UC Riverside

The interaction between the host genetic factors and viral entry mechanisms is crucial in understanding the pathogenesis of infectious diseases such as COVID-19. This thesis explores the role of the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene in regulating the expression of ACE2, the entry receptor for SARS-CoV-2, and its impact on the virus's ability to infect host cells. Utilizing variant Caco-2 BBe epithelial cell lines, including wild type, knock-in, and knock-out models, we examined the effects of PTPN2 deficiency on ACE2 expression and subsequent viral entry efficiency.Our findings demonstrate that PTPN2 deficiency leads to increased ACE2 expression, enhancing SARS-CoV-2 uptake in both intestinal and lung epithelial cells, suggesting a heightened vulnerability to infection in the absence of functional PTPN2. This was complemented by analysis of mucosal biopsy samples from IBD patients, providing a clinical perspective on the genetic modulation of ACE2 expression. Moreover, our study delves into the interaction between PTPN2 and the immune response, particularly the role of interferons and STAT1/3 signaling pathways, revealing that interferon-γ treatment further increases ACE2 levels in PTPN2-deficient cells, exacerbating the susceptibility to viral entry. This thesis underscores the significance of PTPN2 as a key genetic factor in the host's susceptibility to SARS-CoV-2, offering insights into the molecular mechanisms at play and suggesting potential strategies for personalized treatment approaches in viral infections.