Project Summary Although largely asymptomatic, human cytomegalovirus (HCMV) can cause severe and even fatal disease in a subset of susceptible individuals. The large genome of HCMV allows it to devote a number of its gene products to optimizing conditions for replication in the host cell and combat cellular stress and antiviral responses. In some cases, HCMV even exploits these responses to promote infection. The host interferon system, consisting of Type I (T1, a, b, e, k, w), II (T2, g) and III (T3, l 1-4) interferons, has evolved to mediate innate antiviral immunity. However, we found that treatment with Type III interferons, which antiviral effects against a number of viruses including influenza and West Nile viruses, actually enhances the spread of HCMV in both fibroblasts and epithelial cells. These in vitro results were confirmed using an animal model for cytomegalovirus. Lower levels of MCMV infection were detected in several organs of mice lacking the IFN-l receptor when compared to wildtype mouse, confirming a role for IFN-l in promoting cytomegalovirus infection and spread. The experiments in this proposal will define the mechanism for IFN-l-dependent enhancement of cytomegalovirus infection using both in vitro and in vivo systems. This will be done in two specific aims. The first aim will define the pathways involved in proviral IFN-l signaling and how they differ from those that confer an antiviral environment. The second aim will delineate the properties of IFN-l during in vivo infection, including defining the cellular source of IFN-l production and identifying the cellular and molecular IFN-l-targets that mediate the proviral effect. Overall, these studies will define the mechanism by which cytomegaloviruses utilize a normally antiviral signaling response to enhance spread. These results will provide the basis for additional studies investigating the potential for therapeutic intervention of this clinically relevant process.
|Effective start/end date||1/21/22 → 12/31/23|
- National Institute of Allergy and Infectious Diseases: $202,950.00
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