Interplay of CMV with cellular pathways, states and cell types

Introduction

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.

Research Gaps

Despite the high prevalence and pathogenicity of HCMV, numerous fundamental questions about this pathogen remain open. Key areas of uncertainty include:

• The functions of many viral proteins and how they modulate cellular processes.
• The determinants that govern dependencies and vulnerabilities of infection in different cell types.
• The lack of tools that facilitate molecular dissection of HCMV in relevant infection models.

Proposal Overview

In this proposal, we plan to develop and apply unique tool sets to uncover the host pathways and factors that orchestrate the HCMV life cycle in different cell types and in higher complexity infection models.

Research Aims

We propose to combine state-of-the-art high-throughput tools with mechanistic studies to achieve the following aims:

1. Characterize HCMV Proteins: Comprehensively characterize how HCMV proteins perturb central host cellular processes (aim 1).
2. Identify Host Dependencies: Identify HCMV common and cell-specific host dependencies and vulnerabilities in different cell types (aim 2).
3. Develop Advanced Platforms: Develop an advanced platform for probing CMV dependencies in organoid and organism infection models (aim 3).

Expected Outcomes

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.

Broader Impact

More broadly, with its comprehensive and complementary approaches, our work will provide a paradigm for understanding complex host-pathogen interactions.