Abstract
Well-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms. Classical bordetellae are very closely related subspecies that are known to modulate adaptive immunity in a variety of ways, permitting them to either persist for life or repeatedly infect the same host. Exploring the hypothesis that exposure to immune cells would cause bordetellae to induce expression of important immunomodulatory mechanisms, we identified a putative regulator of an immunomodulatory pathway. The deletion of btrS in B. bronchiseptica did not affect colonization or initial growth in the respiratory tract of mice, its natural host, but did increase activation of the inflammasome pathway, and recruitment of inflammatory cells. The mutant lacking btrS recruited many more B and T cells into the lungs, where they rapidly formed highly organized and distinctive Bronchial Associated Lymphoid Tissue (BALT) not induced by any wild type Bordetella species, and a much more rapid and strong antibody response than observed with any of these species. Immunity induced by the mutant was measurably more robust in all respiratory organs, providing completely sterilizing immunity that protected against challenge infections for many months. Moreover, the mutant induced sterilizing immunity against infection with other classical bordetellae, including B. pertussis and B. parapertussis, something the current vaccines do not provide. These findings reveal profound immunomodulation by bordetellae and demonstrate that by disrupting it much more robust protective immunity can be generated, providing a pathway to greatly improve vaccines and preventive treatments against these important pathogens.
Highlights
Well-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms
We observed that btrS was up-regulated 2.5-fold when B. bronchiseptica was internalized in macrophages[60], revealing responsiveness to interactions with immune cells
These data led us to speculate that btrS is a regulator of the Type 3 Secretion System (T3SS), but potentially integrates multiple, diverse signals to coordinate the regulation of numerous immunomodulatory factors that must be carefully controlled in a complex, choreographed manner to optimize bacterial success in the challenging environment of the host immune response
Summary
Well-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms. In the context of such studies, we and others have observed that various Bordetella species manipulate immunity in a variety of ways that would be undetectable in other experimental systems[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25] This immunomodulation allows each Bordetella species to achieve remarkable success by either persisting for life with limited pathology (B. bronchiseptica) or causing acute coughing disease that facilitates extraordinarily rapid transmission to new hosts (B. pertussis)[26,27]. Mice convalescent from infection with this mutant were protected from re-infection with all three wild-type classical Bordetella species, being much better protected against both B. pertussis and B. parapertussis than mice given the current vaccine
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