Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling to control interferon response

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS‐STING and RIG‐I‐MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases

Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion

Summary: Type I interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, the role of IFN-I in SARS-CoV-2 infection remains perplexing. Here, we develop two mouse models, one with constitutively high IFN-I response (hACE2; Irgm1−/−) and the other with dampened IFN-I response (hACE2; Ifnar1−/−), to comprehend the role of IFN-I response. We report that hACE2; Irgm1−/− mice are resistant to lethal SARS-CoV-2 infection. In contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, cytokine storm, and enhanced pathology is observed in the lungs and brain of hACE2; Ifnar1−/− mice. The hACE2; Irgm1−/−Ifnar1−/− double-knockout mice display loss of the protective phenotype observed in hACE2; Irgm1−/− mice, suggesting that heightened IFN-I response accounts for the observed immunity. Taking the results together, we demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2

Hexachlorocyclohexane-degrading bacterial strains Sphingomonas paucimobilis B90A, UT26 and Sp+, having similar lin genes, represent three distinct species, Sphingobium indicum sp. nov., Sphingobium japonicum sp. nov. and Sphingobium francense sp. nov., and reclassification of [Sphingomonas] chungbukensis as Sphingobium chungbukense comb. nov.

Three strains of Sphingomonas paucimobilis, B90A, UT26 and Sp+, isolated from different geographical locations, were found to degrade hexachlorocyclohexane. Phylogenetic analysis based on 16S rRNA gene sequences indicated that these strains do not fall in a clade that includes the type strain, Sphingomonas paucimobilis ATCC 29837T, but form a coherent cluster with [Sphingomonas] chungbukensis IMSNU 11152T followed by Sphingobium chlorophenolicum ATCC 33790T. The three strains showed low DNA–DNA relatedness values with Sphingomonas paucimobilis ATCC 29837T (8–25 %), [Sphingomonas] chungbukensis IMSNU 11152T (10–17 %), Sphingobium chlorophenolicum ATCC 33790T (23–54 %) and Sphingomonas xenophaga DSM 6383T (10–28 %), indicating that they do not belong to any of these species. Although the three strains were found to be closely related to each other based on 16S rRNA gene sequence similarity (99·1–99·4 %), DNA–DNA relatedness (19–59 %) and pulsed-field gel electrophoresis (PFGE) patterns indicated that they possibly represent three novel species of the genus Sphingobium. The three strains could also be readily distinguished by biochemical tests. The three strains showed similar polar lipid profiles and contained sphingoglycolipids. The strains differed from each other in fatty acid composition but contained the predominant fatty acids characteristic of other Sphingobium species. A phylogenetic study based on 16S rRNA gene sequences showed that [Sphingomonas] chungbukensis IMSNU 11152T formed a cluster with members of the genus Sphingobium. Based on these results, it is proposed that strains B90A, UT26 and Sp+, previously known as Sphingomonas paucimobilis, are the type strains of Sphingobium indicum sp. nov. (=MTCC 6364T=CCM 7286T), Sphingobium japonicum sp. nov. (=MTCC 6362T=CCM 7287T) and Sphingobium francense sp. nov. (=MTCC 6363T=CCM 7288T), respectively. It is also proposed that [Sphingomonas] chungbukensis be transferred to Sphingobium chungbukense comb. nov