Screening for regulators of SARS CoV-2 infection and inflammation

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Cells of the innate immune system, such as dendritic cells and macrophages, constantly patrol host mucosal surfaces and peripheral tissues for signs of infection or injury. Since many people infected with SARS-CoV-2 clear the virus without developing symptoms, aspects of the innate immune response may hold the key to defeating this virus and its variants. In prior work, we investigated how biologically active small molecules can impart modulatory effects in innate immune cells, in some cases, providing extended long-term memory. In a screen of biologically active small molecules for regulators of TNF induction, we identified several compounds with the ability to induce training effects on human macrophages. Among these compounds, a Syk kinase inhibitor (SYKi IV) screen hit promoted an enhanced response to LPS similar to that previously reported for beta-glucan. Moreover, we found that Syk kinase inhibitor-trained macrophages exhibit enhanced cytokine output and resistance to multiple SARS CoV-2 variants, OC43 coronavirus and influenza viral infection. In FY2023, we established a collaboration with Jeffrey Strich in the NIH Clinical Center, as he had a cohort of COVID patients who were treated with the Syk inhibitor fostamatinib. We hypothesized that the patients on fostamatinib may undergo innate immune training that could enhance their response to the viral infection. Accordingly, the fostamatinib treated group showed improved COVID outcomes but it was unclear what aspect of their immune cell profile could underlie this effect. We are using the remainder of our COVID funding to run a combined CITE-seq/ATAC-seq study with the Center for Human Immunology (CHI) using PBMCs from the patient cohort, which we treated ex vivo with LPS. This will allow us to determine if the fostamatinib-trained cells have an enhanced inflammatory output and also how the transcriptional profile of the various immune cell subsets (determined via CITE-seq) correlates with the chromatin-accessibility (from the ATAC seq profiles). Further comparison of the fostamatinib-treated and control groups will allow us to assess potential innate immune training effects imparted by Syk kinase inhibition.