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Bordetella pertussis pathogenesis: current and future challenges
Jeffrey A. Melvin1, Erich V. Scheller1, Jeff F. Miller2 and Peggy A. Cotter1
Abstract | Pertussis, also known as whooping cough, has recently re-emerged as a major public health threat despite high levels of vaccination against the aetiological agent Bordetella pertussis. In this Review, we describe the pathogenesis of this disease, with a focus on recent mechanistic insights into B.pertussis virulence-factor function. We also discuss the changing epidemiology of pertussis and the challenges facing vaccine development. Despite decades of research, many aspects of B.pertussis physiology and pathogenesis remain poorly understood. We highlight knowledge gaps that must be addressed to develop improved vaccines and therapeutic strategies.
Pertussis is a highly contagious respiratory disease that is transmitted directly from human to human1, probably via aerosolized respiratory droplets. The primary causative agent, Bordetella pertussis, is a Gram-negative bacterium that was first described by Bordet and Gengou in 1906 (REF.2). The closely related bacterium
Bordetella parapertussisHu is responsible for a minority of cases (approximately 14%) and is less capable of causing severe disease3. Both B.pertussis and B.parapertussisHu
are human-specific, and phylogenetic analyses indicate that they evolved from Bordetella bronchiseptica or a B.bronchiseptica-like ancestor4,5 (BOX1). B.bronchiseptica infects a broad range of mammals, including humans, and although it can cause overt disease such as kennel cough in dogs and atrophic rhinitis in pigs, it typically colonizes its hosts chronically and asymptomatically6.
Despite differences in host range and disease-causing propensity, B.pertussis, B.parapertussisHu and B.bronchiseptica are so closely related that they are now considered to be subspecies. Together, these organisms provide a paradigm for understanding bacterial adaptation to humans and the dichotomy between acute disease and chronic asymptomatic infection4,5. Although other Bordetella species have been isolated from humans, they seem to be primarily opportunistic human pathogens.
In the pre-vaccine era, pertussis was widespread and mainly affected young children (19years old)7. The classical manifestation of the disease in this age group, is characterized by three phases: the catarrhal phase, the paroxysmal phase and the convalescent phase8. Clinical observations, combined with results from studies using animal models (BOX2), suggest that classic pertussis is initiated by the adherence of bacteria to the ciliated
respiratory epithelium in the nasopharynx and trachea9,10. Adherent bacteria survive innate host defences, such...