Modulation of host immune responses, induction of apoptosis and inhibition of NF‐κB activation by the Bordetella type III secretion system

Abstract

SummaryBordetella bronchiseptica establishes respiratory tract infections in laboratory animals with high efficiency. Colonization persists for the life of the animal and infection is usually asymptomatic in immunocompetent hosts. We hypothesize that this reflects a balance between immunostimulatory events associated with infection and immunomodulatory events mediated by the bacteria. We have identified 15 loci that are part of a type III secretion apparatus in B. bronchiseptica and three secreted proteins. The functions of the type III secretion system were investigated by comparing the phenotypes of wild-type bacteria with two strains that are defective in type III secretion using in vivo and in vitro infection models. Type III secretion mutants were defective in long-term colonization of the trachea in immunocompetent mice. The mutants also elicited higher titres of anti-Bordetella antibodies upon infection compared with wild-type bacteria. Type III secretion mutants also showed increased lethal virulence in immunodeficient SCID-beige mice. These observations suggest that type III-secreted products of B. bronchiseptica interact with components of both innate and adaptive immune systems of the host. B. bronchiseptica induced apoptosis in macrophages in vitro and inflammatory cells in vivo and type III secretion was required for this process. Infection of an epithelial cell line with high numbers of wild type, but not type III deficient B. bronchiseptica resulted in rapid aggregation of NF-kB into large complexes in the cytoplasm. NF-kB aggregation was dependent on type III secretion and aggregated NF-kB did not respond to TNFa activation, suggesting B. bronchiseptica may modulate host immunity by inactivating NF-kB. Based on these in vivo and in vitro results, we hypothesize that the Bordetella type III secretion system functions to modulate host immune responses during infection.

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

“…Occupancy of CR3 and binding of LRI͞ IAP in a way that prevents clustering can inhibit respiratory burst in neutrophils and monocytes (58,59), and, thus, FHA may act directly in this regard. Alternatively, or additionally, FHA may perform this function indirectly by allowing the efficient delivery of toxins, such as adenylate cyclase or proteins delivered by the Bordetella type III secretion system, both of which have been implicated in phagocyte inhibition and͞or immunomodulation (50,(60)(61)(62). Although neither RBX9 nor RBFS4 persisted as well as RB50 in the lungs of coinfected mice, RBFS4 persisted better than RBX9 in both single-and coinfection experiments.…”

Bordetella Type III Secretion Modulates Dendritic Cell Migration Resulting in Immunosuppression and Bacterial Persistence

“…Because mice are a natural host for B. bronchiseptica, the murine model of infection is ideal for studying host pathogen interactions that lead to bacterial persistence. Previous studies have demonstrated that the B. bronchiseptica TTSS is required for long-term colonization of the mouse trachea (1,28). We hypothesize that B. bronchiseptica use the TTSS to interact with APCs at mucosal surfaces to alter the ability of these cells to direct a clearing immune response.…”

“…Bordetella bronchiseptica uses a type III secretion system (TTSS) 3 to achieve persistent colonization of the murine respiratory tract (1). Colonization occurs despite the apparent development of a humoral IgG2A and Th1-type cellular immune response (2).…”

Pathogen-induced apoptosis of macrophages: a common end for different pathogenic strategies. Microreview

“…Yersinia is probably not the only pathogen that triggers apoptosis through the inactivation of NF-kB. Bordetella pertussis has recently been shown to trigger apoptosis through an apparently similar mechanism, although the bacterial effector molecules responsible for NF-kB inhibition have yet to be defined (Yuk et al 2000).…”