Vermont Center for Immunobiology and Infectious Disease

Research Lab of Sally Huber, Ph.D.

Overview

Areas of interest: Immunology, infectious/autoimmune diseases, cardiovascular biology & disease, microbial pathogenesis.

Coxsackievirus B3 is a member of the picornavirus family of small RNA viruses. These viruses most frequently cause cold-like symptoms, but also induce severe diseases including myocarditis, dilated cardiomyopathy, insulin dependent diabetes and hepatitis in some people. We study two coxsackieviruses which differ by a single amino acid but vary dramatically in ability to induce myocarditis despite equivalent virus replication. Cardiac injury results from activation of CD8+ autoimmune T cells which recognize a cross-reactive epitope between the virus and cardiac myosin. Activation of these CD8+ effectors depends upon generation of a CD4+ interferon-gamma+ (IFN?+) response to the virus. Only the pathogenic coxsackievirus variant induces a CD4+ IFN?+ response. The pathogenic virus up-regulates the expression of CD1, a major histocompatibility complex class I-like molecule noted for activating innate effectors including T cells expressing the Vg4 T cell receptor. CD1 and Vg4+ cells are required for the CD4+ IFN?+ response. Studies are continuing on the role of CD1 in initiating the innate immune response, why Vg4+ cells are needed for autoimmune CD8+ cell activation, and on the antigenic mimicry between the virus and heart antigens. I am also interested in the role of ?d+ T cells in regulating CD4+ IFN?+ response in murine atherosclerosis. Evidence from both animal and clinical studies indicates that chronic inflammation is an important risk factor in atherosclerosis, and correlates atherosclerosis-susceptibility to IFN? expression in the atheromas. Mice lacking ?d+ cells fail to activate the IFN? response are highly resistant to atherogenesis. The hypothesis is that these innate effectors control developing adaptive immunity and determine pathogenesis by similar mechanism as in viral myocarditis. Furthermore, specific ?d+ subsets may be "hard-wired" so that if V?4+ is activated and recruited to an inflammatory site in any disease, it always causes adaptive immunity to develop an IFN? response.

Programs & Projects

Role of T Regulatory Cells in Viral Myocarditis: Myocarditis is an inflammation of the heart muscle which often follows microbial infections. Many different types of microbes including bacteria, protozoa, fungi, helmiths and viruses can cause this disease. Among viruses, enteroviruses of the picornavirus family are dominant and are found in the cardiac tissues of 14-33% of patients with active myocarditis and 8-35% of patients with dilated cardiomyopathy. Clinically, myocarditis is a male-dominant disease. Twice as many men as women are diagnosed with this disease. A mouse model of viral myocarditis has been developed which shares many of the same histological and epidemiological characteristics as the clinical disease. The goal of my research is to investigate the role of T regulatory cells and sex hormones in the coxsackievirus B3 model of myocarditis. I have investigated coxsackievirus B3 induced myocarditis for over 30 years and have published extensively on the sex bias for cardiac pathology and the optimal development of adaptive immunity and autoimmunity in this viral model. I demonstrated that male mice develop autoimmunity to heart antigens leading to cardiac failure while females fail to activate autoimmunity due to preferential generation of CD4+FoxP3+ T regulatory cells in this sex. Hormones are primarily responsible for the sex bias as castration of males prevents autoimmunity and increases T regulatory cell response while restoration of testosterone in the males restores pathogenesis. Also, administration of estradiol protects the males.

Technologies and functioning of the laboratory: We use both in vitro cell culture and in vivo animal modeling approaches. State-of-the-art techniques in immunology and virology have been established in the laboratory including flow cytometry, viral titers, cytotoxicity assays, ELISA, and tissue culture.