Cardiovascular disease is the number one killer in the US. The incidence and severity of inflammatory heart disease (myocarditis) is higher among men. Proinflammatory cytokines are critical for the development of myocarditis. Recent evidence suggests a link between infections, innate Toll-like receptor (TLR) signaling and increased heart disease. Adjuvants are known to induce inflammatory diseases such as experimental autoimmune myocarditis (EAM) in mice, although the precise mechanisms are unclear. Adjuvants work during the innate immune response to increase proinflammatory cytokines, such as interleukin (IL)-1 and IL- 12, resulting in a T helper (Th)1-type inflammatory response. Recent studies by the PI suggest that coxsackievirus B3 (CVB3) infection induces inflammatory heart disease in mice by mechanisms similar to adjuvant in EAM. We show that TLR4 deficient mice have significantly reduced acute myocarditis and IL-1 levels in the heart and increased levels of the Th1 inhibitory receptor Tim-3, indicating that TLR4 signaling reduces Tim-3 expression during innate immunity resulting in increased inflammation in the heart. Blocking Tim-3 during the innate immune response to CVB3 infection increases TLR4 expression on antigen presenting cells (ARC), indicating that Tim-3 signaling reduces TLR4 expression on ARC following CVB3 infection. Our results demonstrate that cross-talk between TLR4 and Tim-3 signaling regulates the severity of inflammation following viral infection. These results provide a mechanism for how viral infections act similar to adjuvants during the innate immune response to increase acute and chronic myocarditis in males. In this proposal we will examine the following questions using the mouse model of CVB3-induced myocarditis.
Aim 1) Is increased myocarditis in males following CVB3 infection mediated specifically by TLR4, or are other TLR signaling pathways involved? Aim 2) Do proinflammatory cytokines (e.g. IL-1) increase myocarditis using mechanisms similar to virus (i.e. increase TLR4 and decrease Tim-3)? Aim 3) Is active viral infection necessary for the development of myocarditis? Do adjuvants increase inflammation using the same mechanisms as virus? Relevance to Public Health: Heart disease is the leading cause of death in the US. This proposal will examine the adjuvant effect of viral infection during innate immunity on the development of heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087033-05
Application #
8008773
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Adhikari, Bishow B
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$482,308
Indirect Cost
Name
Johns Hopkins University
Department
Miscellaneous
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Penta, Kayla L; Fairweather, DeLisa; Shirley, Devon L et al. (2015) Low-dose mercury heightens early innate response to coxsackievirus infection in female mice. Inflamm Res 64:31-40
Root-Bernstein, Robert; Fairweather, DeLisa (2014) Complexities in the relationship between infection and autoimmunity. Curr Allergy Asthma Rep 14:407
Fairweather, DeLisa; Guilarte, Tomás R; Cooper Jr, Leslie T (2014) Biomarker and more: can translocator protein 18 kDa predict recovery from brain injury and myocarditis? Biomark Med 8:605-7
Fairweather, DeLisa; Coronado, Michael J; Garton, Amanda E et al. (2014) Sex differences in translocator protein 18 kDa (TSPO) in the heart: implications for imaging myocardial inflammation. J Cardiovasc Transl Res 7:192-202
Fairweather, DeLisa; Cooper Jr, Leslie T; Blauwet, Lori A (2013) Sex and gender differences in myocarditis and dilated cardiomyopathy. Curr Probl Cardiol 38:7-46
Abston, Eric D; Coronado, Michael J; Bucek, Adriana et al. (2013) TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4. Am J Physiol Regul Integr Comp Physiol 304:R267-77
Cooper Jr, Leslie T; Fairweather, DeLisa (2013) We see only what we look for: imaging cardiac inflammation. Circ Cardiovasc Imaging 6:165-6
Myers, Jennifer M; Fairweather, DeLisa; Huber, Sally A et al. (2013) Autoimmune myocarditis, valvulitis, and cardiomyopathy. Curr Protoc Immunol Chapter 15:Unit 15.14.1-51
Barin, Jobert G; Baldeviano, G Christian; Talor, Monica V et al. (2013) Fatal eosinophilic myocarditis develops in the absence of IFN-? and IL-17A. J Immunol 191:4038-47
Barin, Jobert G; Baldeviano, G Christian; Talor, Monica V et al. (2012) Macrophages participate in IL-17-mediated inflammation. Eur J Immunol 42:726-36

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