Antimicrobial use in animal agriculture may be contributing to the emerging public health crisis of antimicrobial resistance. The sustained prevalence of infectious diseases driving antimicrobial use industry-wide suggests that traditional methods of bolstering disease resistance are, for some diseases, ineffective. A paradigm shift in our approach to infectious disease control is needed to reduce antimicrobial use and sustain animal and human health and the global economy. Targeting the defensive mechanisms that promote the health of an infected host without impacting pathogen fitness, termed “disease tolerance,” is a novel disease control approach ripe for discovery. This article presents examples of disease tolerance dictating clinical outcomes for several infectious diseases in humans, reveals evidence suggesting a similarly critical role of disease tolerance in the progression of infectious diseases plaguing animal agriculture, and thus substantiates the assertion that exploiting disease tolerance mechanisms can positively impact animal and human health.

Antimicrobial resistance is a growing public health crisis worldwide. In 2019, it was estimated that 1.27 million deaths globally were a direct result of antimicrobial-resistant infections (1)—a number projected to rise by 10 million lives per year by 2050 (2). The use of antimicrobials in the animal agriculture industry is heavily scrutinized as a potential driving force for the emergence of resistance in medically important human pathogens. As an area of intense investigation, some published work suggests that antimicrobial use practices in agricultural animals create a reservoir for resistant bacteria and genes, increasing the concern of contamination of animal products for human consumption with antimicrobial-resistant pathogens (3). Although the degree to which the spread of resistant elements from these animals to humans poses a human health risk is debatable, the industry is a major consumer of antimicrobials. In the United States alone, more than half of medically important antimicrobials sold in 2018 were intended for use in agricultural animals (4). Among some of the top sold antimicrobials were cephalosporins, macrolides, and tetracyclines, which are standard antimicrobial classes used to treat bacterial infections in human medicine (5, 6).

Medically important antimicrobials are used in animals reared for human consumption to treat, control, and prevent disease—a practice regulated by national and international policy. Over the years, new guidelines have been implemented to support the ongoing campaign of antimicrobial stewardship. For example, in the United States, recent legislation established the requirement of veterinary feed directives when medically important antimicrobials are used in agricultural animal feed, bringing the use of antimicrobials under the direct oversight of a licensed veterinarian. Even more recently, the European Union banned the routine use of antimicrobials in these animals and placed additional restrictions on their use to treat individual animals. The judicious use of antimicrobials in animal health is integral to controlling emerging antimicrobial resistance threats and maximizing the therapeutic efficacy of these medications for animal and human populations alike. However, eliminating antimicrobials in animal agriculture without a replacement approach would be unethical and equally detrimental to public health. In the absence of the current widely adopted antimicrobial use practices in animal agriculture, extreme deterioration in animal well-being and widespread infection in groups of animals would occur. The number of sick animals and animals dying of infectious diseases would increase dramatically. Subsequently, the livelihoods of farmers would be in peril. They would experience substantial revenue losses because of increased animal death, greater costs to treat and feed sick animals for an extended time, reduced sale prices for animals that recover, and consumer dissatisfaction with the resultant inhumane conditions for animals. The profitability and sustainability of these operations could be jeopardized, risking the jobs of the billions working in the animal agriculture industry. The effects industry-wide could be catastrophic to the sustainability of the global food supply and the economy, with this industry accounting for 40% of the global agricultural economy in developed countries, an estimated value of $1.4 trillion (7).

Alternative approaches to control disease in this population of animals are imperative to preserving people’s livelihoods, upholding our obligation to safeguard the health and well-being of animals, and promoting the production of a wholesome food supply. Most infectious disease research in agricultural animals focuses on devising strategies to enhance mechanisms of resistance (i.e., methods to prevent infection or promote pathogen elimination). Yet, for some diseases, such as bovine respiratory disease (BRD), interventions (e.g., vaccination) targeting resistance measures are ineffective at controlling the disease when implemented within the industry’s existing infrastructure, necessitating other approaches. Exploiting disease tolerance pathways, or the ability to limit the adverse consequences of infection, have been largely overlooked for their clinical applicability in the industry. Understanding the immune mechanisms regulating disease tolerance could inform novel strategies to combat diseases when sterile immunity is not possible and would work toward the goal of reducing the need for antimicrobials in this industry.

During infection, the host activates immune-driven pathways to detect, neutralize, and eliminate invading pathogens in a process called “resistance” (Fig. 1). Both innate and adaptive immune responses mediate mechanisms of resistance. Although critical in protecting the host from infection, resistance measures substantially impact host fitness, causing variable degrees of host tissue dysfunction and immunopathology (8). Activation of resistance pathways involves the local and systemic reallocation of resources away from basal physiological processes (e.g., growth and reproduction) in favor of supporting immunity (9). Disrupted tissue homeostasis combined with the exuberant immune response that occurs in some individuals can lead to severe disease states, as exemplified by acute respiratory distress syndrome being the primary cause of death in SARS-CoV-2 infection (10). Responding to the maladaptive consequences of the host immune response to infection are the simultaneously activated pathways of disease tolerance (Fig. 1). Distinct from the concept of immune tolerance, disease tolerance mechanisms limit host susceptibility to tissue damage and offset the fitness costs that occur with infection (8, 11, 12). In contrast to mechanisms of resistance, disease tolerance pathways do not alter pathogen burden (13). Described by botanists over a century ago, disease tolerance is an evolutionarily conserved response that has since been recognized as a critical defense strategy used by insects and mammals, including rodents and humans (1319). The balance between resistance and tolerance mechanisms, and thus the extent of host tissue damage, ultimately determines the outcome of infection, ranging from commensalism to colonization, subclinical disease, clinical disease, persistence, or death (20). The degree of contribution of resistance and tolerance pathways during disease is unique to the individual and is pathogen specific. Uncoupling of resistance and tolerance mechanisms can partly explain why variable degrees of morbidity and mortality are observed when individuals are infected with the same pathogen. Indeed, associations between disease severity and the robustness of activated tolerance pathways are exemplified by several diseases, including influenza (21), SARS-CoV-2 (22), salmonellosis (23), malaria (19, 24, 25), and candidiasis (26). For these diseases and others, studies have demonstrated that, independent of pathogen burden, preservation of host tissue function and vital homeostatic parameters within a desired range by activation of tolerance mechanisms confers host fitness and survival (8, 14, 27). Although immune mechanisms of disease resistance have been the focus of infectious disease research for decades, our understanding of the mechanisms regulating disease tolerance is still in its infancy.

FIGURE 1.

Tolerance and resistance defense strategies during infection.

In response to infection, immune-mediated disease resistance pathways are activated and aim to reduce pathogen load. Both pathogen virulence factors and immune resistance mechanisms cause damage to host tissues and homeostasis dysfunction. In contrast, the immune-mediated pathways of disease tolerance do not negatively impact pathogen fitness but can abrogate pathogen virulence factors, restore homeostasis, and support protection and resolution of damaged tissues. The balance between these two pathways ultimately determines the outcome of infection. Created with BioRender.com.

FIGURE 1.

Tolerance and resistance defense strategies during infection.

In response to infection, immune-mediated disease resistance pathways are activated and aim to reduce pathogen load. Both pathogen virulence factors and immune resistance mechanisms cause damage to host tissues and homeostasis dysfunction. In contrast, the immune-mediated pathways of disease tolerance do not negatively impact pathogen fitness but can abrogate pathogen virulence factors, restore homeostasis, and support protection and resolution of damaged tissues. The balance between these two pathways ultimately determines the outcome of infection. Created with BioRender.com.

Close modal

Damage to host tissues during infection results from the concerted interaction between the pathogen and the host. Pathogens express several virulence factors and can mediate host tissue damage directly or secondarily by eliciting a destructive host immune response. Factors inherent to the pathogen can contribute to host pathology at molecular and cellular levels by inducing host cell death and altering signal transduction pathways, leading to dysregulated immune responses and metabolic dysfunction (20). Host-induced tissue destruction occurs after recognition of molecular components of pathogens by germline-encoded innate immune receptors, including TLRs, NOD-like receptors, C-type lectin receptors, retinoic acid–inducible receptors, and others (20). Engagement of these receptors triggers the downstream signaling cascades that typically activate host resistance mechanisms. These mechanisms result in cellular recruitment and stimulate the production of soluble mediators that further activate innate and adaptive immune response pathways. Although activation of these pathways is necessary for pathogen elimination, these pathways also induce collateral damage to host tissues. Host resistance mechanisms can disrupt cellular homeostasis, resulting in the release of damage-associated molecular patterns, including intracellular stores of biologically active cytokines, growth factors, proteases, enzymes, and reactive oxygen species, that lead to necrotic cell death (28, 29). These biomolecules perpetuate a cycle of immune activation that causes immunopathology and, eventually, in some cases, organ dysfunction. Immune effector cells, such as Th1 and Th17 cells, are significant sources of damaging inflammatory molecules during some infections, including influenza (30). For other pathogens, such as respiratory syncytial virus, Th2 responses predominate during severe lung injury (31). This dichotomy highlights the need to understand the inflammatory programs activated across different types of infectious contexts. Counterbalancing the potentially deleterious immune-driven resistance mechanisms activated during infection are the host-mediated mechanisms of disease tolerance. Disease tolerance pathways prevent tissue damage, repair injured tissues, and support tissue regeneration. Tolerance mechanisms maintain host health without affecting pathogen load by preserving tissue function and promoting damage resolution. Several converging pathways contribute to disease tolerance, with many involving direct or indirect modulation of the immune response. Immune-driven tolerance mechanisms appear to be linked to the regulation of the stress- and damage-responsive signaling pathways that are essential in maintaining tissue homeostasis (12, 14, 27). These pathways dampen the proinflammatory events triggered during infection, including modulating the production of host-derived mediators to limit inflammation, increasing the expression of inhibitory receptors, and expanding regulatory immune cell populations to control effector cell function. Recent investigations have provided scientific insights into the specific immune components conferring disease tolerance for some human pathogens causing both acute and chronic disease.

The diverse immune response and the contribution of tissue repair pathways during parasitic infection are described in many publications; yet, only a few have assessed parasite burden and allowed the role of disease tolerance to be concluded definitively. Using a naturally developing parasitic roundworm model in mice, Gentile et al. (32) characterized a robust Th1 immune response driven by NK cells that predominates during early parasite invasion and promotes tolerance. Indeed, the results demonstrated that during early infection, IFN-γ signaling mediated the recruitment of NK cells exclusively to sites of infection. Furthermore, their results showed that the depletion of recruited NK cells at infection sites augmented vascular injury, allowing the authors to speculate that this population of NK cells is crucial in mitigating intestinal damage. These findings were without regard to changes in parasite burden or fitness. For another parasite, Toxoplasma gondii, the cytokine IL-10 is implicated as a significant disease tolerance effector, critical to host survival (33). In several studies, ablation of IL-10 signaling has promoted fulminant disease that is uncoupled from parasite burden (3436). Other work suggests the central role of other cytokines (37) and immune cells, including neutrophils (38) and monocytes (39), in minimizing immunopathology during parasitism. A growing body of evidence demonstrates that the severity of malarial infection is also correlated to the activation of tolerance pathways. Without impacting pathogen load, crosstalk between NO and CD4+ Th cells and CD8+ cytotoxic T cells emits protection against experimental cerebral malaria (24). Moreover, work in this field indicates that previously infected individuals can acquire mechanisms of disease tolerance. Data suggest that although the risk of developing a severe infection is high when first infected, subsequent infections cause mild disease, regardless of pathogen burden (40). Nahrendorf et al. (41) demonstrated that innate memory conferring disease tolerance during reinfection is facilitated by adaptations of monocytes that minimize inflammation, prevent tissue damage, and limit disease severity.

Variations in disease tolerance have also been implicated for the vastly different responses of individuals infected with respiratory viruses, including SARS-CoV-2 and influenza. Despite harboring similar viral loads (42), symptomatic and asymptomatic individuals with SARS-CoV-2 have distinctly different immune responses to infection. Work by Long et al. (43) and Chan et al. (44) demonstrated that asymptomatic patients with SARS-CoV-2 display distinct immune profiles characterized by a Th2 skewed cytokine profile, increased peripheral neutrophil counts, higher levels of virus-specific Th17 cells, and reduced IgG and neutralizing Abs in the early convalescent phase of the disease compared with symptomatic patients. The severity of influenza-induced pulmonary disease is correlated with the degree of immunopathology. A murine model of influenza was recently used to reveal the role of cyclophilin D (CypD) in regulating mitochondrial activity and IL-22 production by NK cells independent of viral load (45). Mice lacking CypD exhibited increased pulmonary edema and loss of barrier integrity secondary to epithelial and endothelial damage and increased inflammatory cells in the pulmonary parenchyma and airways. Other work by Maelfait et al. (46) demonstrated that A20 protein production in bronchial epithelium attenuates the maladaptive immune response triggered during influenza infection by mitigating cytotoxic T cell responses.

Disease tolerance strategies are also integral in bacterial respiratory infections and during bacterial sepsis. Several studies have demonstrated that amphiregulin, the ligand for epidermal growth factor receptor, mitigates lung pathology during influenza infection alone but also with concurrent bacterial infection independent of bacterial numbers (47, 48). Many disease tolerance pathways are implicated in preventing the progressive pathology characteristic of Mycobacterium tuberculosis and linking them to disease outcome and survival (49). Indeed, inducible NO synthase produced by macrophages negatively regulates inflammasome activity to dampen the inflammatory cytokine responses and curtail neutrophil recruitment (50). These effects were proved to be integral to survival, even when the bacterial load was held consistent. Furthermore, the pathology-minimizing effect of CypD, as described above, is not limited to influenza and also has a demonstrated role in tuberculosis (51). A recent study by Bessede et al. (23) elegantly provided mechanistic insight into the pathways conferring tissue protection during bacterial sepsis. In this study, the protective effect against TLR-triggered inflammation was the combined effect of aryl hydrocarbon receptor, a ligand-operated transcription factor; IDO1; and TGF-β.

Collectively, these studies and many others provide the impetus for future investigations into the mechanistic basis underlying the tissue-protective effects of immune components in disease tolerance (Table I). Only recently gaining momentum is the concept of disease tolerance in agricultural animals.

Table I.

Examples of infectious diseases in humans with published evidence that has established or is suggestive of a role of disease tolerance in dictating clinical outcomes and the proposed tolerance mechanisms, if reported, and, in some cases, demonstrated using murine models

Pathogen ClassPathogenProposed MechanismReferences
Viruses    
 Influenza virus Cyclophilin D regulates IL-22 production via NK cells and altered mitochondrial activity; A20 protein mitigates cytotoxic T cell responses. (14, 45, 46, 48
 SARS-CoV-2 Predominance of Th2 cytokines, increased circulating neutrophils, increased virus-specific Th17 cells, reduced IgG and neutralizing Ab (4244
 Herpes simplex virus Aryl hydrocarbon regulation of T cells (90
 HIV HLA haplotype (91
 Dengue virus Reduced inflammation and tissue injury mediated by IL-22 (92
Bacteria    
 Mycobacterium tuberculosis Macrophage produced NO regulates inflammasome to dampen cytokine responses and reduce neutrophil recruitment; cyclophilin D activity regulates T cell responses. (4951
 Legionella pneumophila Amphiregulin during corespiratory viral infection (47
 Salmonella Aryl hydrocarbon regulates TLR-induced inflammation via IDO 1 and TGF-β (23
 Staphylococcus aureus Autophagy-mediated protection against toxin-induced damage, suppression of T cell activation by IL-10, mitochondrial biogenesis via NRF2 (9395
 Streptococcus pyogenes Type 1 IFN regulates inflammation and improves lung barrier. (96
 Listeria monocytogenes Heat shock factor 1 regulation of IL-1β (97
Parasites    
 Plasmodium spp. Crosstalk between NO and T cells, monocyte reprogramming, TLR-mediated signaling (17, 24, 41
 Toxoplasma gondii IL-10 signaling (33, 35, 36
 Trypanosoma cruzi Downregulation of IFN-γ, and Ebi3/IL27p28 (98
 Schistosoma mansoni Downregulation of Th1 response by alternatively activated macrophages (99
Fungi    
 Candida albicans Control of proinflammatory responses, involvement of IDO1, IL-22, and IL-10 (100, 101
Pathogen ClassPathogenProposed MechanismReferences
Viruses    
 Influenza virus Cyclophilin D regulates IL-22 production via NK cells and altered mitochondrial activity; A20 protein mitigates cytotoxic T cell responses. (14, 45, 46, 48
 SARS-CoV-2 Predominance of Th2 cytokines, increased circulating neutrophils, increased virus-specific Th17 cells, reduced IgG and neutralizing Ab (4244
 Herpes simplex virus Aryl hydrocarbon regulation of T cells (90
 HIV HLA haplotype (91
 Dengue virus Reduced inflammation and tissue injury mediated by IL-22 (92
Bacteria    
 Mycobacterium tuberculosis Macrophage produced NO regulates inflammasome to dampen cytokine responses and reduce neutrophil recruitment; cyclophilin D activity regulates T cell responses. (4951
 Legionella pneumophila Amphiregulin during corespiratory viral infection (47
 Salmonella Aryl hydrocarbon regulates TLR-induced inflammation via IDO 1 and TGF-β (23
 Staphylococcus aureus Autophagy-mediated protection against toxin-induced damage, suppression of T cell activation by IL-10, mitochondrial biogenesis via NRF2 (9395
 Streptococcus pyogenes Type 1 IFN regulates inflammation and improves lung barrier. (96
 Listeria monocytogenes Heat shock factor 1 regulation of IL-1β (97
Parasites    
 Plasmodium spp. Crosstalk between NO and T cells, monocyte reprogramming, TLR-mediated signaling (17, 24, 41
 Toxoplasma gondii IL-10 signaling (33, 35, 36
 Trypanosoma cruzi Downregulation of IFN-γ, and Ebi3/IL27p28 (98
 Schistosoma mansoni Downregulation of Th1 response by alternatively activated macrophages (99
Fungi    
 Candida albicans Control of proinflammatory responses, involvement of IDO1, IL-22, and IL-10 (100, 101

The existing paradigm within the animal agriculture research community is to investigate and target disease resistance mechanisms to control diseases in these animals. Only a few studies have explicitly documented the occurrence of disease tolerance in agricultural animals by measuring both parameters of host fitness and pathogen burden.

Trypanosomiasis and theileriosis are two arthropod-borne diseases providing evidence of the role of disease tolerance in controlling disease outcomes in cattle. African trypanosomiasis is a fatal disease impacting both animals and humans in sub-Saharan Africa. Several studies dating back to the 1980s have demonstrated that specific breeds of cattle are more tolerant to trypanosomiasis than are other cattle breeds (5254). Trypanotolerant breeds can limit pathological effects of the parasite, demonstrated by reduced severity of anemia and minimal production losses, despite harboring parasite loads similar to or greater than those in more susceptible breeds (18). Additional research performed since these initial publications has discovered that the degree of tolerance to trypanosomiasis is connected to the cellular and humoral immune responses the pathogen induces. More specifically, in later stages of the disease, skewing of the cytokine milieu toward a Th2 response and development of alternatively activated macrophages favors survival by mitigating collateral damage to the host during infection (31, 55). Similarly, particular cattle breeds are more capable than others of limiting immunopathology during natural Theileria spp. infection. Cattle deemed tolerant to theileriosis were able to restrict pathology by limiting inflammation. This was achieved by reducing circulating levels of acute-phase proteins, decreasing the expression of signal regulatory protein family genes, bovine MHC class II genes, TGF-β2 genes, and restricting the expansion of infected lymphocytes—a significant contributor to disease pathology (54, 56, 57). The precise mechanistic pathways controlling disease tolerance during these infections have yet to be determined.

BRD, a multifactorial syndrome caused by a combination of viral and bacterial pathogens, results in the development of pneumonia of varying severity. One explanation for the varied clinical picture of calves with BRD is disparities in the level of disease tolerance (58). Even in the face of well-controlled challenge studies using the same challenge protocol, a spectrum of clinical signs and lung pathology is observed (59). In these studies and others using naturally occurring disease models, disease severity is uncoupled from pathogen load, with some calves having no clinical signs despite harboring significant pathogen loads (60, 61). Despite the discordant response of calves to BRD infection, a dysregulated immune response characterized by an exuberant inflammatory response is considered a significant contributor to pathology. Evidence from studies using bovine respiratory syncytial virus, a common viral component of BRD, points to tolerance pathways as a potentially novel method in disease control. Indeed, bovine respiratory syncytial virus causes minimal to no cytopathic effect on airway epithelial cells, indicating that pulmonary pathology, which dictates the clinical outcome, is likely host induced and secondary to the activation of host immune-driven resistance mechanisms (62). BRD is the leading natural cause of death, the primary reason for antimicrobial use, and a top source of economic losses in the cattle industry. Alternative approaches to control this disease are desperately needed and would profoundly affect antimicrobial use in the industry.

Another example of disease tolerance in animal agriculture is persistent, asymptomatic Salmonella infection in poultry. Despite harboring Salmonella in their large intestinal tract, most animals remain asymptomatic. This tolerant phenotype is correlated with the development of a Th2 response after the production of IL-10 and TGF-β days after infection and the activity of T regulatory cells that suppress effector T cell function (6367). The immune reprogramming and altered TCR and JAK/STAT signaling pathways (68) that occur after the initial robust inflammatory response to the bacterium acts to minimize pathology during infection. Notably, the unperturbed persistence of Salmonella in the intestinal tract of poultry has significant implications for public health as an important cause of foodborne illness worldwide. This situation highlights the necessity of having a clear understanding of the consequences that fostering disease tolerance mechanisms within a population of animals might have on that prevalence of infectious diseases and, moreover, its implications on human health (69). Ongoing studies aim to elucidate the coevolution of Salmonella and the poultry microbiome.

A recent study by Lough et al. (70) provides the genetic basis of variation in tolerance in swine infected with porcine reproductive and respiratory syndrome virus (PRRSV). In this study, the authors correlated the genetic signature consistent with tolerance pathways with an increased growth rate in PRRSV-challenged pigs. These results contrast their previously reported results (71), emphasizing the importance of accounting for changes in the contribution of disease tolerance throughout infection. In the former study, this was accomplished by partitioning the infection period into early, middle, and late stages, allowing identification of differences in disease tolerance to be detected when they were most pronounced (70). Another disease in which modulation of disease severity has been linked to host genetic variation is African swine fever. African swine fever is a viral disease that typically causes fatal disease in domestic swine. However, several published reports indicate that the virus can cause variable clinical outcomes within specific populations of domestic swine. Despite harboring similar viral loads, some individuals produce an attenuated immune response, surviving viral infection and thus suggestive of a role of disease tolerance (7274). Finally, the loci involved in the development of clinical Mycobacterium avium subspecies paratuberculosis disease in cattle were identified by Zanella et al. (75) in 2011, and, more recently, several candidate genes involved in the repair of damaged DNA and tissues and modulation of inflammation and innate immunity were discovered (76).

These experiments provide supporting evidence for disease tolerance playing a critical role in controlling the outcome of infection for diseases impacting the animal agriculture industry (Table II). Notably, the majority of published studies fail to document pathogen burden, making it likely that some studies characterizing immune resistance mechanisms in these animals are in reality detailing mechanisms of disease tolerance (77).

Table II.

Examples of infectious diseases in agricultural animals with published evidence that has established or is suggestive of a role of disease tolerance in dictating clinical outcomes and the proposed tolerance mechanisms, if reported

Pathogen ClassPathogenProposed MechanismReferences
Viruses    
 Ruminants    
  Bovine respiratory syncytial virus To be determined (62
 Swine    
  Porcine reproductive and respiratory syndrome virus To be determined, evidence suggestive of genetic determinates (70, 71
  African swine fever To be determined, evidence suggestive of genetic determinates, possible role of NF-κB signaling (7274
 Poultry Avian influenza To be determined, evidence suggestive of regulation of inflammatory response (102, 103
Bacteria    
 Ruminants    
  Mycobacterium avium subspecies paratuberculosis Gene candidates in DNA packaging, TNF signaling, and Toxoplasmosis pathways (76
  Anaplasma spp. To be determined evidence suggestive of a role of MHC haplotype (104
 Poultry    
 Salmonella Altered TCR and JAK/STAT signaling pathways (63, 64, 6769
Parasites    
 Ruminants    
 African trypanosomes B cell activation pathways, innate immune responses, and cytotoxic responses (52, 53, 105, 106
 Theileria spp. Reduced expression of proinflammatory cytokines (54, 56, 57
 Babesia spp. MHC haplotype  
 Fasciola spp. To be determined (107
 Nematodes To be determined (108
Pathogen ClassPathogenProposed MechanismReferences
Viruses    
 Ruminants    
  Bovine respiratory syncytial virus To be determined (62
 Swine    
  Porcine reproductive and respiratory syndrome virus To be determined, evidence suggestive of genetic determinates (70, 71
  African swine fever To be determined, evidence suggestive of genetic determinates, possible role of NF-κB signaling (7274
 Poultry Avian influenza To be determined, evidence suggestive of regulation of inflammatory response (102, 103
Bacteria    
 Ruminants    
  Mycobacterium avium subspecies paratuberculosis Gene candidates in DNA packaging, TNF signaling, and Toxoplasmosis pathways (76
  Anaplasma spp. To be determined evidence suggestive of a role of MHC haplotype (104
 Poultry    
 Salmonella Altered TCR and JAK/STAT signaling pathways (63, 64, 6769
Parasites    
 Ruminants    
 African trypanosomes B cell activation pathways, innate immune responses, and cytotoxic responses (52, 53, 105, 106
 Theileria spp. Reduced expression of proinflammatory cytokines (54, 56, 57
 Babesia spp. MHC haplotype  
 Fasciola spp. To be determined (107
 Nematodes To be determined (108

Undoubtedly, interventions targeting disease resistance mechanisms have been highly effective in preventing and limiting the severity of infectious diseases, including vaccinations and antimicrobials. But the evolutionary implications of modulating host resistance mechanisms by targeting pathogen biology are highlighted by the current antimicrobial resistance crisis described herein. Exploiting host resistance pathways induces selection pressures on pathogens driving the development of evasion mechanisms. The evolutionary cycle is then propagated by the natural or artificial (selective breeding) selection of hosts exhibiting the desired counterresistant trait needed to overcome evolved pathogen resistance (78). This feedback loop partly explains the inevitable failure of some approaches that target resistance mechanisms to reduce disease morbidity and mortality. Furthermore, it has been demonstrated that genetic selection of resistance pathways can lead to trade-offs in responses to other pathogens and, in some cases, impact animal growth, reproduction, and development. Several studies in poultry have demonstrated decreased disease resistance and altered immune responses in animals genetically selected for increased growth rates (7983). Similarly, positive correlations between milk yield and disease traits in dairy cattle (84, 85) and between fleece weight and fecal egg counts in sheep (86) have been established. Because improved productivity is the aim of any animal agriculture breeding program, the unpredictable and potentially unfavorable consequences of either genetic selection or genome editing to yield disease-resistant animals are a significant concern (87). Although these technologies will likely revolutionize animal health and help address the challenges facing the industry, they require thorough exploration before their implementation in breeding schemes and may not be a realistic approach in all situations.

Like the selective breeding of resistant animals, breeding programs focused on propagating desirable tolerance traits within a population may be an effective means to reduce dependence on antimicrobial use practices without compromising animal performance. The genetic selection of disease-tolerant animals will not provoke the evolution of resistant pathogens and may even provide cross-protection against pathogen variants, unlike the selection of resistant animals (17). Still, breeding programs and genome editing approaches under the context of disease tolerance create concerns similar to those described above and a few others. Increasing the number of disease-tolerant animals in a herd will also maintain or increase the prevalence of a pathogen within that population. As a result, tolerant animals could serve as a reservoir of infection for susceptible animals (87), including replacement animals and animals with altered immune states, including immunologically naive neonates and pregnant or lactating animals. As such, the overall impact of implementing the selection of tolerance traits in breeding programs on herd health and animal management must be considered. A more practical approach to reaping the benefits of exploiting disease tolerance mechanisms to control infectious diseases might be the timed application of immunomodulators or selective altering of gene expression to enhance immune-driven tolerance mechanisms in the short term.

Many disease tolerance and resistance pathways are inseparable, with both pathways active in parallel or divergent times during infection. Thus, the challenge to overcome when conducting studies aimed at demystifying tolerance mechanisms and harnessing their therapeutic potential is the need to disentangle these complementary mechanisms. The impact on both pathways must be accounted for if shared immune signaling networks are the target for developing novel immunotherapies. Therapies must be applied at the opportune time. They should selectively augment pathways to control immunologically mediated local and systemic tissue damage without abolishing the resistance mechanisms necessary to prevent mortality. A pathogen-tailored approach accounting for the possibility that augmenting tolerance pathways to improve outcomes for one disease may prove detrimental for another cannot be overlooked. The short- and long-term effects of these therapies in amplifying other undesirable disease states, including autoimmune disease and neoplasia, must be evaluated. For example, phase II clinical trials are underway to assess the use of an IL-22–like biopharmaceutical in intestinal repair (NCT02406651) (88). Yet, the potential risks of chronic administration of IL-22, including carcinogenesis and enhanced autoimmune inflammation, are of concern (89). Considerations such as these will further dictate the constraints of clinical application of disease tolerance–directed therapies. Devising ways to strike a balance between resistance and tolerance pathways will likely be imperative if therapies are to achieve the greatest impact. Finally, the implications of these therapies on host-pathogen evolutionary ecology and public health are of utmost importance.

Investigation into methods to augment disease tolerance as a means of infectious disease control will require more than just a fundamental change in our research approach; it will require overcoming the significant hurdle presented by the lack of available funding to support exploratory research efforts. The number of public agencies and private sector foundations that invest in animal agriculture research is limited, and many of these organizations are experiencing flattening or declining budgets. Existing funding programs tend to prioritize applied or developmental research that has the potential to benefit the industry immediately. Frequently overlooked is basic science or curiosity-driven research. Although these studies are highly transformative and a prerequisite for future scientific breakthroughs because the results have no immediate application to the industry, they are less highly regarded in the competitive arena of grant funding. Furthermore, the funding agencies that support research to enhance human health will typically invest in animal agriculture research only if there is a direct, tangible benefit to human health. Despite agricultural animals, in some instances, serving as a superior yet underused model for investigating several diseases that impact them and humans, the health and welfare of these animals have important implications for public health and the global economy and should be a top priority for even these organizations. The scarcity of funding mechanisms that support basic research in animal agriculture, as well as the select preferences of current funding programs, are stifling researchers’ creativity and the progress of science and contributing to the current uncertain sustainability of today’s animal agriculture industry. Innovative lines of research are desperately needed to combat the industry’s existing and anticipated challenges, including the threat of emerging diseases and zoonoses. Although a shift in our research approach, as described herein, is imperative to meet the fluctuating demands of the industry, equally important is a change in the mindset of funding organizations to recognize that many basic science research objectives in animal agriculture research should be considered a high priority because of their potential future impact on animal and human health alike.

Despite decades of research, the sustained prevalence of many infectious diseases highlights the need to question current paradigms in infectious disease control programs. Published literature on several human diseases ranging from SARS-CoV-2 to malaria and some in agricultural animal diseases, including BRD and PRRSV, suggests that novel approaches to infectious disease control that exploit mechanisms of disease tolerance will be rewarding. Exploring immune-driven tolerance pathways is an untapped resource that can inform the discovery of new preventative and therapeutic strategies with applications across diverse models of tissue injury. Within the animal agriculture industry, this customized approach will circumvent the need to mass-medicate animals with antimicrobials and decrease the iterations of antimicrobial treatment. Indeed, it will open doors for the development of advanced diagnostic tools. It will enable veterinary professionals to assist producers in identifying animals that will remain healthy throughout the production cycle while permitting them to accurately detect animals that would benefit from treatment and determine the proper time to implement that treatment. Improved animal production efficiency created by these approaches will help reduce the environmental impact of animal agriculture because fewer natural resources will be required to support the production of healthy animals. The industry’s sustainability will translate to a greater capacity and more resources to provide public goods and services and will ensure that, globally, people will have reliable access to effective antimicrobials and an affordable, safe, and wholesome food supply. By investigating these innovative lines of research, we can make strides toward improving animal health and human health and minimizing the public and economic burden of infectious diseases.

Abbreviations used in this article

     
  • BRD

    bovine respiratory disease

  •  
  • CypD

    cyclophilin D

  •  
  • PRRSV

    porcine reproductive and respiratory syndrome virus

1.
Antimicrobial Resistance Collaborators
.
2022
.
Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. [Published erratum appears in 2022 Lancet 400: 1102.]
Lancet
399
:
629
655
.
2.
Pokharel
S.
,
P.
Shrestha
,
B.
Adhikari
.
2020
.
Antimicrobial use in food animals and human health: time to implement ‘One Health’ approach.
Antimicrob. Resist. Infect. Control
9
:
181
.
3.
Gousia
P.
,
V.
Economou
,
H.
Sakkas
,
S.
Leveidiotou
,
C.
Papadopoulou
.
2011
.
Antimicrobial resistance of major foodborne pathogens from major meat products.
Foodborne Pathog. Dis.
8
:
27
38
.
4.
Food and Drug Administration (FDA)
.
2019
.
2018 Summary report on antimicrobials sold or distributed for use in food-producing animals.
Laurel, MD
:
FDA Center for Veterinary Medicine
.
5.
Landers
T. F.
,
B.
Cohen
,
T. E.
Wittum
,
E. L.
Larson
.
2012
.
A review of antibiotic use in food animals: perspective, policy, and potential.
Public Health Rep.
127
:
4
22
.
6.
Fair
R. J.
,
Y.
Tor
.
2014
.
Antibiotics and bacterial resistance in the 21st century.
Perspect. Medicin. Chem.
6
:
25
64
.
7.
Thornton
P. K.
2010
.
Livestock production: recent trends, future prospects.
Philos. Trans. R. Soc. Lond. B Biol. Sci.
365
:
2853
2867
.
8.
Medzhitov
R.
,
D. S.
Schneider
,
M. P.
Soares
.
2012
.
Disease tolerance as a defense strategy.
Science
335
:
936
941
.
9.
Rauw
W. M.
2012
.
Immune response from a resource allocation perspective.
Front. Genet.
3
:
267
.
10.
Huang
C.
,
Y.
Wang
,
X.
Li
,
L.
Ren
,
J.
Zhao
,
Y.
Hu
,
L.
Zhang
,
G.
Fan
,
J.
Xu
,
X.
Gu
, et al
2020
.
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
Lancet
395
:
497
506
.
11.
Soares
M. P.
,
L.
Teixeira
,
L. F.
Moita
.
2017
.
Disease tolerance and immunity in host protection against infection.
Nat. Rev. Immunol.
17
:
83
96
.
12.
Soares
M. P.
2014
.
“Nuts and bolts” of disease tolerance.
Immunity
41
:
176
178
.
13.
Clarke
D.
1986
.
Tolerance of parasites and disease in plants and its significance in host-parasite interactions.
Adv. Plant Pathol.
5
:
161
.
14.
Martins
R.
,
A. R.
Carlos
,
F.
Braza
,
J. A.
Thompson
,
P.
Bastos-Amador
,
S.
Ramos
,
M. P.
Soares
.
2019
.
Disease tolerance as an inherent component of immunity.
Annu. Rev. Immunol.
37
:
405
437
.
15.
Råberg
L.
,
D.
Sim
,
A. F.
Read
.
2007
.
Disentangling genetic variation for resistance and tolerance to infectious diseases in animals.
Science
318
:
812
814
.
16.
Gozzelino
R.
,
B. B.
Andrade
,
R.
Larsen
,
N. F.
Luz
,
L.
Vanoaica
,
E.
Seixas
,
A.
Coutinho
,
S.
Cardoso
,
S.
Rebelo
,
M.
Poli
, et al
2012
.
Metabolic adaptation to tissue iron overload confers tolerance to malaria.
Cell Host Microbe
12
:
693
704
.
17.
Schneider
D. S.
,
J. S.
Ayres
.
2008
.
Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases.
Nat. Rev. Immunol.
8
:
889
895
.
18.
Schafer
J. F.
1971
.
Tolerance to plant disease.
Annu. Rev. Phytopathol.
9
:
235
252
.
19.
Seixas
E.
,
R.
Gozzelino
,
A.
Chora
,
A.
Ferreira
,
G.
Silva
,
R.
Larsen
,
S.
Rebelo
,
C.
Penido
,
N. R.
Smith
,
A.
Coutinho
,
M. P.
Soares
.
2009
.
Heme oxygenase-1 affords protection against noncerebral forms of severe malaria.
Proc. Natl. Acad. Sci. USA
106
:
15837
15842
.
20.
Casadevall
A.
,
L. A.
Pirofski
.
2003
.
The damage-response framework of microbial pathogenesis.
Nat. Rev. Microbiol.
1
:
17
24
.
21.
Wang
A.
,
S. C.
Huen
,
H. H.
Luan
,
S.
Yu
,
C.
Zhang
,
J. D.
Gallezot
,
C. J.
Booth
,
R.
Medzhitov
.
2016
.
Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation.
Cell
166
:
1512
1525.e12
.
22.
Elahi
S.
2020
.
Neonatal and children’s immune system and COVID-19: biased immune tolerance versus resistance strategy.
J. Immunol.
205
:
1990
1997
.
23.
Bessede
A.
,
M.
Gargaro
,
M. T.
Pallotta
,
D.
Matino
,
G.
Servillo
,
C.
Brunacci
,
S.
Bicciato
,
E. M. C.
Mazza
,
A.
Macchiarulo
,
C.
Vacca
, et al
2014
.
Aryl hydrocarbon receptor control of a disease tolerance defence pathway.
Nature
511
:
184
190
.
24.
Jeney
V.
,
S.
Ramos
,
M. L.
Bergman
,
I.
Bechmann
,
J.
Tischer
,
A.
Ferreira
,
V.
Oliveira-Marques
,
C. J.
Janse
,
S.
Rebelo
,
S.
Cardoso
,
M. P.
Soares
.
2014
.
Control of disease tolerance to malaria by nitric oxide and carbon monoxide.
Cell Rep.
8
:
126
136
.
25.
Sinton
J. A.
1938
.
Immunity or tolerance in malarial infections.
Proc. R. Soc. Med.
31
:
1298
1302
.
26.
Huang
J.
,
S.
Meng
,
S.
Hong
,
X.
Lin
,
W.
Jin
,
C.
Dong
.
2016
.
IL-17C is required for lethal inflammation during systemic fungal infection.
Cell. Mol. Immunol.
13
:
474
483
.
27.
Chovatiya
R.
,
R.
Medzhitov
.
2014
.
Stress, inflammation, and defense of homeostasis.
Mol. Cell
54
:
281
288
.
28.
Soares
M. P.
,
R.
Gozzelino
,
S.
Weis
.
2014
.
Tissue damage control in disease tolerance.
Trends Immunol.
35
:
483
494
.
29.
Chen
G. Y.
,
G.
Nuñez
.
2010
.
Sterile inflammation: sensing and reacting to damage.
Nat. Rev. Immunol.
10
:
826
837
.
30.
Rouse
B. T.
,
S.
Sehrawat
.
2010
.
Immunity and immunopathology to viruses: what decides the outcome?
Nat. Rev. Immunol.
10
:
514
526
.
31.
Culley
F. J.
,
A. M.
Pennycook
,
J. S.
Tregoning
,
T.
Hussell
,
P. J.
Openshaw
.
2006
.
Differential chemokine expression following respiratory virus infection reflects Th1- or Th2-biased immunopathology.
J. Virol.
80
:
4521
4527
.
32.
Gentile
M. E.
,
Y.
Li
,
A.
Robertson
,
K.
Shah
,
G.
Fontes
,
E.
Kaufmann
,
B.
Polese
,
N.
Khan
,
M.
Parisien
,
H. M.
Munter
, et al
2020
.
NK cell recruitment limits tissue damage during an enteric helminth infection.
Mucosal Immunol.
13
:
357
370
.
33.
Melchor
S. J.
,
S. E.
Ewald
.
2019
.
Disease tolerance in Toxoplasma infection.
Front. Cell. Infect. Microbiol.
9
:
185
.
34.
Gazzinelli
R. T.
,
M.
Wysocka
,
S.
Hieny
,
T.
Scharton-Kersten
,
A.
Cheever
,
R.
Kühn
,
W.
Müller
,
G.
Trinchieri
,
A.
Sher
.
1996
.
In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha.
J. Immunol.
157
:
798
805
.
35.
Neyer
L. E.
,
G.
Grunig
,
M.
Fort
,
J. S.
Remington
,
D.
Rennick
,
C. A.
Hunter
.
1997
.
Role of interleukin-10 in regulation of T-cell-dependent and T-cell-independent mechanisms of resistance to Toxoplasma gondii.
Infect. Immun.
65
:
1675
1682
.
36.
Wilson
E. H.
,
U.
Wille-Reece
,
F.
Dzierszinski
,
C. A.
Hunter
.
2005
.
A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis.
J. Neuroimmunol.
165
:
63
74
.
37.
Villarino
A. V.
,
J. S.
Stumhofer
,
C. J.
Saris
,
R. A.
Kastelein
,
F. J.
de Sauvage
,
C. A.
Hunter
.
2006
.
IL-27 limits IL-2 production during Th1 differentiation.
J. Immunol.
176
:
237
247
.
38.
Molloy
M. J.
,
J. R.
Grainger
,
N.
Bouladoux
,
T. W.
Hand
,
L. Y.
Koo
,
S.
Naik
,
M.
Quinones
,
A. K.
Dzutsev
,
J. L.
Gao
,
G.
Trinchieri
, et al
2013
.
Intraluminal containment of commensal outgrowth in the gut during infection-induced dysbiosis.
Cell Host Microbe
14
:
318
328
.
39.
Grainger
J. R.
,
E. A.
Wohlfert
,
I. J.
Fuss
,
N.
Bouladoux
,
M. H.
Askenase
,
F.
Legrand
,
L. Y.
Koo
,
J. M.
Brenchley
,
I. D.
Fraser
,
Y.
Belkaid
.
2013
.
Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection.
Nat. Med.
19
:
713
721
.
40.
Gonçalves
B. P.
,
C.-Y.
Huang
,
R.
Morrison
,
S.
Holte
,
E.
Kabyemela
,
D. R.
Prevots
,
M.
Fried
,
P. E.
Duffy
.
2014
.
Parasite burden and severity of malaria in Tanzanian children.
N. Engl. J. Med.
370
:
1799
1808
.
41.
Nahrendorf
W.
,
A.
Ivens
,
P. J.
Spence
.
2021
.
Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria.
eLife
10
:
e63838
.
42.
Lee
S.
,
T.
Kim
,
E.
Lee
,
C.
Lee
,
H.
Kim
,
H.
Rhee
,
S. Y.
Park
,
H. J.
Son
,
S.
Yu
,
J. W.
Park
, et al
2020
.
Clinical course and molecular viral shedding among asymptomatic and symptomatic patients with SARS-CoV-2 infection in a community treatment center in the Republic of Korea.
JAMA Intern. Med.
180
:
1447
1452
.
43.
Long
Q. X.
,
X. J.
Tang
,
Q. L.
Shi
,
Q.
Li
,
H. J.
Deng
,
J.
Yuan
,
J. L.
Hu
,
W.
Xu
,
Y.
Zhang
,
F. J.
Lv
, et al
2020
.
Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.
Nat. Med.
26
:
1200
1204
.
44.
Chan
Y. H.
,
S. W.
Fong
,
C. M.
Poh
,
G.
Carissimo
,
N. K.
Yeo
,
S. N.
Amrun
,
Y. S.
Goh
,
J.
Lim
,
W.
Xu
,
R. S.
Chee
, et al
2021
.
Asymptomatic COVID-19: disease tolerance with efficient anti-viral immunity against SARS-CoV-2.
EMBO Mol. Med.
13
:
e14045
.
45.
Downey
J.
,
H. E.
Randolph
,
E.
Pernet
,
K. A.
Tran
,
S. A.
Khader
,
I. L.
King
,
L. B.
Barreiro
,
M.
Divangahi
.
2022
.
Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus.
Cell Rep.
39
:
110974
.
46.
Maelfait
J.
,
K.
Roose
,
L.
Vereecke
,
C.
Mc Guire
,
M.
Sze
,
M. J.
Schuijs
,
M.
Willart
,
L. I.
Ibañez
,
H.
Hammad
,
B. N.
Lambrecht
, et al
2016
.
A20 deficiency in lung epithelial cells protects against influenza A virus infection.
PLoS Pathog.
12
:
e1005410
.
47.
Jamieson
A. M.
,
L.
Pasman
,
S.
Yu
,
P.
Gamradt
,
R. J.
Homer
,
T.
Decker
,
R.
Medzhitov
.
2013
.
Role of tissue protection in lethal respiratory viral-bacterial coinfection.
Science
340
:
1230
1234
.
48.
Monticelli
L. A.
,
G. F.
Sonnenberg
,
M. C.
Abt
,
T.
Alenghat
,
C. G. K.
Ziegler
,
T. A.
Doering
,
J. M.
Angelosanto
,
B. J.
Laidlaw
,
C. Y.
Yang
,
T.
Sathaliyawala
, et al
2011
.
Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.
Nat. Immunol.
12
:
1045
1054
.
49.
Olive
A. J.
,
C. M.
Sassetti
.
2018
.
Tolerating the unwelcome guest; how the host withstands persistent Mycobacterium tuberculosis.
Front. Immunol.
9
:
2094
.
50.
Mishra
B. B.
,
V. A.
Rathinam
,
G. W.
Martens
,
A. J.
Martinot
,
H.
Kornfeld
,
K. A.
Fitzgerald
,
C. M.
Sassetti
.
2013
.
Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β.
Nat. Immunol.
14
:
52
60
.
51.
Tzelepis
F.
,
J.
Blagih
,
N.
Khan
,
J.
Gillard
,
L.
Mendonca
,
D. G.
Roy
,
E. H.
Ma
,
P.
Joubert
,
R. G.
Jones
,
M.
Divangahi
.
2018
.
Mitochondrial cyclophilin D regulates T cell metabolic responses and disease tolerance to tuberculosis.
Sci. Immunol.
3
:
eaar4135
.
52.
Murray
M.
,
W. I.
Morrison
,
D. D.
Whitelaw
.
1982
.
Host susceptibility to African trypanosomiasis: trypanotolerance.
Adv. Parasitol.
21
:
1
68
.
53.
Dolan
R. B.
1987
.
Genetics and trypanotolerance.
Parasitol. Today
3
:
137
143
.
54.
Latre de Late
P.
,
E. A. J.
Cook
,
D.
Wragg
,
E. J.
Poole
,
G.
Ndambuki
,
A. A.
Miyunga
,
M. C.
Chepkwony
,
S.
Mwaura
,
N.
Ndiwa
,
G.
Prettejohn
, et al
2021
.
Inherited tolerance in cattle to the apicomplexan protozoan Theileria parva is associated with decreased proliferation of parasite-infected lymphocytes.
Front. Cell. Infect. Microbiol.
11
:
751671
.
55.
O’Gorman
G. M.
,
S. D.
Park
,
E. W.
Hill
,
K. G.
Meade
,
L. C.
Mitchell
,
M.
Agaba
,
J. P.
Gibson
,
O.
Hanotte
,
J.
Naessens
,
S. J.
Kemp
,
D. E.
MacHugh
.
2006
.
Cytokine mRNA profiling of peripheral blood mononuclear cells from trypanotolerant and trypanosusceptible cattle infected with Trypanosoma congolense.
Physiol. Genomics
28
:
53
61
.
56.
Glass
E. J.
,
P. M.
Preston
,
A.
Springbett
,
S.
Craigmile
,
E.
Kirvar
,
G.
Wilkie
,
C. G.
Brown
.
2005
.
Bos taurus and Bos indicus (Sahiwal) calves respond differently to infection with Theileria annulata and produce markedly different levels of acute phase proteins.
Int. J. Parasitol.
35
:
337
347
.
57.
Glass
E. J.
,
S.
Crutchley
,
K.
Jensen
.
2012
.
Living with the enemy or uninvited guests: functional genomics approaches to investigating host resistance or tolerance traits to a protozoan parasite, Theileria annulata, in cattle.
Vet. Immunol. Immunopathol.
148
:
178
189
.
58.
Bassel
L. L.
,
S.
Tabatabaei
,
J. L.
Caswell
.
2020
.
Host tolerance to infection with the bacteria that cause bovine respiratory disease.
Vet. Clin. North Am. Food Anim. Pract.
36
:
349
359
.
59.
Vulikh
K.
,
L. L.
Bassel
,
L.
Sergejewich
,
E. I.
Kaufman
,
J.
Hewson
,
J. I.
MacInnes
,
S.
Tabatabaei
,
J. L.
Caswell
.
2019
.
Effect of tracheal antimicrobial peptide on the development of Mannheimia haemolytica pneumonia in cattle.
PLoS One
14
:
e0225533
.
60.
Ollivett
T. L.
,
J. L.
Caswell
,
D. V.
Nydam
,
T.
Duffield
,
K. E.
Leslie
,
J.
Hewson
,
D.
Kelton
.
2015
.
Thoracic ultrasonography and bronchoalveolar lavage fluid analysis in Holstein calves with subclinical lung lesions.
J. Vet. Intern. Med.
29
:
1728
1734
.
61.
Timsit
E.
,
N.
Dendukuri
,
I.
Schiller
,
S.
Buczinski
.
2016
.
Diagnostic accuracy of clinical illness for bovine respiratory disease (BRD) diagnosis in beef cattle placed in feedlots: a systematic literature review and hierarchical Bayesian latent-class meta-analysis.
Prev. Vet. Med.
135
:
67
73
.
62.
Valarcher
J. F.
,
G.
Taylor
.
2007
.
Bovine respiratory syncytial virus infection.
Vet. Res.
38
:
153
180
.
63.
Shanmugasundaram
R.
,
M. H.
Kogut
,
R. J.
Arsenault
,
C. L.
Swaggerty
,
K.
Cole
,
J. M.
Reddish
,
R. K.
Selvaraj
.
2015
.
Effect of Salmonella infection on cecal tonsil regulatory T cell properties in chickens.
Poult. Sci.
94
:
1828
1835
.
64.
Kogut
M. H.
,
R. J.
Arsenault
.
2015
.
A role for the non-canonical Wnt-β-catenin and TGF-β signaling pathways in the induction of tolerance during the establishment of a Salmonella enterica serovar enteritidis persistent cecal infection in chickens.
Front. Vet. Sci.
2
:
33
.
65.
Withanage
G. S.
,
P.
Wigley
,
P.
Kaiser
,
P.
Mastroeni
,
H.
Brooks
,
C.
Powers
,
R.
Beal
,
P.
Barrow
,
D.
Maskell
,
I.
McConnell
.
2005
.
Cytokine and chemokine responses associated with clearance of a primary Salmonella enterica serovar Typhimurium infection in the chicken and in protective immunity to rechallenge.
Infect. Immun.
73
:
5173
5182
.
66.
Setta
A. M.
,
P. A.
Barrow
,
P.
Kaiser
,
M. A.
Jones
.
2012
.
Early immune dynamics following infection with Salmonella enterica serovars Enteritidis, Infantis, Pullorum and Gallinarum: cytokine and chemokine gene expression profile and cellular changes of chicken cecal tonsils.
Comp. Immunol. Microbiol. Infect. Dis.
35
:
397
410
.
67.
Kogut
M. H.
,
R. J.
Arsenault
.
2017
.
Immunometabolic phenotype alterations associated with the induction of disease tolerance and persistent asymptomatic infection of Salmonella in the chicken intestine.
Front. Immunol.
8
:
372
.
68.
Kogut
M. H.
,
C. L.
Swaggerty
,
J. A.
Byrd
,
R.
Selvaraj
,
R. J.
Arsenault
.
2016
.
Chicken-specific kinome array reveals that Salmonella enterica serovar Enteritidis modulates host immune signaling pathways in the cecum to establish a persistence infection.
Int. J. Mol. Sci.
17
:
1207
.
69.
Hozé
N.
,
S.
Bonhoeffer
,
R.
Regoes
.
2018
.
Assessing the public health impact of tolerance-based therapies with mathematical models.
PLoS Comput. Biol.
14
:
e1006119
.
70.
Lough
G.
,
A.
Hess
,
M.
Hess
,
H.
Rashidi
,
O.
Matika
,
J. K.
Lunney
,
R. R. R.
Rowland
,
I.
Kyriazakis
,
H. A.
Mulder
,
J. C. M.
Dekkers
,
A.
Doeschl-Wilson
.
2018
.
Harnessing longitudinal information to identify genetic variation in tolerance of pigs to porcine reproductive and respiratory syndrome virus infection.
Genet. Sel. Evol.
50
:
50
.
71.
Lough
G.
,
H.
Rashidi
,
I.
Kyriazakis
,
J. C. M.
Dekkers
,
A.
Hess
,
M.
Hess
,
N.
Deeb
,
A.
Kause
,
J. K.
Lunney
,
R. R. R.
Rowland
, et al
2017
.
Use of multi-trait and random regression models to identify genetic variation in tolerance to porcine reproductive and respiratory syndrome virus.
Genet. Sel. Evol.
49
:
37
.
72.
Palgrave
C. J.
,
L.
Gilmour
,
C. S.
Lowden
,
S. G.
Lillico
,
M. A.
Mellencamp
,
C. B.
Whitelaw
.
2011
.
Species-specific variation in RELA underlies differences in NF-κB activity: a potential role in African swine fever pathogenesis.
J. Virol.
85
:
6008
6014
.
73.
Post
J.
,
E.
Weesendorp
,
M.
Montoya
,
W. L.
Loeffen
.
2017
.
Influence of age and dose of African swine fever virus infections on clinical outcome and blood parameters in pigs.
Viral Immunol.
30
:
58
69
.
74.
Netherton
C. L.
,
S.
Connell
,
C. T. O.
Benfield
,
L. K.
Dixon
.
2019
.
The genetics of life and death: virus-host interactions underpinning resistance to African swine fever, a viral hemorrhagic disease.
Front. Genet.
10
:
402
.
75.
Zanella
R.
,
M. L.
Settles
,
S. D.
McKay
,
R.
Schnabel
,
J.
Taylor
,
R. H.
Whitlock
,
Y.
Schukken
,
J. S.
Van Kessel
,
J. M.
Smith
,
H. L.
Neibergs
.
2011
.
Identification of loci associated with tolerance to Johne’s disease in Holstein cattle.
Anim. Genet.
42
:
28
38
.
76.
Canive
M.
,
G.
Badia-Bringué
,
P.
Vázquez
,
J. M.
Garrido
,
R. A.
Juste
,
A.
Fernandez
,
O.
González-Recio
,
M.
Alonso-Hearn
.
2022
.
A genome-wide association study for tolerance to paratuberculosis identifies candidate genes involved in DNA packaging, DNA damage repair, innate immunity, and pathogen persistence.
Front. Immunol.
13
:
820965
.
77.
Doeschl-Wilson
A. B.
,
B.
Villanueva
,
I.
Kyriazakis
.
2012
.
The first step toward genetic selection for host tolerance to infectious pathogens: obtaining the tolerance phenotype through group estimates.
Front. Genet.
3
:
265
.
78.
Rausher
M. D.
2001
.
Co-evolution and plant resistance to natural enemies.
Nature
411
:
857
864
.
79.
van der Most
P. J.
,
B.
de Jong
,
H. K.
Parmentier
,
S.
Verhulst
.
2011
.
Trade-off between growth and immune function: a meta-analysis of selection experiments.
Funct. Ecol.
25
:
74
80
.
80.
Bayyari
G. R.
,
W. E.
Huff
,
N. C.
Rath
,
J. M.
Balog
,
L. A.
Newberry
,
J. D.
Villines
,
J. K.
Skeeles
,
N. B.
Anthony
,
K. E.
Nestor
.
1997
.
Effect of the genetic selection of turkeys for increased body weight and egg production on immune and physiological responses.
Poult. Sci.
76
:
289
296
.
81.
Koenen
M. E.
,
A. G.
Boonstra-Blom
,
S. H.
Jeurissen
.
2002
.
Immunological differences between layer- and broiler-type chickens.
Vet. Immunol. Immunopathol.
89
:
47
56
.
82.
Zerjal
T.
,
S.
Härtle
,
D.
Gourichon
,
V.
Guillory
,
N.
Bruneau
,
D.
Laloë
,
M.-H.
Pinard-van der Laan
,
S.
Trapp
,
B.
Bed’hom
,
P.
Quéré
.
2021
.
Assessment of trade-offs between feed efficiency, growth-related traits, and immune activity in experimental lines of layer chickens.
Genet. Sel. Evol.
53
:
44
.
83.
Nakov
D.
,
S.
Hristov
,
B.
Stankovic
,
F.
Pol
,
I.
Dimitrov
,
V.
Ilieski
,
P.
Mormede
,
J.
Hervé
,
E.
Terenina
,
B.
Lieubeau
, et al
2019
.
Methodologies for assessing disease tolerance in pigs.
Front. Vet. Sci.
5
:
329
.
84.
Simianer
H.
,
H.
Solbu
,
L. R.
Schaeffer
.
1991
.
Estimated genetic correlations between disease and yield traits in dairy cattle.
J. Dairy Sci.
74
:
4358
4365
.
85.
Van Dorp
T. E.
,
J. C. M.
Dekkers
,
S. W.
Martin
,
J. P. T. M.
Noordhuizen
.
1998
.
Genetic parameters of health disorders, and relationships with 305-day milk yield and conformation traits of registered Holstein cows.
J. Dairy Sci.
81
:
2264
2270
.
86.
Williamson
J. F.
,
H. T.
Blair
,
D. J.
Garrick
,
W. E.
Pomroy
,
P. G. C.
Douch
,
R. S.
Green
,
H. V.
Simpson
.
1995
.
Parasitism and production in fleece‐weight‐selected and control sheep.
N. Z. J. Agric. Res.
38
:
381
387
.
87.
Guy
S. Z.
,
P. C.
Thomson
,
S.
Hermesch
.
2012
.
Selection of pigs for improved coping with health and environmental challenges: breeding for resistance or tolerance?
Front. Genet.
3
:
281
.
88.
Ponce
D. M.
,
A. M.
Alousi
,
R.
Nakamura
,
K. S.
Sandhu
,
J. N.
Barker
,
J.
Shia
,
X.
Yan
,
W. L.
Daley
,
G.
Moore
,
S.
Fatmi
, et al
2020
.
A phase 2 study of F-652, a novel tissue-targeted recombinant human interleukin-22 (IL-22) dimer, for treatment of newly diagnosed acute GVHD of the lower GI tract [abstract].
Biol. Blood Marrow Transplant.
26
:
S51
S52
.
89.
Mühl
H.
,
P.
Scheiermann
,
M.
Bachmann
,
L.
Härdle
,
A.
Heinrichs
,
J.
Pfeilschifter
.
2013
.
IL-22 in tissue-protective therapy.
Br. J. Pharmacol.
169
:
761
771
.
90.
Veiga-Parga
T.
,
A.
Suryawanshi
,
B. T.
Rouse
.
2011
.
Controlling viral immuno-inflammatory lesions by modulating aryl hydrocarbon receptor signaling.
PLoS Pathog.
7
:
e1002427
.
91.
Regoes
R. R.
,
P. J.
McLaren
,
M.
Battegay
,
E.
Bernasconi
,
A.
Calmy
,
H. F.
Günthard
,
M.
Hoffmann
,
A.
Rauch
,
A.
Telenti
,
J.
Fellay
;
Swiss HIV Cohort Study
.
2014
.
Disentangling human tolerance and resistance against HIV.
PLoS Biol.
12
:
e1001951
.
92.
Guabiraba
R.
,
A. G.
Besnard
,
R. E.
Marques
,
I.
Maillet
,
C. T.
Fagundes
,
T. M.
Conceição
,
N. M.
Rust
,
S.
Charreau
,
I.
Paris
,
J. C.
Lecron
, et al
2013
.
IL-22 modulates IL-17A production and controls inflammation and tissue damage in experimental dengue infection.
Eur. J. Immunol.
43
:
1529
1544
.
93.
Maurer
K.
,
T.
Reyes-Robles
,
F.
Alonzo
III
,
J.
Durbin
,
V. J.
Torres
,
K.
Cadwell
.
2015
.
Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin.
Cell Host Microbe
17
:
429
440
.
94.
Li
Z.
,
A. G.
Peres
,
A. C.
Damian
,
J.
Madrenas
.
2015
.
Immunomodulation and disease tolerance to Staphylococcus aureus.
Pathogens
4
:
793
815
.
95.
Athale
J.
,
A.
Ulrich
,
N. C.
MacGarvey
,
R. R.
Bartz
,
K. E.
Welty-Wolf
,
H. B.
Suliman
,
C. A.
Piantadosi
.
2012
.
Nrf2 promotes alveolar mitochondrial biogenesis and resolution of lung injury in Staphylococcus aureus pneumonia in mice.
Free Radic. Biol. Med.
53
:
1584
1594
.
96.
Maier
B. B.
,
A.
Hladik
,
K.
Lakovits
,
A.
Korosec
,
R.
Martins
,
J. B.
Kral
,
I.
Mesteri
,
B.
Strobl
,
M.
Müller
,
U.
Kalinke
, et al
2016
.
Type I interferon promotes alveolar epithelial type II cell survival during pulmonary Streptococcus pneumoniae infection and sterile lung injury in mice.
Eur. J. Immunol.
46
:
2175
2186
.
97.
Murapa
P.
,
M. R.
Ward
,
S. K.
Gandhapudi
,
J. G.
Woodward
,
S. E.
D’Orazio
.
2011
.
Heat shock factor 1 protects mice from rapid death during Listeria monocytogenes infection by regulating expression of tumor necrosis factor alpha during fever.
Infect. Immun.
79
:
177
184
.
98.
Chevillard
C.
,
J. P. S.
Nunes
,
A. F.
Frade
,
R. R.
Almeida
,
R. P.
Pandey
,
M. S.
Nascimento
,
J.
Kalil
,
E.
Cunha-Neto
.
2018
.
Disease tolerance and pathogen resistance genes may underlie Trypanosoma cruzi persistence and differential progression to Chagas disease cardiomyopathy.
Front. Immunol.
9
:
2791
.
99.
Herbert
D. R.
,
C.
Hölscher
,
M.
Mohrs
,
B.
Arendse
,
A.
Schwegmann
,
M.
Radwanska
,
M.
Leeto
,
R.
Kirsch
,
P.
Hall
,
H.
Mossmann
, et al
2004
.
Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology.
Immunity
20
:
623
635
.
100.
Majer
O.
,
C.
Bourgeois
,
F.
Zwolanek
,
C.
Lassnig
,
D.
Kerjaschki
,
M.
Mack
,
M.
Müller
,
K.
Kuchler
.
2012
.
Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
PLoS Pathog.
8
:
e1002811
.
101.
De Luca
A.
,
A.
Carvalho
,
C.
Cunha
,
R. G.
Iannitti
,
L.
Pitzurra
,
G.
Giovannini
,
A.
Mencacci
,
L.
Bartolommei
,
S.
Moretti
,
C.
Massi-Benedetti
, et al
2013
.
IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis.
PLoS Pathog.
9
:
e1003486
.
102.
Matsuu
A.
,
T.
Kobayashi
,
T.
Patchimasiri
,
T.
Shiina
,
S.
Suzuki
,
K.
Chaichoune
,
P.
Ratanakorn
,
Y.
Hiromoto
,
H.
Abe
,
S.
Parchariyanon
,
T.
Saito
.
2016
.
Pathogenicity of genetically similar, H5N1 highly pathogenic avian influenza virus strains in chicken and the differences in sensitivity among different chicken breeds.
PLoS One
11
:
e0153649
.
103.
Perlas
A.
,
J.
Argilaguet
,
K.
Bertran
,
R.
Sánchez-González
,
M.
Nofrarías
,
R.
Valle
,
A.
Ramis
,
M.
Cortey
,
N.
Majó
.
2021
.
Dual host and pathogen RNA-seq analysis unravels chicken genes potentially involved in resistance to highly pathogenic avian influenza virus infection. [Published erratum appears in 2022 Front. Immunol. 13: 939849.]
Front. Immunol.
12
:
800188
.
104.
Duangjinda
M.
,
Y.
Jindatajak
,
W.
Tipvong
,
J.
Sriwarothai
,
V.
Pattarajinda
,
S.
Katawatin
,
W.
Boonkum
.
2013
.
Association of BoLA-DRB3 alleles with tick-borne disease tolerance in dairy cattle in a tropical environment.
Vet. Parasitol.
196
:
314
320
.
105.
O’Gorman
G. M.
,
S. D. E.
Park
,
E. W.
Hill
,
K. G.
Meade
,
P. M.
Coussens
,
M.
Agaba
,
J.
Naessens
,
S. J.
Kemp
,
D. E.
MacHugh
.
2009
.
Transcriptional profiling of cattle infected with Trypanosoma congolense highlights gene expression signatures underlying trypanotolerance and trypanosusceptibility.
BMC Genomics
10
:
207
.
106.
Glass
E. J.
2012
.
The molecular pathways underlying host resistance and tolerance to pathogens.
Front. Genet.
3
:
263
.
107.
Hayward
A. D.
,
P. J.
Skuce
,
T. N.
McNeilly
.
2021
.
Tolerance of liver fluke infection varies between breeds and producers in beef cattle.
Animal
15
:
100126
.
108.
Hayward
A. D.
,
D. H.
Nussey
,
A. J.
Wilson
,
C.
Berenos
,
J. G.
Pilkington
,
K. A.
Watt
,
J. M.
Pemberton
,
A. L.
Graham
.
2014
.
Natural selection on individual variation in tolerance of gastrointestinal nematode infection.
PLoS Biol.
12
:
e1001917
.

The author has no conflicts of interest to disclose.

This article is distributed under the terms of the CC BY-NC 4.0 Unported license.