Cytomegalovirus (CMV) is a ubiquitous herpesvirus that establishes a systemic, persistent infection. CMV rarely causes serious disease in humans because systemic, life-long immune surveillance keeps the virus in check. In fact, CMV stimulates the largest known T cell populations in the circulation of humans. These T cells accumulate over time in a process called "memory inflation" and control CMV by shutting down viral reactivation from latency. For these reasons, CMV may serve as a tool for new vaccines against diseases such as cancer and HIV. However, CMV can cause devastating disease in a developing fetus when the virus is transmitted to a pregnant woman. Thus, a vaccine to prevent CMV transmission is rated as a highest priority by the Institute of Medicine. Understanding immune surveillance at sites of viral shedding will be key to preventing transmission and CMV disease. Recent work has shown that a T cell population called "resident memory" T cells (TRM) are established at sites in the body that may face viral reactivation. Indeed, TRM cells may help control herpesvirus reactivation. However, there have been no studies of CMV-specific TRM cells. Using the natural mouse herpesvirus, murine (M)CMV, our data show that many MCMV-specific TRM cells developed in the salivary and mammary glands - two sites from which HCMV and MCMV are known to be shed. More broadly, the salivary and mammary glands are two sites from which several human herpesviruses are shed. The ontogeny and function of TRM cells is poorly defined, and this gap is critical because these T cells are best positioned and possibly critical for controlling herpesvirus reactivation. Moreover, the promotion of such "first responders" - cells positioned at the site of pathogen invasion - is the major advantage of CMV- vectored vaccines.
Aim 1 : We will determine whether MCMV-specific TRM cells control viral latency and whether vaccines that elicit TRM formation will limit viral replication.
Aim 2 : Both repeated antigen recognition and the local cytokine environment are thought to modulate TRM development. Critically, infection with a spread-defective ?gL-MCMV, which can not spread to the salivary gland, increased the formation of salivary gland MCMV-specific TRM cells, implying that viral replication or repeated antigen recognition by T cells antagonizes TRM development. We will distinguish between these possibilities using a series of recombinant viruses.
Aim 3 : Our preliminary data show that memory inflation in circulation is driven by a competition for viral antigen. T cells that successfully compete, inflate;those that fail to compete do not. Remarkably, our data suggest that MCMV-specific TRM cells were enriched for T cells that do not undergo memory inflation. Thus, we will determine whether T cells that fail to compete for MCMV antigen are preferentially enriched in the TRM pool. Together, these experiments will determine the ontogeny and function of MCMV-specific TRM cells that reside at these critical mucosal sites of herpesvirus shedding.

Public Health Relevance

Cytomegalovirus is a herpesvirus that persists and is periodically shed from mucosal surfaces. Using the natural mouse pathogen murine (M)CMV, we found that many T cells in the salivary and mammary glands, both sites of viral shedding, developed into resident memory T cells, which are thought to provide a first line-of-defense against viral reactivation. The experiments in this proposal will investigate the maintenance of these resident T cells and their ability to control MCMV at these critical sites of shedding.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106810-01A1
Application #
8651139
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Beisel, Christopher E
Project Start
2014-01-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$163,913
Indirect Cost
$58,163
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Smith, Corinne J; Turula, Holly; Snyder, Christopher M (2014) Systemic hematogenous maintenance of memory inflation by MCMV infection. PLoS Pathog 10:e1004233