Bordetellafilamentous hemagglutinin plays a critical role in immunomodulation, suggesting a mechanism for host specificity

Abstract

Bordetella pertussis, the causative agent of the acute childhood respiratory disease whooping cough, is a human-adapted variant of Bordetella bronchiseptica, which displays a broad host range and typically causes chronic, asymptomatic infections. These pathogens express a similar but not identical surface-exposed and secreted protein called filamentous hemagglutinin (FHA) that has been proposed to function as both a primary adhesin and an immunomodulator. To test the hypothesis that FHA plays an important role in determining host specificity and͞or the propensity to cause acute versus chronic disease, we constructed a B. bronchiseptica strain expressing FHA from B. pertussis (FHA Bp) and compared it with wild-type B. bronchiseptica in several naturalhost infection models. FHA Bp was able to substitute for FHA from B. bronchiseptica (FHA Bb) with regard to its ability to mediate adherence to several epithelial and macrophage-like cell lines in vitro, but it was unable to substitute for FHA Bb in vivo. Specifically, FHA Bb, but not FHABp, allowed B. bronchiseptica to colonize the lower respiratory tracts of rats, to modulate the inflammatory response in the lungs of immunocompetent mice, resulting in decreased lung damage and increased bacterial persistence, to induce a robust anti-Bordetella antibody response in these immunocompetent mice, and to overcome innate immunity and cause a lethal infection in immunodeficient mice. These results indicate a critical role for FHA in B. bronchiseptica-mediated immunomodulation, and they suggest a role for FHA in host specificity.inflammation ͉ adhesin ͉ respiratory infection ͉ filamentous hemagglutinin D espite widespread vaccine coverage, whooping cough, or pertussis, remains a serious threat to human health, and its incidence has been increasing in recent years (1, 2). The causative agents, Bordetella pertussis and Bordetella parapertussis hu , are human-adapted pathogens that belong to a clade of very closely related Gram-negative bacteria that cause respiratory infections in mammals. Phylogenetic analyses indicate that Bordetella bronchiseptica, which displays a broad host range and typically colonizes its hosts chronically and asymptomatically, was the progenitor of this clade, with B. pertussis diverging relatively early and B. parapertussis hu diverging independently and much more recently than B. pertussis (3-6). Adaptation to humans and the propensity to cause acute disease (in which the infection is eventually cleared) rather than chronic disease (characterized by persistence of the bacteria, often for the lifetime of the host) has, therefore, evolved twice within this group of bacteria. Although a variety of Bordetella virulence factors have been characterized (4, 7-10), the mechanisms that determine host specificity and disease characteristics are not understood.Filamentous hemagglutinin (FHA), a primary component of acellular pertussis vaccines, is a large, ␤-helical, highly immunogenic protein that is both surface-associated and secreted (11)(12)(13). In vitro...

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“…4) alongside a large hypothetical exoprotein (encoded by PFLU2428) that contains a domain related to an adhesion virulence factor (Inatsuka et al ., 2005). All Pseudomonas screened encode Psp3.…”

A Novel Sensor Kinase Is Required for Bordetella bronchiseptica To Colonize the Lower Respiratory Tract

“…Inflammation has been documented by recruitment of macrophages and neutrophils via observation of stained lung sections of infected mice (26). In this model, wild-type B. bronchiseptica induces a significant inflammatory response and is able to persist in the lungs for several weeks (26,27,32,68). We wondered if plrS might contribute to the bacteria's ability to survive under these experimental conditions.…”

“…In this model, a large dose of B. bronchiseptica is deposited directly into the trachea and lungs to induce an inflammatory response, which represents the first line of immune defense to infection. Inflammation has been documented by recruitment of macrophages and neutrophils via observation of stained lung sections of infected mice (26). In this model, wild-type B. bronchiseptica induces a significant inflammatory response and is able to persist in the lungs for several weeks (26,27,32,68).…”

“…FHA is an adhesin and immunomodulatory protein that has been shown to be indispensable for B. bronchiseptica colonization of the trachea, but not the nasal cavity (13,26). We therefore evaluated expression levels of fhaB, the gene encoding FHA, in RB50⌬plrS and also examined FHA function by observing bacterial adherence to rat lung epithelial cells, a phenotype entirely dependent on the surface expression of FHA (13,26). Figure 4A shows that the expression of fhaB in RB50⌬plrS is similar to that in the wild-type strain.…”

“…Overnight-grown wild-type or mutant B. bronchiseptica (500,000 CFU) in a 50-l volume was inoculated directly into the trachea and lungs (26). At 1 hour, 4 days, 11 days, and 28 days postinoculation, the nasal septa, tracheae, and three right lung lobes were recovered and bacterial levels were determined by plating aliquots of tissue extracts on LB agar supplemented with streptomycin as described previously (42).…”