AUTHOR=First Nicholas J. , Pedreira-Lopez Jose , San-Silvestre Manuel R. F. , Parrish Katelyn M. , Lu Xiao-Hong , Gestal Monica C. 

TITLE=Bordetella spp. utilize the type 3 secretion system to manipulate the VIP/VPAC2 signaling and promote colonization and persistence of the three classical Bordetella in the lower respiratory tract

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1111502

DOI=10.3389/fcimb.2023.1111502

ISSN=2235-2988

ABSTRACT=<sec><title>Introduction</title><p><italic>Bordetella</italic> are respiratory pathogens comprised of three classical <italic>Bordetella</italic> species: <italic>B. pertussis, B. parapertussis</italic>, and <italic>B. bronchiseptica</italic>. With recent surges in <italic>Bordetella</italic> spp. cases and antibiotics becoming less effective to combat infectious diseases, there is an imperative need for novel antimicrobial therapies. Our goal is to investigate the possible targets of host immunomodulatory mechanisms that can be exploited to promote clearance of <italic>Bordetella</italic> spp. infections. Vasoactive intestinal peptide (VIP) is a neuropeptide that promotes Th2 anti-inflammatory responses through VPAC1 and VPAC2 receptor binding and activation of downstream signaling cascades.</p></sec><sec><title>Methods</title><p>We used classical growth <italic>in vitro</italic> assays to evaluate the effects of VIP on <italic>Bordetella</italic> spp. growth and survival. Using the three classical <italic>Bordetella</italic> spp. in combination with different mouse strains we were able to evaluate the role of VIP/VPAC2 signaling in the infectious dose 50 and infection dynamics. Finally using the <italic>B. bronchiseptica</italic> murine model we determine the suitability of VPAC2 antagonists as possible therapy for <italic>Bordetella</italic> spp. infections.</p></sec><sec><title>Results</title><p>Under the hypothesis that inhibition of VIP/VPAC2 signaling would promote clearance, we found that VPAC2<sup>-/-</sup> mice, lacking a functional VIP/VPAC2 axis, hinder the ability of the bacteria to colonize the lungs, resulting in decreased bacterial burden by all three classical <italic>Bordetella</italic> species. Moreover, treatment with VPAC2 antagonists decrease lung pathology, suggesting its potential use to prevent lung damage and dysfunction caused by infection. Our results indicate that the ability of <italic>Bordetella</italic> spp. to manipulate VIP/VPAC signaling pathway appears to be mediated by the type 3 secretion system (T3SS), suggesting that this might serve as a therapeutical target for other gram-negative bacteria.</p></sec><sec><title>Conclusion</title><p>Taken together, our findings uncover a novel mechanism of bacteria-host crosstalk that could provide a target for the future treatment for whooping cough as well as other infectious diseases caused primarily by persistent mucosal infections.</p></sec>