Contribution of Bordetella Filamentous Hemagglutinin and Adenylate Cyclase Toxin to Suppression and Evasion of Interleukin-17-Mediated Inflammation

Abstract

<jats:title>ABSTRACT</jats:title><jats:p><jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Bordetella pertussis</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Bordetella bronchiseptica</jats:named-content>establish respiratory infections with notorious efficiency. Our previous studies showed that the<jats:italic>fhaB</jats:italic>genes of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. pertussis</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. bronchiseptica</jats:named-content>, which encode filamentous hemagglutinin (FHA), are functionally interchangeable and provided evidence that FHA-deficient<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. bronchiseptica</jats:named-content>induces more inflammation in the lungs of mice than wild-type<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. bronchiseptica</jats:named-content>. We show here that the robust inflammatory response to FHA-deficient<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. bronchiseptica</jats:named-content>is characterized by the early and sustained influx of interleukin-17 (IL-17)-positive neutrophils and macrophages and, at 72 h postinoculation, IL-17-positive CD4<jats:sup>+</jats:sup>T cells, suggesting that FHA allows the bacteria to suppress the development of an IL-17-mediated inflammatory response. We also show that the<jats:italic>cyaA</jats:italic>genes of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. pertussis</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. bronchiseptica</jats:named-content>, which encode adenylate cyclase toxin (ACT), are functionally interchangeable and that ACT, specifically its catalytic activity, is required for<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">B. bronchiseptica</jats:named-content>to resist phagocytic clearance but is neither required for nor inhibitory of the induction of inflammation if bacteria are present in numbers sufficient to persist during the first 3 days postinoculation. Incubation of bone marrow-derived macrophages with a Δ<jats:italic>cyaA</jats:italic>strain caused decreased production of IL-1β and increased production of tumor necrosis factor alpha (TNF-α) and IL-12, while incubation with a Δ<jats:italic>cyaA</jats:italic>Δ<jats:italic>fhaB</jats:italic>strain caused increased production of IL-23. These data suggest that FHA and ACT both contribute to suppress the recruitment of neutrophils and the development of an IL-17-mediated immune response. To our knowledge, this is the first demonstration of a microbial pathogen suppressing IL-17-mediated inflammation<jats:italic>in vivo</jats:italic>as a strategy to evade innate immunity.</jats:p>

The Bordetella Adenylate Cyclase Repeat-in-Toxin (RTX) Domain Is Immunodominant and Elicits Neutralizing Antibodies

“…At physiologically relevant concentrations (Ͻ50 ng/ml) (69), ACT results in cytotoxicity to the murine macrophage cell line J774A.1 after 2 h of exposure; ACT also causes chlorine efflux from polarized epithelial cells and hinders IL-2 secretion and proliferation of T cells (42). More recently, ACT has been shown to suppress development of an IL-17-mediated immune response that appears key for bacterial clearance (21). As a result, passively administered antibodies blocking ACT function may be able to enhance neutrophil-mediated phagocytosis of opsonized bacteria (67).…”

Bordetella PlrSR regulatory system controls BvgAS activity and virulence in the lower respiratory tract

“…B. bronchiseptica and B. pertussis are sufficiently closely related to be considered members of the same species (35), and several vags have been shown to be functionally interchangeable (48)(49)(50)(51). As in B. bronchiseptica, a B. pertussis plrS mutant was defective in persistence in the LRT.…”

Bordetella pertussisand pertactin-deficient clinical isolates: lessons for pertussis vaccines

“…FHA-mediated adherence of B. pertussis to the respiratory epithelium is in addition enhanced by AC-Hly [44] and the presence of cholesterol containing lipid rafts [45]. FHA might also possess immunomodulatory activities by acting on macrophages, dendritic cells and inflammation [46]. The FHA-mediated induction of IL-6 and IL-10 and suppression of IL-12 lead to the generation of IL-10-producing Treg cells, in turn suppressing IFN-g production necessary for generation of a Th1 immune response, thus delaying the development of a cell-mediated immunity [4] and maybe helping to establish colonization.…”