Mechanistic interrogation of the role of Type I IFN pathway in protection from SARS-CoV-2 infection in nonhuman primates

$499,999P51FY2022ODNIH

Texas Biomedical Research Institute, San Antonio TX

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Abstract

Summary While Type I IFN responses are a critical anti-viral mechanism, there is a lack of clarity about their role in protecting against or driving severity to COVID-19. In our NHP model of SARS-CoV-2 infection, (RMs) mounted a strong Type I IFN response. Dynamic changes to these robust levels of Type I IFN cytokines correlate strongly with the increase and the decrease in lung compartment viral loads, suggesting that there is a strong early role for this signaling in the control of SARS-CoV-2 infection. Recently, the NHP Reagent Resource funded by the NIH developed a simianized version of a Type I IFN depleting antibody (anifrolumab), which functions well, and which we have validated. We therefore propose to perform mechanistic experiments where the progression of viral infection, disease parameters, and cytokine responses will be compared SARS-CoV-2 infected RMs (n=6, Group 1), with those treated with Type I IFN inhibiting antibody from NHPRR (n=6; Group 2) and those treated with recombinant IFNï¡ molecule (n=6, Group 3). We will compare viral replication, lung pathology and pneumonia and cytokine levels in the three groups of rhesus macaques. Using these experiments, we will be able to definitively address if silencing Type I IFN signaling at the time of infection result in more SARS-CoV-2 replication and progression to COVID-19.

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