Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
Autophagy is an evolutionarily conserved process to catabolize cytoplasmic proteins and organelles1, 2. During starvation, the target of rapamycin (TOR), a nutrient-responsive kinase, is inhibited, thereby inducing autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of autophagosome cargo in autolysosomes3-5, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly defined. Here we show that mTOR signaling is inhibited during autophagy initiation, but reactivated with prolonged starvation. mTOR reactivation is autophagy-dependent, and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell – a process we identify in multiple animal species. Thus, an evolutionarily-conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation.
A key question in mammalian immunology is how CD4+CD25+Foxp3+ regulatory T cells (Tregs) suppress immune responses. Here we show that Tregs induce apoptosis of effector CD4+ T cells in vitro and in a mouse inflammatory bowel disease (IBD) model without affecting their early activation or proliferation. They also induced Foxp3 expression in Tresps that resisted death in vitro. Common gamma chain cytokines reversed Treg‐induced apoptosis. Death required Bcl‐2 interacting mediator of cell death (BIM) and Akt1/Protein Kinase‐B induced dephosphorylation of the bcl‐2 antagonist of cell death (BAD) protein. Thus, cytokine deprivation induced apoptosis is a prominent event in Treg‐inhibition of T cell responses.
This work was supported by the intramural research program of NIAID, NIH. P.P is supported by a National Academy of Sciences/National Research Council fellowship.
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