Novel Cytomegalovirus' Chemokines Contribute to Innate Immune Cell Viral Dissemination

University Of Tennessee Knoxville, Knoxville TN

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Abstract

HCMV is a common opportunistic pathogen in immunocompromised individuals which can lead to severe disease within this population upon systemic dissemination and inflammation. Often-overlooked players in HCMV dissemination are unique HCMV chemokines (chemoattractant cytokines) involved in controlling leukocyte trafficking during innate and adaptive immune responses Our hypothesis is that the HCMV vCXCL-1 chemokine enhances neutrophilic and monocytic responses, which increases viral dissemination kinetics and virulence. Thus, providing a target to decrease HCMV dissemination and subsequent morbidity in immune compromised patients. Aim 1: Determine the differential effects of the virulent Toledo and the less virulent Towne strain vCXCL-1 variants (vCXCL-1Tol vs vCXCL-1Towne) on neutrophil and monocyte physiology. Aim 2: Assess the role of the viral chemokines in viral dissemination and pathogenesis in vivo using the mouse model. 2a. Examine the impact of vCXCL-1Tol and vCXCL-1Towne expression on MCMV pathogenesis and dissemination. 2b. Determine the cell type responsible for differences in dissemination and the importance the CXCR2 chemokine receptor engagement during infection with recombinant MCMVs. 2c. Investigate vCXCL-1?s role in inducing inflammatory responses. Impact: In this R15 proposal we will investigate the role of unique HCMV chemokines on innate cells, which are often-overlooked as important players in HCMV dissemination. During these studies, undergraduate and graduate students will learn cutting edge molecular virology techniques and functional characterization of viral chemokines, at biochemical, cellular, and organismal levels. This will provide an excellent foundation in experimental design, data analysis, and scientific presentations for undergraduates continuing in STEMM disciplines.