Coping with Stress: Rewiring of Host Stress Responses by Human Cytomegalovirus to Redirect Protein Translation

Abstract

Human cytomegalovirus (HCMV) is a highly prevent pathogen with seropositivity ranging from 40-90% in North America, and in excess of 100% in developing nations. Although HCMV infections are often mild to asymptomatic among immunocompetent hosts, HCMV represents a significant cause of morbidity and mortality for those with compromised immune systems. HCMV's systemic dissemination within the host is facilitated by infected blood monocytes. Within monocytes, HCMV establishes a quiescent infection, thus acting as "Trojan horses", delivering the virus to distant end organs all while remaining hidden from innate immune detection. Blood monocytes are inherently short-lived however, with an average lifespan of only 48 h. To circumvent this shortcoming HCMV aberrantly regulates the Akt/mTORC1 signaling axis. Our lab has previously shown that HCMV binding and entering into target monocytes elicits a unique action of Akt, characterized by the preferential phosphorylation at Serine 473 (S473). Critically, downstream substrate specificity of Akt signaling is dictated by the ratio of S473 to threonine 308 phosphorylation, suggesting this unique Akt activation would have biologic significance during infection. The studies of this thesis reveal that a major consequence of HCMV-mediated aberrantly regulated Akt is a robust increase in protein translation through the activation of mTORC1 and its downstream signaling substrates. Moreover, HCMV uniquely usurps the activity of heat shock factor 1 (HSF1) to bypass cellular stress response traditionally intended to limit protein synthesis through the direct interaction between HSF1 and mTOR. The tightly regulated signaling events downstream of Akt and mTORC1 lead to a reshaping of the host translatome to redirect protein synthesis towards antiapoptotic factors necessary for the induction of monocyte survival beyond their canonical 48 h lifespan. Elucidating the molecular mechanisms behind HCMV's control over protein translation may allow for the development of novel therapies that specifically target HCMV-infected monocytes, thus preventing viral dissemination and the establishment of disease.