sköld
M.
,
Ignatowicz
L.
,
Yoshimura
A.
,
Wigzell
H.
,
Rottenberg
M. E.
.
2011
.
Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-gamma (IFN-gamma)-dependent manner.
J. Biol. Chem.
286
:
26873
26887
.
92
Almeida
A. S.
,
Lago
P. M.
,
Boechat
N.
,
Huard
R. C.
,
Lazzarini
L. C.
,
Santos
A. R.
,
Nociari
M.
,
Zhu
H.
,
Perez-Sweeney
B. M.
,
Bang
H.
, et al
.
2009
.
Tuberculosis is associated with a down-modulatory lung immune response that impairs Th1-type immunity.
J. Immunol.
183
:
718
731
.
93
Masood
K. I.
,
Rottenberg
M. E.
,
Salahuddin
N.
,
Irfan
M.
,
Rao
N.
,
Carow
B.
,
Islam
M.
,
Hussain
R.
,
Hasan
Z.
.
2013
.
Expression of M. tuberculosis-induced suppressor of cytokine signaling (SOCS) 1, SOCS3, FoxP3 and secretion of IL-6 associates with differing clinical severity of tuberculosis.
BMC Infect. Dis.
13
:
13
.
94
Teles
R. M.
,
Graeber
T. G.
,
Krutzik
S. R.
,
Montoya
D.
,
Schenk
M.
,
Lee
D. J.
,
Komisopoulou
E.
,
Kelly-Scumpia
K.
,
Chun
R.
,
Iyer
S. S.
, et al
.
2013
.
Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses.
Science
339
:
1448
1453
.
95
Pechous
R. D.
,
McCarthy
T. R.
,
Zahrt
T. C.
.
2009
.
Working toward the future: insights into Francisella tularensis pathogenesis and vaccine development.
Microbiol. Mol. Biol. Rev.
73
:
684
711
.
96
Dennis
D. T.
,
Inglesby
T. V.
,
Henderson
D. A.
,
Bartlett
J. G.
,
Ascher
M. S.
,
Eitzen
E.
,
Fine
A. D.
,
Friedlander
A. M.
,
Hauer
J.
,
Layton
M.
, et al
Working Group on Civilian Biodefense
.
2001
.
Tularemia as a biological weapon: medical and public health management.
JAMA
285
:
2763
2773
.
97
Elkins
K. L.
,
Cowley
S. C.
,
Bosio
C. M.
.
2003
.
Innate and adaptive immune responses to an intracellular bacterium, Francisella tularensis live vaccine strain.
Microbes Infect.
5
:
135
142
.
98
Sjöstedt
A.
2006
.
Intracellular survival mechanisms of Francisella tularensis, a stealth pathogen.
Microbes Infect.
8
:
561
567
.
99
Checroun
C.
,
Wehrly
T. D.
,
Fischer
E. R.
,
Hayes
S. F.
,
Celli
J.
.
2006
.
Autophagy-mediated reentry of Francisella tularensis into the endocytic compartment after cytoplasmic replication.
Proc. Natl. Acad. Sci. USA
103
:
14578
14583
.
100
Clemens
D. L.
,
Lee
B. Y.
,
Horwitz
M. A.
.
2004
.
Virulent and avirulent strains of Francisella tularensis prevent acidification and maturation of their phagosomes and escape into the cytoplasm in human macrophages.
Infect. Immun.
72
:
3204
3217
.
101
Golovliov
I.
,
Baranov
V.
,
Krocova
Z.
,
Kovarova
H.
,
Sjöstedt
A.
.
2003
.
An attenuated strain of the facultative intracellular bacterium Francisella tularensis can escape the phagosome of monocytic cells.
Infect. Immun.
71
:
5940
5950
.
102
Henry
T.
,
Brotcke
A.
,
Weiss
D. S.
,
Thompson
L. J.
,
Monack
D. M.
.
2007
.
Type I interferon signaling is required for activation of the inflammasome during Francisella infection.
J. Exp. Med.
204
:
987
994
.
103
Fernandes-Alnemri
T.
,
Yu
J. W.
,
Juliana
C.
,
Solorzano
L.
,
Kang
S.
,
Wu
J.
,
Datta
P.
,
McCormick
M.
,
Huang
L.
,
McDermott
E.
, et al
.
2010
.
The AIM2 inflammasome is critical for innate immunity to Francisella tularensis.
Nat. Immunol.
11
:
385
393
.
104
Jones
J. W.
,
Kayagaki
N.
,
Broz
P.
,
Henry
T.
,
Newton
K.
,
O’Rourke
K.
,
Chan
S.
,
Dong
J.
,
Qu
Y.
,
Roose-Girma
M.
, et al
.
2010
.
Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis.
Proc. Natl. Acad. Sci. USA
107
:
9771
9776
.
105
Broz
P.
,
Monack
D. M.
.
2013
.
Newly described pattern recognition receptors team up against intracellular pathogens.
Nat. Rev. Immunol.
13
:
551
565
.
106
Gavrilin
M. A.
,
Bouakl
I. J.
,
Knatz
N. L.
,
Duncan
M. D.
,
Hall
M. W.
,
Gunn
J. S.
,
Wewers
M. D.
.
2006
.
Internalization and phagosome escape required for Francisella to induce human monocyte IL-1beta processing and release.
Proc. Natl. Acad. Sci. USA
103
:
141
146
.
107
Mariathasan
S.
,
Weiss
D. S.
,
Dixit
V. M.
,
Monack
D. M.
.
2005
.
Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis.
J. Exp. Med.
202
:
1043
1049
.
108
Henry
T.
,
Kirimanjeswara
G. S.
,
Ruby
T.
,
Jones
J. W.
,
Peng
K.
,
Perret
M.
,
Ho
L.
,
Sauer
J. D.
,
Iwakura
Y.
,
Metzger
D. W.
,
Monack
D. M.
.
2010
.
Type I IFN signaling constrains IL-17A/F secretion by gammadelta T cells during bacterial infections.
J. Immunol.
184
:
3755
3767
.
109
Furuya
Y.
,
Steiner
D.
,
Metzger
D. W.
.
2014
.
Does Type I Interferon Limit Protective Neutrophil Responses during Pulmonary Francisella tularensis Infection?
Front. Immunol.
5
:
355
.
110
Metzger
D. W.
,
Bakshi
C. S.
,
Kirimanjeswara
G.
.
2007
.
Mucosal immunopathogenesis of Francisella tularensis.
Ann. N. Y. Acad. Sci.
1105
:
266
283
.
111
de Jong
H. K.
,
Parry
C. M.
,
van der Poll
T.
,
Wiersinga
W. J.
.
2012
.
Host-pathogen interaction in invasive Salmonellosis.
PLoS Pathog.
8
:
e1002933
.
112
Yamamoto
M.
,
Sato
S.
,
Hemmi
H.
,
Hoshino
K.
,
Kaisho
T.
,
Sanjo
H.
,
Takeuchi
O.
,
Sugiyama
M.
,
Okabe
M.
,
Takeda
K.
,
Akira
S.
.
2003
.
Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.
Science
301
:
640
643
.
113
Schmolke
M.
,
Patel
J. R.
,
de Castro
E.
,
Sánchez-Aparicio
M. T.
,
Uccellini
M. B.
,
Miller
J. C.
,
Manicassamy
B.
,
Satoh
T.
,
Kawai
T.
,
Akira
S.
, et al
.
2014
.
RIG-I detects mRNA of intracellular Salmonella enterica serovar Typhimurium during bacterial infection.
MBio
5
:
e01006
e01014
.
114
Robinson
N.
,
McComb
S.
,
Mulligan
R.
,
Dudani
R.
,
Krishnan
L.
,
Sad
S.
.
2012
.
Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium.
Nat. Immunol.
13
:
954
962
.
115
McComb
S.
,
Cessford
E.
,
Alturki
N. A.
,
Joseph
J.
,
Shutinoski
B.
,
Startek
J. B.
,
Gamero
A. M.
,
Mossman
K. L.
,
Sad
S.
.
2014
.
Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages.
Proc. Natl. Acad. Sci. USA
111
:
E3206
E3213
.
116
Rottenberg
M. E.
,
Gigliotti-Rothfuchs
A.
,
Wigzell
H.
.
2002
.
The role of IFN-gamma in the outcome of chlamydial infection.
Curr. Opin. Immunol.
14
:
444
451
.
117
Derbigny
W. A.
,
Johnson
R. M.
,
Toomey
K. S.
,
Ofner
S.
,
Jayarapu
K.
.
2010
.
The Chlamydia muridarum-induced IFN-β response is TLR3-dependent in murine oviduct epithelial cells.
J. Immunol.
185
:
6689
6697
.
118
Derbigny
W. A.
,
Hong
S. C.
,
Kerr
M. S.
,
Temkit
M.
,
Johnson
R. M.
.
2007
.
Chlamydia muridarum infection elicits a beta interferon response in murine oviduct epithelial cells dependent on interferon regulatory factor 3 and TRIF.
Infect. Immun.
75
:
1280
1290
.
119
Prantner
D.
,
Darville
T.
,
Nagarajan
U. M.
.
2010
.
Stimulator of IFN gene is critical for induction of IFN-beta during Chlamydia muridarum infection.
J. Immunol.
184
:
2551
2560
.
120
Zhang
Y.
,
Yeruva
L.
,
Marinov
A.
,
Prantner
D.
,
Wyrick
P. B.
,
Lupashin
V.
,
Nagarajan
U. M.
.
2014
.
The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-β during Chlamydia trachomatis infection.
J. Immunol.
193
:
2394
2404
.
121
Barker
J. R.
,
Koestler
B. J.
,
Carpenter
V. K.
,
Burdette
D. L.
,
Waters
C. M.
,
Vance
R. E.
,
Valdivia
R. H.
.
2013
.
STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection.
MBio
4
:
00018
13
.
122
Nagarajan
U. M.
,
Prantner
D.
,
Sikes
J. D.
,
Andrews
C. W.
 Jr.
,
Goodwin
A. M.
,
Nagarajan
S.
,
Darville
T.
.
2008
.
Type I interferon signaling exacerbates Chlamydia muridarum genital infection in a murine model.
Infect. Immun.
76
:
4642
4648
.
123
Qiu
H.
,
Fan
Y.
,
Joyee
A. G.
,
Wang
S.
,
Han
X.
,
Bai
H.
,
Jiao
L.
,
Van Rooijen
N.
,
Yang
X.
.
2008
.
Type I IFNs enhance susceptibility to Chlamydia muridarum lung infection by enhancing apoptosis of local macrophages.
J. Immunol.
181
:
2092
2102
.
124
Fung
K. Y.
,
Mangan
N. E.
,
Cumming
H.
,
Horvat
J. C.
,
Mayall
J. R.
,
Stifter
S. A.
,
De Weerd
N.
,
Roisman
L. C.
,
Rossjohn
J.
,
Robertson
S. A.
, et al
.
2013
.
Interferon-ε protects the female reproductive tract from viral and bacterial infection.
Science
339
:
1088
1092
.
125
Klevens
R. M.
,
Morrison
M. A.
,
Nadle
J.
,
Petit
S.
,
Gershman
K.
,
Ray
S.
,
Harrison
L. H.
,
Lynfield
R.
,
Dumyati
G.
,
Townes
J. M.
, et al
Active Bacterial Core surveillance (ABCs) MRSA Investigators
.
2007
.
Invasive methicillin-resistant Staphylococcus aureus infections in the United States.
JAMA
298
:
1763
1771
.
126
Fournier
B.
,
Philpott
D. J.
.
2005
.
Recognition of Staphylococcus aureus by the innate immune system.
Clin. Microbiol. Rev.
18
:
521
540
.
127
Rigby
K. M.
,
DeLeo
F. R.
.
2012
.
Neutrophils in innate host defense against Staphylococcus aureus infections.
Semin. Immunopathol.
34
:
237
259
.
128
Martin
F. J.
,
Gomez
M. I.
,
Wetzel
D. M.
,
Memmi
G.
,
O’Seaghdha
M.
,
Soong
G.
,
Schindler
C.
,
Prince
A.
.
2009
.
Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A.
J. Clin. Invest.
119
:
1931
1939
.
129
Parker
D.
,
Prince
A.
.
2012
.
Staphylococcus aureus induces type I IFN signaling in dendritic cells via TLR9.
J. Immunol.
189
:
4040
4046
.
130
Parker
D.
,
Planet
P. J.
,
Soong
G.
,
Narechania
A.
,
Prince
A.
.
2014
.
Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.
PLoS Pathog.
10
:
e1003951
.
131
Sudbery
P. E.
2011
.
Growth of Candida albicans hyphae.
Nat. Rev. Microbiol.
9
:
737
748
.
132
Lionakis
M. S.
,
Netea
M. G.
.
2013
.
Candida and host determinants of susceptibility to invasive candidiasis.
PLoS Pathog.
9
:
e1003079
.
133
Bourgeois
C.
,
Majer
O.
,
Frohner
I. E.
,
Lesiak-Markowicz
I.
,
Hildering
K. S.
,
Glaser
W.
,
Stockinger
S.
,
Decker
T.
,
Akira
S.
,
Müller
M.
,
Kuchler
K.
.
2011
.
Conventional dendritic cells mount a type I IFN response against Candida spp. requiring novel phagosomal TLR7-mediated IFN-β signaling.
J. Immunol.
186
:
3104
3112
.
134
Jensen
J.
,
Vazquez-Torres
A.
,
Balish
E.
.
1992
.
Poly(I.C)-induced interferons enhance susceptibility of SCID mice to systemic candidiasis.
Infect. Immun.
60
:
4549
4557
.
135
Majer
O.
,
Bourgeois
C.
,
Zwolanek
F.
,
Lassnig
C.
,
Kerjaschki
D.
,
Mack
M.
,
Müller
M.
,
Kuchler
K.
.
2012
.
Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
PLoS Pathog.
8
:
e1002811
.
136
Worthington
M.
,
Hasenclever
H. F.
.
1972
.
Effect of an interferon stimulator, polyinosinic: polycytidylic acid, on experimental fungus infections.
Infect. Immun.
5
:
199
202
.
137
Guarda
G.
,
Braun
M.
,
Staehli
F.
,
Tardivel
A.
,
Mattmann
C.
,
Förster
I.
,
Farlik
M.
,
Decker
T.
,
Du Pasquier
R. A.
,
Romero
P.
,
Tschopp
J.
.
2011
.
Type I interferon inhibits interleukin-1 production and inflammasome activation.
Immunity
34
:
213
223
.
138
Brener
Z.
,
Gazzinelli
R. T.
.
1997
.
Immunological control of Trypanosoma cruzi infection and pathogenesis of Chagas’ disease.
Int. Arch. Allergy Immunol.
114
:
103
110
.
139
Tálas
M.
,
Gláz
E. T.
.
1979
.
Type I interferon induced in mice by infection with Trypanosoma equiperdum.
J. Infect. Dis.
139
:
595
598
.
140
Vaena de Avalos
S.
,
Blader
I. J.
,
Fisher
M.
,
Boothroyd
J. C.
,
Burleigh
B. A.
.
2002
.
Immediate/early response to Trypanosoma cruzi infection involves minimal modulation of host cell transcription.
J. Biol. Chem.
277
:
639
644
.
141
Koga
R.
,
Hamano
S.
,
Kuwata
H.
,
Atarashi
K.
,
Ogawa
M.
,
Hisaeda
H.
,
Yamamoto
M.
,
Akira
S.
,
Himeno
K.
,
Matsumoto
M.
,
Takeda
K.
.
2006
.
TLR-dependent induction of IFN-beta mediates host defense against Trypanosoma cruzi.
J. Immunol.
177
:
7059
7066
.
142
Chessler
A. D.
,
Unnikrishnan
M.
,
Bei
A. K.
,
Daily
J. P.
,
Burleigh
B. A.
.
2009
.
Trypanosoma cruzi triggers an early type I IFN response in vivo at the site of intradermal infection.
J. Immunol.
182
:
2288
2296
.
143
Chessler
A. D.
,
Caradonna
K. L.
,
Da’dara
A.
,
Burleigh
B. A.
.
2011
.
Type I interferons increase host susceptibility to Trypanosoma cruzi infection.
Infect. Immun.
79
:
2112
2119
.
144
Lopez
R.
,
Demick
K. P.
,
Mansfield
J. M.
,
Paulnock
D. M.
.
2008
.
Type I IFNs play a role in early resistance, but subsequent susceptibility, to the African trypanosomes.
J. Immunol.
181
:
4908
4917
.
145
Kaye
P.
,
Scott
P.
.
2011
.
Leishmaniasis: complexity at the host-pathogen interface.
Nat. Rev. Microbiol.
9
:
604
615
.
146
Sacks
D.
,
Noben-Trauth
N.
.
2002
.
The immunology of susceptibility and resistance to Leishmania major in mice.
Nat. Rev. Immunol.
2
:
845
858
.
147
Diefenbach
A.
,
Schindler
H.
,
Donhauser
N.
,
Lorenz
E.
,
Laskay
T.
,
MacMicking
J.
,
Röllinghoff
M.
,
Gresser
I.
,
Bogdan
C.
.
1998
.
Type 1 interferon (IFNalpha/beta) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite.
Immunity
8
:
77
87
.
148
Mattner
J.
,
Wandersee-Steinhäuser
A.
,
Pahl
A.
,
Röllinghoff
M.
,
Majeau
G. R.
,
Hochman
P. S.
,
Bogdan
C.
.
2004
.
Protection against progressive leishmaniasis by IFN-beta.
J. Immunol.
172
:
7574
7582
.
149
Favila
M. A.
,
Geraci
N. S.
,
Zeng
E.
,
Harker
B.
,
Condon
D.
,
Cotton
R. N.
,
Jayakumar
A.
,
Tripathi
V.
,
McDowell
M. A.
.
2014
.
Human dendritic cells exhibit a pronounced type I IFN signature following Leishmania major infection that is required for IL-12 induction.
J. Immunol.
192
:
5863
5872
.
150
Khouri
R.
,
Bafica
A.
,
Silva
Mda. P.
,
Noronha
A.
,
Kolb
J. P.
,
Wietzerbin
J.
,
Barral
A.
,
Barral-Netto
M.
,
Van Weyenbergh
J.
.
2009
.
IFN-beta impairs superoxide-dependent parasite killing in human macrophages: evidence for a deleterious role of SOD1 in cutaneous leishmaniasis.
J. Immunol.
182
:
2525
2531
.
151
Pereira
R. M.
,
Teixeira
K. L.
,
Barreto-de-Souza
V.
,
Calegari-Silva
T. C.
,
De-Melo
L. D.
,
Soares
D. C.
,
Bou-Habib
D. C.
,
Silva
A. M.
,
Saraiva
E. M.
,
Lopes
U. G.
.
2010
.
Novel role for the double-stranded RNA-activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite Leishmania.
FASEB J.
24
:
617
626
.
152
Xin
L.
,
Vargas-Inchaustegui
D. A.
,
Raimer
S. S.
,
Kelly
B. C.
,
Hu
J.
,
Zhu
L.
,
Sun
J.
,
Soong
L.
.
2010
.
Type I IFN receptor regulates neutrophil functions and innate immunity to Leishmania parasites.
J. Immunol.
184
:
7047
7056
.
153
Guilbride
L.
,
Myler
P. J.
,
Stuart
K.
.
1992
.
Distribution and sequence divergence of LRV1 viruses among different Leishmania species.
Mol. Biochem. Parasitol.
54
:
101
104
.
154
Salinas
G.
,
Zamora
M.
,
Stuart
K.
,
Saravia
N.
.
1996
.
Leishmania RNA viruses in Leishmania of the Viannia subgenus.
Am. J. Trop. Med. Hyg.
54
:
425
429
.
155
Widmer
G.
,
Dooley
S.
.
1995
.
Phylogenetic analysis of Leishmania RNA virus and Leishmania suggests ancient virus-parasite association.
Nucleic Acids Res.
23
:
2300
2304
.
156
Ives
A.
,
Ronet
C.
,
Prevel
F.
,
Ruzzante
G.
,
Fuertes-Marraco
S.
,
Schutz
F.
,
Zangger
H.
,
Revaz-Breton
M.
,
Lye
L. F.
,
Hickerson
S. M.
, et al
.
2011
.
Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis.
Science
331
:
775
778
.
157
Scheffter
S. M.
,
Ro
Y. T.
,
Chung
I. K.
,
Patterson
J. L.
.
1995
.
The complete sequence of Leishmania RNA virus LRV2-1, a virus of an Old World parasite strain.
Virology
212
:
84
90
.
158
Stevenson
M. M.
,
Riley
E. M.
.
2004
.
Innate immunity to malaria.
Nat. Rev. Immunol.
4
:
169
180
.
159
Stanisic
D. I.
,
Barry
A. E.
,
Good
M. F.
.
2013
.
Escaping the immune system: How the malaria parasite makes vaccine development a challenge.
Trends Parasitol.
29
:
612
622
.
160
Pichyangkul
S.
,
Yongvanitchit
K.
,
Kum-arb
U.
,
Hemmi
H.
,
Akira
S.
,
Krieg
A. M.
,
Heppner
D. G.
,
Stewart
V. A.
,
Hasegawa
H.
,
Looareesuwan
S.
, et al
.
2004
.
Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway.
J. Immunol.
172
:
4926
4933
.
161
Baccarella
A.
,
Fontana
M. F.
,
Chen
E. C.
,
Kim
C. C.
.
2013
.
Toll-like receptor 7 mediates early innate immune responses to malaria.
Infect. Immun.
81
:
4431
4442
.
162
Sharma
S.
,
DeOliveira
R. B.
,
Kalantari
P.
,
Parroche
P.
,
Goutagny
N.
,
Jiang
Z.
,
Chan
J.
,
Bartholomeu
D. C.
,
Lauw
F.
,
Hall
J. P.
, et al
.
2011
.
Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome.
Immunity
35
:
194
207
.
163
Liehl
P.
,
Zuzarte-Luís
V.
,
Chan
J.
,
Zillinger
T.
,
Baptista
F.
,
Carapau
D.
,
Konert
M.
,
Hanson
K. K.
,
Carret
C.
,
Lassnig
C.
, et al
.
2014
.
Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.
Nat. Med.
20
:
47
53
.
164
Vigário
A. M.
,
Belnoue
E.
,
Cumano
A.
,
Marussig
M.
,
Miltgen
F.
,
Landau
I.
,
Mazier
D.
,
Gresser
I.
,
Rénia
L.
.
2001
.
Inhibition of Plasmodium yoelii blood-stage malaria by interferon alpha through the inhibition of the production of its target cell, the reticulocyte.
Blood
97
:
3966
3971
.
165
Miller
J. L.
,
Sack
B. K.
,
Baldwin
M.
,
Vaughan
A. M.
,
Kappe
S. H.
.
2014
.
Interferon-mediated innate immune responses against malaria parasite liver stages.
Cell Reports
7
:
436
447
.
166
Palomo
J.
,
Fauconnier
M.
,
Coquard
L.
,
Gilles
M.
,
Meme
S.
,
Szeremeta
F.
,
Fick
L.
,
Franetich
J. F.
,
Jacobs
M.
,
Togbe
D.
, et al
.
2013
.
Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stage Plasmodium berghei ANKA.
Eur. J. Immunol.
43
:
2683
2695
.
167
Haque
A.
,
Best
S. E.
,
Ammerdorffer
A.
,
Desbarrieres
L.
,
de Oca
M. M.
,
Amante
F. H.
,
de Labastida Rivera
F.
,
Hertzog
P.
,
Boyle
G. M.
,
Hill
G. R.
,
Engwerda
C. R.
.
2011
.
Type I interferons suppress CD4+ T-cell-dependent parasite control during blood-stage Plasmodium infection.
Eur. J. Immunol.
41
:
2688
2698
.
168
Haque
A.
,
Best
S. E.
,
Montes de Oca
M.
,
James
K. R.
,
Ammerdorffer
A.
,
Edwards
C. L.
,
de Labastida Rivera
F.
,
Amante
F. H.
,
Bunn
P. T.
,
Sheel
M.
, et al
.
2014
.
Type I IFN signaling in CD8− DCs impairs Th1-dependent malaria immunity.
J. Clin. Invest.
124
:
2483
2496
.
169
Centers for Disease Control and Prevention. LCMV Fact Sheet. Available at: http://www.cdc.gov/vhf/lcm/pdf/LCM-FactSheet.pdf. Accessed: October 20, 2014
.
170
Zhou
X.
,
Ramachandran
S.
,
Mann
M.
,
Popkin
D. L.
.
2012
.
Role of lymphocytic choriomeningitis virus (LCMV) in understanding viral immunology: past, present and future.
Viruses
4
:
2650
2669
.
171
Ahmed
R.
,
Salmi
A.
,
Butler
L. D.
,
Chiller
J. M.
,
Oldstone
M. B.
.
1984
.
Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence.
J. Exp. Med.
160
:
521
540
.
172
Ahmed
R.
,
Simon
R. S.
,
Matloubian
M.
,
Kolhekar
S. R.
,
Southern
P. J.
,
Freedman
D. M.
.
1988
.
Genetic analysis of in vivo-selected viral variants causing chronic infection: importance of mutation in the L RNA segment of lymphocytic choriomeningitis virus.
J. Virol.
62
:
3301
3308
.
173
Tishon
A.
,
Lewicki
H.
,
Rall
G.
,
Von Herrath
M.
,
Oldstone
M. B.
.
1995
.
An essential role for type 1 interferon-gamma in terminating persistent viral infection.
Virology
212
:
244
250
.
174
Leist
T. P.
,
Eppler
M.
,
Zinkernagel
R. M.
.
1989
.
Enhanced virus replication and inhibition of lymphocytic choriomeningitis virus disease in anti-gamma interferon-treated mice.
J. Virol.
63
:
2813
2819
.
175
Huang
S.
,
Hendriks
W.
,
Althage
A.
,
Hemmi
S.
,
Bluethmann
H.
,
Kamijo
R.
,
Vilcek
J.
,
Zinkernagel
R. M.
,
Aguet
M.
.
1993
.
Immune response in mice that lack the interferon-gamma receptor.
Science
259
:
1742
1745
.
176
Teijaro
J. R.
,
Ng
C.
,
Lee
A. M.
,
Sullivan
B. M.
,
Sheehan
K. C.
,
Welch
M.
,
Schreiber
R. D.
,
de la Torre
J. C.
,
Oldstone
M. B.
.
2013
.
Persistent LCMV infection is controlled by blockade of type I interferon signaling.
Science
340
:
207
211
.
177
Wilson
E. B.
,
Yamada
D. H.
,
Elsaesser
H.
,
Herskovitz
J.
,
Deng
J.
,
Cheng
G.
,
Aronow
B. J.
,
Karp
C. L.
,
Brooks
D. G.
.
2013
.
Blockade of chronic type I interferon signaling to control persistent LCMV infection.
Science
340
:
202
207
.
178
Aichele
P.
,
Unsoeld
H.
,
Koschella
M.
,
Schweier
O.
,
Kalinke
U.
,
Vucikuja
S.
.
2006
.
CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion.
J. Immunol.
176
:
4525
4529
.
179
Kolumam
G. A.
,
Thomas
S.
,
Thompson
L. J.
,
Sprent
J.
,
Murali-Krishna
K.
.
2005
.
Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection.
J. Exp. Med.
202
:
637
650
.
180
Thompson
L. J.
,
Kolumam
G. A.
,
Thomas
S.
,
Murali-Krishna
K.
.
2006
.
Innate inflammatory signals induced by various pathogens differentially dictate the IFN-I dependence of CD8 T cells for clonal expansion and memory formation.
J. Immunol.
177
:
1746
1754
.
181
Wherry
E. J.
2011
.
T cell exhaustion.
Nat. Immunol.
12
:
492
499
.
182
Crawford
A.
,
Angelosanto
J. M.
,
Kao
C.
,
Doering
T. A.
,
Odorizzi
P. M.
,
Barnett
B. E.
,
Wherry
E. J.
.
2014
.
Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection.
Immunity
40
:
289
302
.
183
Brooks
D. G.
,
Trifilo
M. J.
,
Edelmann
K. H.
,
Teyton
L.
,
McGavern
D. B.
,
Oldstone
M. B.
.
2006
.
Interleukin-10 determines viral clearance or persistence in vivo.
Nat. Med.
12
:
1301
1309
.
184
Brooks
D. G.
,
Ha
S. J.
,
Elsaesser
H.
,
Sharpe
A. H.
,
Freeman
G. J.
,
Oldstone
M. B.
.
2008
.
IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection.
Proc. Natl. Acad. Sci. USA
105
:
20428
20433
.
185
Baccala
R.
,
Welch
M. J.
,
Gonzalez-Quintial
R.
,
Walsh
K. B.
,
Teijaro
J. R.
,
Nguyen
A.
,
Ng
C. T.
,
Sullivan
B. M.
,
Zarpellon
A.
,
Ruggeri
Z. M.
, et al
.
2014
.
Type I interferon is a therapeutic target for virus-induced lethal vascular damage.
Proc. Natl. Acad. Sci. USA
111
:
8925
8930
.
186
Simon
V.
,
Ho
D. D.
,
Abdool Karim
Q.
.
2006
.
HIV/AIDS epidemiology, pathogenesis, prevention, and treatment.
Lancet
368
:
489
504
.
187
Colonna
M.
,
Trinchieri
G.
,
Liu
Y. J.
.
2004
.
Plasmacytoid dendritic cells in immunity.
Nat. Immunol.
5
:
1219
1226
.
188
Hosmalin
A.
,
Lebon
P.
.
2006
.
Type I interferon production in HIV-infected patients.
J. Leukoc. Biol.
80
:
984
993
.
189
Herbeuval
J. P.
,
Shearer
G. M.
.
2007
.
HIV-1 immunopathogenesis: how good interferon turns bad.
Clin. Immunol.
123
:
121
128
.
190
Lehmann
C.
,
Harper
J. M.
,
Taubert
D.
,
Hartmann
P.
,
Fätkenheuer
G.
,
Jung
N.
,
van Lunzen
J.
,
Stellbrink
H. J.
,
Gallo
R. C.
,
Romerio
F.
.
2008
.
Increased interferon alpha expression in circulating plasmacytoid dendritic cells of HIV-1-infected patients.
J. Acquir. Immune Defic. Syndr.
48
:
522
530
.
191
Gringeri
A.
,
Musicco
M.
,
Hermans
P.
,
Bentwich
Z.
,
Cusini
M.
,
Bergamasco
A.
,
Santagostino
E.
,
Burny
A.
,
Bizzini
B.
,
Zagury
D.
.
1999
.
Active anti-interferon-alpha immunization: a European-Israeli, randomized, double-blind, placebo-controlled clinical trial in 242 HIV-1–infected patients (the EURIS study).
J. Acquir. Immune Defic. Syndr. Hum. Retrovirol.
20
:
358
370
.
192
Zagury
D.
,
Lachgar
A.
,
Chams
V.
,
Fall
L. S.
,
Bernard
J.
,
Zagury
J. F.
,
Bizzini
B.
,
Gringeri
A.
,
Santagostino
E.
,
Rappaport
J.
, et al
.
1998
.
Interferon alpha and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS.
Proc. Natl. Acad. Sci. USA
95
:
3851
3856
.
193
Herbeuval
J. P.
,
Grivel
J. C.
,
Boasso
A.
,
Hardy
A. W.
,
Chougnet
C.
,
Dolan
M. J.
,
Yagita
H.
,
Lifson
J. D.
,
Shearer
G. M.
.
2005
.
CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis.
Blood
106
:
3524
3531
.
194
Herbeuval
J. P.
,
Nilsson
J.
,
Boasso
A.
,
Hardy
A. W.
,
Kruhlak
M. J.
,
Anderson
S. A.
,
Dolan
M. J.
,
Dy
M.
,
Andersson
J.
,
Shearer
G. M.
.
2006
.
Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients.
Proc. Natl. Acad. Sci. USA
103
:
7000
7005
.
195
Fraietta
J. A.
,
Mueller
Y. M.
,
Yang
G.
,
Boesteanu
A. C.
,
Gracias
D. T.
,
Do
D. H.
,
Hope
J. L.
,
Kathuria
N.
,
McGettigan
S. E.
,
Lewis
M. G.
, et al
.
2013
.
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.
PLoS Pathog.
9
:
e1003658
.
196
Sandler
N. G.
,
Bosinger
S. E.
,
Estes
J. D.
,
Zhu
R. T.
,
Tharp
G. K.
,
Boritz
E.
,
Levin
D.
,
Wijeyesinghe
S.
,
Makamdop
K. N.
,
del Prete
G. Q.
, et al
.
2014
.
Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.
Nature
511
:
601
605
.
197
Le Saout
C.
,
Hasley
R. B.
,
Imamichi
H.
,
Tcheung
L.
,
Hu
Z.
,
Luckey
M. A.
,
Park
J. H.
,
Durum
S. K.
,
Smith
M.
,
Rupert
A. W.
, et al
.
2014
.
Chronic exposure to type-I IFN under lymphopenic conditions alters CD4 T cell homeostasis.
PLoS Pathog.
10
:
e1003976
.
198
McCullers
J. A.
2014
.
The co-pathogenesis of influenza viruses with bacteria in the lung.
Nat. Rev. Microbiol.
12
:
252
262
.
199
Bordon
J.
,
Aliberti
S.
,
Fernandez-Botran
R.
,
Uriarte
S. M.
,
Rane
M. J.
,
Duvvuri
P.
,
Peyrani
P.
,
Morlacchi
L. C.
,
Blasi
F.
,
Ramirez
J. A.
.
2013
.
Understanding the roles of cytokines and neutrophil activity and neutrophil apoptosis in the protective versus deleterious inflammatory response in pneumonia.
Int. J. Infect. Dis.
17
:
e76
e83
.
200
Dockrell
D. H.
,
Marriott
H. M.
,
Prince
L. R.
,
Ridger
V. C.
,
Ince
P. G.
,
Hellewell
P. G.
,
Whyte
M. K.
.
2003
.
Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection.
J. Immunol.
171
:
5380
5388
.
201
Shahangian
A.
,
Chow
E. K.
,
Tian
X.
,
Kang
J. R.
,
Ghaffari
A.
,
Liu
S. Y.
,
Belperio
J. A.
,
Cheng
G.
,
Deng
J. C.
.
2009
.
Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice.
J. Clin. Invest.
119
:
1910
1920
.
202
Kudva
A.
,
Scheller
E. V.
,
Robinson
K. M.
,
Crowe
C. R.
,
Choi
S. M.
,
Slight
S. R.
,
Khader
S. A.
,
Dubin
P. J.
,
Enelow
R. I.
,
Kolls
J. K.
,
Alcorn
J. F.
.
2011
.
Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice.
J. Immunol.
186
:
1666
1674
.
203
Li
W.
,
Moltedo
B.
,
Moran
T. M.
.
2012
.
Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of γδ T cells.
J. Virol.
86
:
12304
12312
.
204
Laan
M.
,
Cui
Z. H.
,
Hoshino
H.
,
Lötvall
J.
,
Sjöstrand
M.
,
Gruenert
D. C.
,
Skoogh
B. E.
,
Lindén
A.
.
1999
.
Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways.
J. Immunol.
162
:
2347
2352
.
205
Nakamura
S.
,
Davis
K. M.
,
Weiser
J. N.
.
2011
.
Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice.
J. Clin. Invest.
121
:
3657
3665
.
206
Flórido
M.
,
Grima
M. A.
,
Gillis
C. M.
,
Xia
Y.
,
Turner
S. J.
,
Triccas
J. A.
,
Stambas
J.
,
Britton
W. J.
.
2013
.
Influenza A virus infection impairs mycobacteria-specific T cell responses and mycobacterial clearance in the lung during pulmonary coinfection.
J. Immunol.
191
:
302
311
.
207
Redford
P. S.
,
Mayer-Barber
K. D.
,
McNab
F. W.
,
Stavropoulos
E.
,
Wack
A.
,
Sher
A.
,
O'Garra
A.
.
2014
.
Influenza A virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon receptor-dependent pathway.
J. Infect. Dis.
209
:
270
274

The authors have no financial conflicts of interest.