Enhancement of immune response against Bordetella spp. by disrupting immunomodulation

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.

Acellular Pertussis Vaccine Components: Today and Tomorrow

“…Another approach to a live vaccine is based on the concept of disrupting the expression of immunomodulators. A strain of Bordetella bronchiseptica , lacking a regulator of immunomodulators ( btrS ), provided completely sterilizing immunity to all of the classical Bordetellae ( B. pertussis, Bordetella parapertussis and B. bronchiseptica ), demonstrating that it is possible to induce better protection than convalescent immunity [ 77 ]. Utilizing this btrS -deficient strain, or a simliar B. pertussis mutant strain, along with the understanding gained from functional studies, should make it possible to substantially improve vaccine efficacy.…”

Bordetella Type III Secretion Injectosome and Effector Proteins

“…The first cluster required the presence of BtrS for transcription (bscN to bsp22, and bopN to orf2) whereas genes in the other cluster (bscC to bscO, and bcrD to bscF) showed very little dependence, if any, on the presence of BtrS (Ahuja et al, 2016). Mattoo et al, 2004;Ahuja et al, 2016 Besides of the ECF sigma factor BtrS, which controls also other regulatory networks (Gestal et al, 2019), additional genes encoded in the btr locus are linked to the injectosome function. These comprise the anti-sigma factor BtrA and the partnerswitcher proteins BtrU, BtrW, and BtrV, respectively ( Figure 3A, Table 3).…”

“…Besides of the ECF sigma factor BtrS, which controls also other regulatory networks (Gestal et al, 2019 ), additional genes encoded in the btr locus are linked to the injectosome function. These comprise the anti-sigma factor BtrA and the partner-switcher proteins BtrU, BtrW, and BtrV, respectively ( Figure 3A , Table 3 ).…”

“NETs and EETs, a Whole Web of Mess”

“…Since this topic has been extensively covered in several reviews [50,84,[128][129][130], only a few highlights are mentioned here. Bordetella pertussis harbors many immunomodulators that control several aspects of the host immune response [1,131,132] including NETs. B. pertussis suppresses the generation of ROS inhibiting NET formation.…”

“…The Bordetella bronchiseptica sigma factor, btrS, regulates many immunomodulators associated with suppressing different aspects of the immune response [202]. B. bronchiseptica btrS-null trigger a prompt and robust adaptive response [131]. Some insight into the possible mechanisms associated with this increase in adaptive responses points two different cells, macrophages and eosinophils.…”