The central focus of my research is cellular immunology and regulation pathways, particularly the mechanisms of antigen presentation to T cells through MHC class I proteins. We extended this investigation field to understand the immune mechanisms underpinning bacterial and viral infections. Recently, we initiated a collaborative research focused on the regulation of inflammation during SARS-CoV-2 infection. The pathologic consequences of severe COVID-19 caused by SARS-CoV-2 include elevated inflammatory responses and dysregulated vascular function associated with thrombosis. This pathology is exacerbated by comorbidities such as diabetes, which is a major risk factor and increases COVID-19 mortality. Our current research is focused on the molecular pathways mediating the pathological outcome of SARS-CoV-2 infection including interactions of hemopoietic cells with endothelium during COVID-19 with or without co-existing diabetes. Host defense mechanisms to viral infections are mainly regulated via interferon responses. Induction of STAT signaling upon SARS-CoV-2 infection down-regulates the function of ACE2 and concomitantly up-regulates activities of CD147 and GRP78 pathways. The latter two components, respectively, are broad key regulators mediating thrombosis, angiogenesis, and endothelial performance. Both SARS-CoV-2 infection and diabetes- affect the ACE2, CD147, and GRP78 signaling pathways. Importantly, CD147 and GRP78 pathways are ubiquitous to many hemopoietic cells, including CD169+ macrophages that are involved in inflammation. Our pilot findings implicate dysregulated expression of these pathways and downstream signaling in SARS-CoV-2-infected macrophages that may contribute to aberrant macrophage-endothelial cell interactions and subsequent thrombosis. This hypothesis is currently tested in a hamster model of pulmonary SARS-CoV-2 infection with or without induced comorbidities. The ultimate goals are to identify the mediators of vascular disease in COVID-19 and diabetes that will provide novel therapeutic targets and biomarkers.
- Title
- Professor
- bushkiyu@njms.rutgers.edu