Dissertation/Thesis Abstract

Bordetella pertussis Infection Exacerbates Influenza Virus Infection through Pertussis Toxin-Mediated Modulation of Host Immunity
by Ayala, Victor I., Ph.D., University of Maryland, Baltimore, 2011, 177; 3454666
Abstract (Summary)

Pertussis is a highly contagious respiratory infection caused by Bordetella pertussis. Disease is frequently complicated by concomitant infections with respiratory viruses; however, contributing factors are currently unknown. Here we report the effect of B. pertussis infection on a subsequent influenza virus (PR8) infection in mouse models and the role of pertussis toxin (PT) in this effect. BALB/c mice infected with a wild-type strain of B. pertussis (WT) and subsequently infected with PR8 had significantly increased pulmonary viral titers, lung pathologies and mortality compared to mice similarly infected with a PT-deficient mutant strain (ΔPT) and PR8 or PR8 alone. Intranasal treatment with purified active PT replicated the exacerbating effects of WT infection, demonstrating the toxin's role in disease. Investigation of viral growth in vitro ruled out the possibility that PT enhanced virus replication directly; therefore, we hypothesized that PT modulates host immunity. Examination of the type I interferon response indicated that PT had no significant impact on this pathway. Instead, a whole genome microarray analysis of lung tissue from PR8-infected mice revealed that PT suppressed numerous pathways associated with phagocyte function and communication between innate and adaptive immune responses at 12 and 36 h post-virus inoculation. Assessment of alveolar macrophage involvement showed that depletion of these cells abrogates the PT effect. Furthermore, PT suppressed expression of airway pro-inflammatory cytokines and chemokines in addition to recruitment of innate effector cells to the airways 2 days after PR8 infection. Unexpectedly, we found that PT had the opposite effect during the later stages of infection. At day 4-post virus inoculation, inflammatory mediators were significantly elevated and persisted to day 8, while IL-10 expression was down. Additionally, PT increased the number of neutrophils, macrophages and NK cells in the luminal space on days 6-8. These hyperimmune responses likely contribute to immunopathology and may also account for the increased mortality in PT-treated mice. Together these findings demonstrate that infection with B. pertussis through PT activity predisposes the host to exacerbated-influenza infection by initially countering protective innate immune responses that control virus titers, and later by promoting an excessive immune response that contributes to immunopathology and mortality.

Indexing (document details)
Advisor: Carbonetti, Nicholas H.
Commitee: Bavoil, Patrik, Hassel, Bret, Medvedev, Andrei, Perez, Daniel
School: University of Maryland, Baltimore
Department: Molecular Microbiology and Immunology
School Location: United States -- Maryland
Source: DAI-B 72/08, Dissertation Abstracts International
Subjects: Microbiology, Virology, Immunology
Keywords: Bordetella pertussis, Coinfection, Influenza virus, Pertussis toxin, Respiratory infection, Whooping cough
Publication Number: 3454666
ISBN: 9781124645568
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