Bordetella pertussis Infection Exacerbates Influenza Virus Infection through Pertussis Toxin-Mediated Suppression of Innate Immunity

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.

Bacterial Lipopolysaccharide Inhibits Influenza Virus Infection of Human Macrophages and the Consequent Induction of CD8+ T Cell Immunity

“…Alternatively, bacterial toxins may suppress key components of the anti-viral response such that the pathogenicity of IAV is increased [5]. Recent studies have suggested that the bacterial species that constitute an individual's normal flora represent a key component of the host defence against IAV [6,7].…”

Bordetella protein toxins

“…Coadministration of PTX also enhanced B. parapertussis infection, and this was found to depend on the presence of alveolar macrophages, but not on the presence of neutrophils. Influenza virus infection in mice is also exacerbated by B. pertussis infection [83]. Prior infection with PTX-producing B. pertussis increased the pulmonary viral load, lung pathology, and mortality compared to mice infected with PTXdeficient B. pertussis.…”

Correlation Between Serum Acute Phase Proteins, Lung Pathology, and Disease Severity in Pigs Experimentally Co-Infected with H3N2 Swine Influenza Virus and Bordetella Bronchiseptica

“…co-infections) with influenza, or develop after influenza infection. It has been shown that the bacteria belonging to the genus Bordetella can be responsible for a potentially severe complication of influenza that can progress rapidly to a serious infection with severe pneumonia (2,20). In pigs, Bbr is involved in the aetiology of atrophic rhinitis, bronchopneumonia, and has been shown to contribute to porcine respiratory disease complex (PRDC) (7).…”