Doctor of Philosophy, The Ohio State University, 2022, Molecular, Cellular and Developmental Biology

Many viral species are known to infect the human heart and drive cardiovascular disease. Through a combination of directly damaging cardiac tissue and driving excessive inflammation, cardiac viruses can cause heart failure, an irreversible disease with high prevalence, cost, and morbidity. Virus-induced heart failure is an underappreciated problem, and treatment strategies are lacking. Understanding the molecular mechanisms through which the heart responds to viral infection and through which viruses exert their pathological effects could aid in the development of future therapeutics. We have identified the protein brain expressed x-linked 1 (BEX1) as a regulator of cardiac immune function, and here we characterize its role during viral infection of the heart. Using a combination of BEX1 gain- and loss-of-function mouse models as well as cell culture systems, we have demonstrated an antiviral and cardioprotective role of BEX1 during infection. BEX1 lossof-function mice infected with a cardiotropic virus experience greater viral replication, greater virus-induced reductions in cardiac function, and greater virus-induced cardiac fibrosis. Mice lacking BEX1 are also unable to recruit immune cells to the infected myocardium as efficiently as control mice. Mechanistically, it appears that BEX1 regulates several key molecular pathways involved in antiviral immunity and inflammation, including interferon beta and nuclear factor kappa B pathways. Overall, we have found that BEX1 is a novel antiviral factor that plays an important role in protecting the heart from infection.

Committee: Federica Accornero (Advisor); Shyam Bansal (Committee Member); Guramrit Singh (Committee Member); Karin Musier-Forsyth (Committee Member) Subjects: Biology; Virology

Doctor of Philosophy in Regulatory Biology, Cleveland State University, 2007, College of Science

Background: This project examined JAK-STAT pathway activation in two mouse models of cardiac hypertrophy: autoimmune myocarditis and pressure overload (PO). Methods: Myocarditis was induced with cardiac myosin; PO was induced by transverse aortic constriction. STAT1, 3, and 5 binding was assessed by gel shift. STATs, JAKs, SERCA2A, and calsequestrin (CSQ) were quantified. In myocarditis, P-STAT3 localization to cardiac myocyte nuclei was ascertained, and plasma IL-6 and ventricular ANF mRNA were analyzed. Results: In myocarditis, STAT3/3 and STAT1/1 activation, inflammation, increased ventricle weight (P < 0.0001), and ANF mRNA (P = 0.005) occurred on days 14, 21, and 28. In PO, activation appeared on day 7 and persisted to failure. P-STAT3 increased (myocarditis, P < 0.0001; pressure overload, P < 0.05). P-JAK1 increased in myocarditis on days 21 and 28 (P < 0.007). In PO, CSQ and SERCA2A levels did not differ, but in myocarditis CSQ decreased (P = 0.02). In myocarditis, a biphasic elevation in plasma IL-6 occurred (P = 0.003). Conclusions: Although JAK-STAT signaling is activated in both models, it occurs earlier in PO and persists to heart failure, whereas in myocarditis it declines to basal levels as inflammation and plasma IL-6 return to baseline.

Committee: Christine Moravec (Advisor) Subjects: