Interplay of CMV with cellular pathways, states and cell types

Objective

The herpesvirus human cytomegalovirus (HCMV), the largest known human virus, is a ubiquitous pathogen that infects the majority of the world's population. Although subclinical in most healthy individuals, HCMV can lead to a severe congenital disease, as well as morbidity and mortality in immunocompromised adults. Despite the high prevalence and pathogenicity of HCMV, numerous fundamental questions about this pathogen remain open. We still do not know what many of its viral proteins do and how they modulate cellular processes, we do not understand the determinants that govern dependencies and vulnerabilities of infection in different cell types, and we are missing tools that facilitate molecular dissection of HCMV in relevant infection models. In this proposal, we plan to develop and apply unique tool sets to uncover the host pathways and factors that orchestrate HCMV life cycle in different cell types and in higher complexity infection models. We propose to combine state-of-the-art high-throughput tools with mechanistic studies to comprehensively characterize how HCMV proteins perturb central host cellular processes (aim 1), identify HCMV common and cell-specific host dependencies and vulnerabilities in different cell types (aim 2) and develop an advanced platform for probing CMV dependencies in organoid and organism infection models (aim 3). The knowledge generated from these objectives will provide a comprehensive depiction of the interplay of HCMV with its host and could help expand our therapeutic options. More broadly, with its comprehensive and complementary approaches, our work will provide a paradigm for understanding complex host-pathogen interactions.