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Title

Influenza Induces Chronic Inflammatory Disease

Date of Award

Spring 5-15-2014

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

ABSTRACT OF THE DISSERTATION

Influenza Induces a Chronic Inflammatory Lung Disease

By

Michael Edward Hinojosa

Doctor of Philosophy in Biology and Biomedical Sciences (Immunology)

Washington University in St. Louis, 2014

Dr. Michael J. Holtzman, Chairperson

Asthma is a heterogeneous chronic lung disease characterized by inflammation of the airways, mucus cell metaplasia (MCM), mucus hypersecretion, and airway hyperreactivity (AHR) that manifests as recurrent wheezing and airway obstruction. Respiratory viral infections early in life such as human respiratory syncytial virus (RSV) are associated with development of post viral chronic airway disease or asthma later in life. Recently, reports have correlated severe influenza infection early in life with subsequent development of chronic wheeze.

We developed a mouse model that translates influenza A virus (IAV) infection into a chronic inflammatory disease resembling asthma. C57BL/6 mice infected with IAV (A/WS/33 H1N1) developed the chronic hallmarks of asthma despite efficient clearance of infectious virus. Additionally, we were able to detect non-infectious viral genome at least 105 days post infection. Similar to human RSV and influenza infections, we find that chronic disease in mice is correlated with severity of acute illness. Ferrets infected with a non-rodent adapted strain (A/CA/07/2009 H1N1) also developed chronic disease demonstrating that this outcome of severe infection is a phenomenon broadly applicable to mammalian hosts.

Human studies and experimental allergy models implicate Th2 cells and IL-13 as a central mediator of disease. However, we found that IL-13 and STAT6 were dispensable for disease. Furthermore, the CD4 compartment was not necessary for chronic disease. We also determined that disease was independent of NKT cells which are a requirement for post Sendai virus (paramyxovirus) chronic lung disease. MX1 is an interferon stimulated gene that is specifically protective against influenza in mice. Most inbred lab strains of mice do not express a functional MX1 gene product. MX1 complemented mice cleared infection more efficiently relative to WT animals and developed chronic inflammation and had detectible viral remnant 49 days post infection. However, despite persistent inflammation and viral persistence, MX1 complemented mice failed to develop chronic MCM.

Severe influenza infection induces a chronic inflammatory lung disease that is mechanistically distinct from conventional paradigm.

Language

English (en)

Chair and Committee

Michael Holtzman

Committee Members

Michael Diamond, Deborah Lenschow, Ted Hansen, Jacco Boon, Monika Vig, Paul Allen

Comments

Permanent URL: https://doi.org/10.7936/K7862DCF

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