Date of Award

Fall 2012

Degree Type

Thesis

Degree Name

Master of Science (MSc)

Department

Medical Sciences (Molecular Virology and Immunology Program)

Supervisor

Martin R. Stampfli

Co-Supervisor

Mark R. McDermott

Language

English

Committee Member

Manel Jordana

Abstract

Despite the advanced knowledge of the mechanisms of influenza infection and improved vaccines, Influenza A Virus still causes a life-threatening respiratory disease, especially during pandemics. Past investigations have proposed a synergism between Influenza A virus and a simultaneous or subsequent bacterial superinfection as the predominant cause of death. The recent development of animal models to study these heterologous infections has shed light onto the diverse mechanisms by which Influenza A Virus may increase the susceptibility to contract a secondary bacterial infection. These studies suggested an important role for the innate immune system in mediating such disease. We developed a model of heterologous infection combining Influenza A Virus and Bordetella parapertussis that demonstrated a critical role for MIP-2 to drive pulmonary neutrophilia in the pathology associated with bacterial superinfection of influenza. However, the origin of this increased MIP-2 production and the mechanisms underlying the immunopathology remained to be elucidated. The present studies proposed IL-1β overproduction as the upstream cause of the increased MIP-2 production observed in heterologous infection. This exaggerated IL-1β production was likely related to the increased bacterial burden observed in heterologously infected mice. This study also demonstrated that reduction in IL-1β production by blockade of the inflammasome seemed to provide an improvement in the clinical symptoms and the immunopathology of the disease. Thus, interventions to attenuate the exacerbated bacterial burden and the inflammatory responses derived from the subsequent IL-1β overproduction should be further investigate as possible therapeutic approaches to treat bacterial superinfections.

McMaster University Library


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