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Role of proteolytic processing of tumor necrosis factor-[alpha] in immunopathology during influenza infection / by Matthew Peter DeBerge.

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Author	DeBerge, Matthew Peter.
Title	Role of proteolytic processing of tumor necrosis factor-[alpha] in immunopathology during influenza infection / by Matthew Peter DeBerge.
Date	2013
Abstract	Influenza virus is a respiratory pathogen that is capable of causing considerable pulmonary pathology and respiratory dysfunction in humans. Seasonal influenza epidemics and the occasional influenza pandemic are responsible for significant morbidity and mortality and represent challenging economic and public health burdens. It is largely believed that a dysregulated host immune response can contribute to the severity of disease seen in humans infected with influenza virus. The goal of the studies outlined in the dissertation was to identify elements of the host response that exacerbate lung injury during influenza infection. We hypothesized that proteolytic processing of tumor necrosis factor (TNF)-[alpha] was a critical event regulating immunopathology during influenza infection. The first aim was to examine the role of TNF-[alpha] processing in viral clearance and the host response to influenza viral challenge in mice. The second aim was to investigate the specific contribution of TNF-[alpha] processing by influenza-specific CD8⁺ T cells for the development of acute lung injury in a transgenic mouse model of influenza infection. The third aim was designed to determine the mechanisms by which CD8⁺ T cells regulated TNF-[alpha] processing. Whereas, TNF-[alpha] processing was required in the whole animal during a sub-lethal influenza infection to limit the immune response and the extent of lung injury, we found that specific inhibition of TNF-[alpha] processing by influenza-specific CD8⁺ T cells mitigated severe and lethal lung injury in a transgenic mouse model of highly pathogenic influenza infection. Moreover, we show that T-cell receptor signaling can induce proteolytic processing and this process is dependent on the MAPK/ERK signaling pathway. These studies highlight the complex nature of TNF-[alpha] processing and demonstrate that the outcome of this event is influenced in part by the viral load and cellular source of TNF-[alpha]. To our knowledge, these studies are the first to show that
Description	xv, 232 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Paul M. Guyre, Richard I. Enelow, Charles R. Wira, James C. Leiter, Mercedes Rincon
College	Dartmouth Medical School. Department of Physiology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.953

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Role of proteolytic processing of tumor necrosis factor-[alpha] in immunopathology during influenza infection / by Matthew Peter DeBerge.

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