Date of Award

5-2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T Rouse

Committee Members

Melissa Kennedy, Seung Baek, Sarah Lebeis

Abstract

Ocular infection with herpes simplex virus 1 (HSV-1) can result in a chronic immunoinflammatory stromal keratitis (SK) lesion that is a significant cause of human blindness. These lesions are mainly orchestrated by IFN-gamma producing CD4+ T cells (Th1) and neutrophils. HSV being neurotropic in nature can also disseminate into the brain and lead to herpes simplex encephalitis (HSE). In this study we investigated the role of miR-155 in the pathogenesis of HSK and HSE.

The first part of the dissertation (I) reviews literature regarding the contribution of miRNAs in innate and adaptive immune responses. It also focuses on their involvement in neuroinflammation during inflammatory and viral diseases.

In the second part (II) we investigated the role of miR-155 in HSV-1 latency and HSE. We observed that miR-155-/- (microRNA-155 knockout) mice are highly susceptible to HSE and zosteriform lesions. These miR-155-/- animals also show increased viral reactivation from latency when compared to the control WT (wild type) animals. One explanation for these observations was diminished CD8 T cell effector responses in miR-155-/- animals.

In the third part (III) we evaluate the role of miR-155 in the pathogenesis of SK. Our results showed that miR-155 expression is increased in corneas after HSV-1 infection and suppression of miR-155 production resulted in milder lesions that was associated with diminished Th1 and Th17 responses as well as reduced inflammatory cytokine production.

Collectively, these studies identified a novel role for miR-155 in regulating HSE and promoting inflammation during HSK.

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