Immunomodulation in the pathogenesis of Bordetella pertussis infection and disease

Bordetella pertussis infection of the airways causes the disease pertussis (or whooping cough). The infection can be fatal in infants, but in older children, adolescents and adults usually results in a chronic cough of varying severity that persists long after clearance of the infection. The cause of the cough is unknown, but is presumably a result of the pathogenic effects of one or more of the various virulence factors produced by this bacterium. Accumulating recent evidence indicates that the majority of the virulence-associated effects of these factors is devoted to suppression and modulation of the host immune response, which can be skewed towards the recently described Th17 profile. Although the interplay between virulence factors and immune mechanisms might have evolved to benefit both partners in the host–pathogen interaction, it could also contribute to the severe disease pathology associated with this infection.

Introduction

Bordetella pertussis is a Gram-negative bacterial pathogen that infects the human respiratory tract and causes the disease pertussis (or whooping cough). A comprehensive review on B. pertussis [1^•] and other useful reviews on the organism and disease have been published recently [2, 3]. Although pertussis was traditionally considered a childhood disease, recent surveys and investigations have revealed that large numbers of older children, adolescents and adults are also infected and suffer from cough disease, causing serious public health issues. The classical disease symptom is a paroxysmal cough with whooping and vomiting, which is most frequently observed in unvaccinated infants. Whooping is less common in older individuals, in which the severity of cough varies widely. Apnea is another frequent problem of the disease in infants, and other complications include pneumonia, hypoxia, seizures, encephalopathy and secondary respiratory infections. Another hallmark of pertussis cough disease is its longevity, typically lasting several weeks (the Chinese term for pertussis is ‘the cough of a hundred days’) with gradually decreasing frequency and severity. The pathology of the airways in non-fatal cases is poorly characterized, although mucus hypersecretion is common. Pathological findings from postmortem observations, experimental animal infections and organ culture experiments include epithelial and ciliary damage, bronchopneumonia, pulmonary edema and focal hemorrhage.

What causes the cough pathology of pertussis? In truth, we have little or no evidence to answer this question. Furthermore, despite detailed molecular knowledge of several virulence-associated factors of B. pertussis, there remain significant gaps in our understanding of the pathogenesis of this infection and disease. Contributing to this problem is the lack of either experimental human challenge studies or small animal models of the cough disease after B. pertussis infection. The most frequently used animal model for this infection is the mouse intranasal or aerosol inoculation model. Although overt symptomatic disease is not observed (mice cannot cough), several characteristics of the human infection are reproduced in this model, including multiplication and clearance of bacteria, limitation of infection to the respiratory tract, increased severity of infection in young animals, and various systemic physiological and neurological changes; the model can also be useful for the preclinical assessment of acellular pertussis vaccine efficacy [4]. This model has been particularly informative on the nature of protective immune responses elicited by B. pertussis infection and pertussis vaccination [4], and the availability of immunodeficient mice, developed either by genetic mutation or by chemical treatment, has facilitated further understanding of the interplay between the bacterial pathogen and host immunity.

This review focuses on the pathogenesis of B. pertussis infection, with a particular emphasis on the immune suppression, evasion and subversion mechanisms employed by this pathogen, as revealed by recent literature. It appears that much of the activity of B. pertussis virulence factors is dedicated to this ‘anti-immunology’ aspect of pathogenesis, in common with other bacterial and viral pathogens as outlined in a recent review [5]. In addition, there is speculation that these immunomodulatory virulence mechanisms may not only aid B. pertussis infection but might also be crucially involved in pertussis disease pathogenesis.