PROJECT SUMMARY/ABSTRACT The role that chronic viral infection plays in shaping the immune system and responses to subsequent infections is critically important but understudied. It is estimated that >80% of adults harbor at least 5 latent herpesviruses. Gammaherpesviruses establish latency in immune cells, further highlighting the importance of understanding how latency impacts host immune responses to subsequent infections. Currently there is a substantial knowledge gap in the role played by latency and/or mechanisms by which prior gammaherpesvirus infection contributes to subsequent immune responses, particularly in the lung. Despite the known deleterious effects of herpesvirus infection on human health, emerging evidence suggests the possibility the latent herpesvirus infection may actually protect from secondary infections. Therefore, to uncover key mechanisms by which latency impacts subsequent immune responses, I propose the following: I will test the premise that gammaherpesvirus latency impacts host protection during subsequent pulmonary infections that are prevalent across Kingdoms and dissect how latently infected immune cells intrinsically respond to heterologous pathogens. I will also delineate the impact of the microbiota on establishment and maintenance of herpesvirus latency given the critical impact of the microbiota on immune responses and the broad use of potent antibiotics in medical practice. These distinct but equally important directives will fill key knowledge gaps. At the completion, I expect to define the role of latency and reactivation on human immune responsiveness and develop a framework to define how the balance between microbiota and secondary infections are informed by latency. Moreover, this study is clinically relevant and fundamentally significant as these findings have the potential to define novel mechanisms and pathways important for pathogen control and tissue repair. In alignment with the Stephen I. Katz funding mechanism, this proposal represents a new direction for my research program. While I have previously studied cytokine regulation of herpesvirus latency during my doctoral thesis and identified protective microbial metabolites in pulmonary infection as a postdoctoral fellow, I have not investigated how viral latency intrinsically impacts immune cell function during secondary pulmonary infections or how the microbiota influences the establishment and maintenance of latency. This new investigation will require acquisition of novel tools and technologies that will reshape my research program and enhance its scope and impact. I am perfectly positioned to direct and execute this unique line of investigation as I have expertise across multiple relevant domains including virology, microbiology, immunology, and critical care medicine. Additionally as an Early Stage Investigator, I have established collaborations with experts across diverse domains of microbial pathogenesis.