Top Reads

African swine fever virus (ASFV), a member of Asfarviridae, is a large dsDNA virus that can infect domestic pigs through direct contact with other infected pigs or through tick-borne transmission. ASFV is endemic to sub-Saharan Africa, but has caused devastating fatal outbreaks in domestic pigs in Asia and Europe. Recent studies have shown that ASFV strains associated with outbreaks can inhibit the type I IFN pathway by targeting the cyclic GMP–AMP synthase (cGAS)-STING DNA sensing pathway. In this Top Read, Li et al. (p. 1844) identified the ASFV MGF-505-7R protein as a negative regulator of cGAS–STING signaling through its direct interaction with STING. MGF-505-7R can also upregulate expression of the autophagy-related protein ULK1, which can degrade STING. MGF-505-7R–deficient ASFV was associated with increased IFN-β production relative to wild-type (WT) ASFV, and MGF-505-7R–deficient ASFV resulted in an attenuated response in pigs compared with its WT counterpart. These findings demonstrate how MGF-505-7R targets the cGAS–STING pathway and provide a strategy for the potential development of an attenuated, vaccine-strain virus.

Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease found in the mitochondrial matrix. CLPP functions as a proteolytic subunit that can cleave damaged or misfolded peptides and proteins. CLPP null mice (CLPP-knockout [KO]) share phenotypic similarities with individuals who suffer from Perrault syndrome, and previous studies have shown that CLPP-KO mice have an elevated antiviral gene signature suggestive of steady-state innate immune system activation. In this Top Read, Torres-Odio et al. (p. 1890) show that IFN-I signaling in CLPP-KO mice requires cGAS–STING signaling. Deletion of STING or the IFN-α/β receptor in CLPP-KO murine embryo fibroblasts was associated with a reduction in antiviral gene expression, including IFN-stimulated genes, and reduced protection against RNA or DNA virus infection. CLPP-KO cells also showed greater mitochondrial DNA (mtDNA) instability, indicating that mtDNA release is a key driver of IFN-I responses in CLPP-KO mice. Taken together, these results suggest that cGAS–STING–IFN-I signaling occurs downstream of CLPP and may explain immunopathologies associated with CLPP dysregulation.

Regulatory T cells (Tregs) have critical roles in suppressing undesirable immune responses, and are being considered for therapeutic applications to manage autoimmune diseases or transplant rejection. Strategies are needed for ex vivo expansion of Tregs, and one approach includes stimulating Tregs with a TNF receptor 2 (TNFR2) agonist. A previous study described the generation of a TNF mutant, R2agoTNF, which is a TNFR2-specific agonist for mice. In this Top Read, Inoue et al. (p. 1740) show that R2agoTNF treatment can selectively induce expansion and activation of mouse Tregs. The agonist was optimized through structural modifications, either by internal covalent cross-linking or by creating an IgG-Fc fusion (scR2agoTNF-Fc), improving Treg expansion both ex vivo and in vivo. In addition, mice treated with scR2agoTNF-Fc were better protected from contact hypersensitivity. These data suggest that a TNFR2-selective agonist may be a potential approach for the expansion of functional Tregs.

Neutrophils are a key immune cell population that drive inflammatory responses, and there is great interest in developing targeted therapies that can block neutrophil activation. In this Top Read, Chen et al. (p. 1858) describe a high-throughput–enabled drug screening assay to identify such candidates. They constructed a C57BL/6 reporter mouse that was engineered to have the DsRed reporter gene expressed under control of the IL-1β promoter, as this cytokine is readily released by neutrophils under inflammatory conditions. The authors screened a library of FDA-approved drugs and identified pinaverium bromide (PVB) as the most potent inhibitor of IL-1–driven neutrophil activation in response to LPS or cecal slurry challenge. PVB was effective in limiting neutrophil responses to LPS challenge when given prophylactically or therapeutically, limiting liver and lung-associated inflammation. PVB also inhibited respiratory bursts and neutrophil migration, impairing phenotypic shifts associated with neutrophil priming. Together, these data point to PVB as a potential therapeutic candidate for limiting neutrophil-driven inflammation.