Coxsackieviruses are the commonest infectious cause of acute myocarditis, a disease that causes substantial human morbidity and mortality. Even after the virus has (apparently) been cleared, low- grade inflammation may continue, eventually leading to the serious outcome of dilated cardiomyopathy. There is general agreement that the innate and adaptive host immune responses contribute both to virus control, and to (immunopathological) heart disease. However, our knowledge of coxsackievirus-induced immune responses is rudimentary. In this proposal, using existing and new mouse models of coxsackievirus B3 (CVB3) infection, we shall evaluate the intracardiac effects of type I interferons (T1IFN) on acute and persistent CVB3 infection, and we shall use a unique set of reagents, developed in my laboratory, to assess CVB-specific T cell responses in the hearts of infected mice. There are 3 Specific Aims : 1. The effects of T1IFN in the heart are controversial. Some published work suggests that these innate cytokines may clear virus from the heart, but other work has suggested that they play no role whatsoever within the infected heart. We shall cross two existing mouse strains to develop a new mouse model in which the expression of T1IFN receptor on cardiomyocytes can be ablated at will. These mice will allow us to resolve the above controversy, and to determine if T1IFN is responsible for constraining viral spread in the acutely-infected heart. In addition, by removing this receptor during persistent infection, we shall be able to determine if T1IFN is required for the maintenance of the persistent state. 2. Despite many years of study, our understanding of CVB-specific T cell responses remains minimal. To address this deficiency, my lab has generated a variety of unique reagents including recombinant CVB that expressed well-characterized CD4+ and CD8+ T cell epitopes, and genetically-marked T cells specific for those epitopes. We shall exploit our reagents to investigate the kinetics of CVB- specific CD4+ &CD8+ T cell infiltration in the heart over the course of acute myocarditis, and will determine the extent to which this T cell infiltration is regulated by T1IFN. 3. We also shall use the above reagents to map CVB3 antigen expression within the heart during acute and persistent infection. In which heart cells are antigens expressed? How quickly do antigen- specific CD4+ and CD8+ T cells home to the infected heart at various times after infection? For how long after viral clearance do epitopes remain detectable in the heart? How do virus-specific CD4+ and CD8+ T cells contribute to virus clearance, and to the development of immunopathological heart disease?

Public Health Relevance

Coxsackieviruses infect millions of people each year in the USA. In most cases, the infections cause little harm, but in some cases the virus causes severe inflammation in the heart. This can be serious, and sometimes fatal. This research will help us understand how various parts of our immune system act inside the heart to combat this viral infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093177-03
Application #
8258340
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kaltman, Jonathan R
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$470,003
Indirect Cost
$222,503
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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