Immunology And Pathology Of Acute and Chronic Murine Leukemia Virus Infections

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

In FY2022 the Retroviral Immunology Section expanded on previous studies identifying the first checkpoint response triggered during innate immunity to a pathogen. Briefly, immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, which we hypothesized was to to limit inflammation and prevent immunopathogenic responses. Studies using CD47 blockade in Ebola virus infections of mice proved this hypothesis to be true, particularly in infections such as Ebola virus that naturally promote inflammatory responses and cytokine cascades (Rao et al. Antiviral Res 197, 105226. https://doi.org/10.1016/j.antiviral.2021.105226). Additional studies on CD47 blockade, which is used to therapeutically enhance tumor killing in human clinical trials, showed that CD47 Blockade Leads to Chemokine-Dependent Monocyte Infiltration and Loss of B Cells from the Splenic Marginal Zone. This is important information as it demonstrates that CD47-SIRP interactions help maintain homeostatic lymphocyte levels, particularly splenic marginal zone B cells (Yiu et al. J Immunol 208, 1371-1377. https://doi.org/10.4049/jimmunol.2100352). We also finished a collaboration with the Santiago lab showing differential interferon subtype responses to SARS-CoV-2 infections. The study identifies the most successful interferons for inhibiting SARS-CoV-2 in vitro. Our data also revealed increased interferon resistance in emerging SARS-CoV-2 variants, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution (Guo et al. Proc Natl Acad Sci U S A 119, e2203760119. https://doi.org/10.1073/pnas.2203760119)