# Cytomegalovirus DNA Replication and Inversion

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $385,908

## Abstract

This project focuses on the interplay of cytomegalovirus (CMV)-encoded immunomodulators and host defense
pathways that control the initial stages of viral infection within the natural host. These cell-autonomous
pathways dictate parameters of acute infection, such as tissue tropism and dissemination. They also control
establishment of a reservior for life-long persistence and latency and constantly defend against host immune
clearance mechanisms. Importantly, we have shown that herpesviruses such as human (H) or murine (M)
CMV, as well as herpes simplex virus (HSV)1 and HSV2, all employ evolutionarily related cell death
suppressors that block programmed cell death. In MCMV, suppressors prolong infection and enhance spread,
providing a tractable model to elaborate the contribution of specific cellular compartments to the ancient virus-
host arms race that plays out during natural infection. The host pathways we study are conserved in humans
as well as mice, providing key insights that cannot be obtained using HCMV or primate CMV models.
Macrophages are important partners for all CMVs, starting from the initial encounter with virus inoculum,
proceeding with the orchestration of viral dissemination, resulting in the deposition in sites of persistence and
latency, and critical for the reappearence of virus sporadically or as a result of immunosuppression. All of the
insights into murine CMV pathogenesis and latency from the studies we propose will point relevant directions
for studies in human CMV. Our unique approach involves the use of viruses that lack specific cell death
suppressors combined with mice that are deficient in the cognate host defense pathways that these
suppressors target. We propose to move to a new phase of study and dissect the contribution of apoptosis,
necroptosis and other programmed cell death pathways within specific tissue compartments. These studies are
therefore relevant to an expanding range of human pathogens, most immediately HSV and other human
herpesviruses. The specific host defense value of necroptosis has recently emerged along with the fascinating
observation that this and other cell death pathways are interlaced and interdependent. Necroptosis is capable
of completely preventing infection of a naïve host because all exposed cells die within hours of exposure. In
the next period, we will specifically investigate the contribution of serine protease death pathways that were
first brought to light in our studies of HCMV in macrophages. Importantly, the project will determine the
contribution of cell death in monocytes, macrophages, endothelial cells and epithelial cells during natural
infection in mice. As a result, the contribution of specific programmed cell death pathways to all relevant
stages of viral pathogenesis will emerge.

## Key facts

- **NIH application ID:** 10061525
- **Project number:** 5R01AI020211-34
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** EDWARD S. Edward S Mocarski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,908
- **Award type:** 5
- **Project period:** 1984-03-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061525

## Citation

> US National Institutes of Health, RePORTER application 10061525, Cytomegalovirus DNA Replication and Inversion (5R01AI020211-34). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10061525. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*