Date of Award

Spring 5-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes acute and chronic polyarthritis. The virus has rapidly emerged over the last decade, and in 2013, CHIKV spread to the Western Hemisphere for the first time, infecting more than 1.8 million people. CHIKV targets the joints and musculoskeletal tissues, resulting in severe myalgia and symmetric polyarthritis that clinically mimics rheumatoid arthritis. Currently, no approved treatment is effective in preventing or controlling CHIKV infection or disease. Pathogenesis of CHIKV is still poorly understood but is thought to reflect an interplay between viral replication and detrimental immune responses. CHIKV patients have increased numbers of circulating CD4+ and CD8+ T cells, and mice lacking or depleted of CD4+ T cells show reduced foot swelling and arthritis during acute CHIKV infection, suggesting that CD4+ T cells contribute to the pathology of arthritis. Additionally, monocytes and/or macrophages are also thought to promote disease because depletion of macrophages with clodronate liposomes or inhibiting production of monocyte chemoattractant protein-1 (MCP-1) with bindarit improved symptoms. Though immunopathology appears to play an important role in CHIKV pathogenesis, not all host responses are detrimental. Central to controlling CHIKV and other alphavirus infections is the type I interferon (IFN-I) response, as mice lacking the IFN-I receptor rapidly succumb to infection. IFN-I are well known for their antiviral and immunomodulatory properties, but their mechanism of action during CHIKV infection is poorly understood.

IFN-Is are composed of 14 IFN-α subtypes and single forms of IFN-β, IFN-ε, IFN-κ, and IFN-ω, and despite their central role in protection against a number of viruses, little is known about the biological roles of individual IFN-I subtypes during viral infection. To address this issue we used genetic deletion mutants and blockade with antibodies targeting specific IFN subtypes to determine the contributions of IFN-α and IFN-β during acute CHIKV infection. We found that both IFN-α and IFN-β play important protective roles in limiting clinical CHIKV disease, but they do so by distinct mechanisms. The loss of IFN-α (through IRF7 knockout or IFN-α blocking Abs) resulted in increased CHIKV replication and dissemination. In contrast, a loss of IFN-β (through IFN-β knockout or IFN-β blocking Abs) had minimal impact on viral replication and dissemination. Instead, the loss of IFN-β lead to increased neutrophil recruitment and elevated IL-9 induction. Further, the increased clinical disease observed in IFN-β knockout mice could be rescued with neutrophil depletion. Thus, our findings suggest distinct protective roles for the IFN-I subtypes during CHIKV infection, with IFN-α functioning to limit early viral replication and spread and IFN-β modulating neutrophil-mediated immunopathology.

Previous data have shown that immune cells and proinflammatory cytokines contribute to CHIKV arthritis in mice. Because chronic CHIKV arthritis is clinically similar to seronegative rheumatoid arthritis, we examined the efficacy of several U.S. Food and Drug Administration (FDA)-approved rheumatoid arthritis therapies in a mouse model of CHIKV infection. We identified CTLA4-Ig (abatacept) as a disease-modifying antirheumatic drug (DMARD) with efficacy during acute CHIKV arthritis. CTLA4-Ig, which blocks T cell activation, reduced T cell accumulation in the joints of infected animals without affecting viral replication. When paired with the neutralizing anti-CHIKV human monoclonal antibody, 4N12, it was highly effective at reducing joint inflammation, periarticular swelling, migration of inflammatory leukocytes, and infection, even when administered several days after virus inoculation. Thus, combination of anti-inflammatory and antibody-based antiviral therapy may serve as a model for treating humans with arthritis caused by CHIKV or other related viruses.

Collectively, these data provide important mechanistic insight into the host factors that control and promote CHIKV pathogenesis. Continued pursuit of defining interactions between CHIKV and the host immune responses will be paramount in developing effective therapeutics and vaccines to combat CHIKV and other emerging tropical diseases, which remain a global health and economic burden.

Language

English (en)

Chair and Committee

Deborah J. Lenschow

Committee Members

Robert D. Schreiber, Michael S. Diamond, Adrianus C. Boon, Haina Shin,

Comments

Permanent URL: https://doi.org/10.7936/K7M90841

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