Abstract
Pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. Here we report the effect of Bordetella pertussis infection on 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 (up to 14 days later) infected with PR8 had significantly increased pulmonary viral titers, lung pathology and mortality compared to mice similarly infected with a PT-deficient mutant strain (ΔPT) and PR8. Substitution of WT infection by intranasal treatment with purified active PT was sufficient to replicate the exacerbating effects on PR8 infection in BALB/c and C57/BL6 mice, but the effects of PT were lost when toxin was administered 24 h after virus inoculation. PT had no effect on virus titers in primary cultures of murine tracheal epithelial cells (mTECs) in vitro, suggesting the toxin targets an early immune response to increase viral titers in the mouse model. However, type I interferon responses were not affected by PT. Whole genome microarray analysis of gene expression in lung tissue from PT-treated and control PR8-infected mice at 12 and 36 h post-virus inoculation revealed that PT treatment suppressed numerous genes associated with communication between innate and adaptive immune responses. In mice depleted of alveolar macrophages, increase of pulmonary viral titers by PT treatment was lost. PT also suppressed levels of IL-1β, IL-12, IFN-γ, IL-6, KC, MCP-1 and TNF-α in the airways after PR8 infection. Furthermore PT treatment inhibited early recruitment of neutrophils and NK cells to the airways. Together these findings demonstrate that infection with B. pertussis through PT activity predisposes the host to exacerbated influenza infection by countering protective innate immune responses that control virus titers.
Highlights
In 2010 the California Department of Public Health declared a pertussis epidemic across California, the worst the state has seen in 63 years, with over 9400 cases and 10 infant deaths [1,2]
Effect of B. pertussis infection on subsequent influenza virus infection and the role of pertussis toxin (PT) To assess the effects of B. pertussis infection and the role of PT on secondary infection with influenza virus, BALB/c mice were inoculated intranasally with 56105 colony forming units (CFU) of B. pertussis (WT) or a mutant strain deficient in PT (DPT)
Mice inoculated with wild type B. pertussis (WT) and subsequently infected with influenza virus (PR8) had increased pulmonary viral titers at early, peak and clearance phases of infection, which was not observed in mice inoculated with an isogenic strain of B. pertussis deficient for PT (DPT)
Summary
The resurgence of pertussis or whooping cough in vaccinated populations poses a significant public health concern, especially for cases of mixed respiratory infections with viruses [3,4]. Several pathogenic viruses, including adenovirus, rhinovirus and influenza virus, have been detected in the airways of patients with confirmed pertussis [9,10,11,12,13]. Analysis of sputum and nasal aspirates from acute and convalescent phase pertussis patients indicates that the rate of viral co-infection can be as much as 30% in adult populations and 16% in infants, and infection with more than one virus is common [1,9,12,18]. The high prevalence of viral infections and associated pathological conditions supports the theory that B. pertussis predisposes to such infections, possibly through the effects of its virulence factors [3,5,10]
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