Toll‐Like Receptor 4 Is Critical to Innate Host Defense in a Murine Model of Bordetellosis

Mann, Paul B.; Kennett, Mary J.; Harvill, Eric T.

doi:10.1086/381898

Cited by 49 publications

(60 citation statements)

References 15 publications

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“…Interestingly, the bacterial burden was exacerbated in IL-17 2/2 mice, although not as significantly as in IL-1RI 2/2 mice, suggesting that some, but not all, of the effects of IL-1b involve induction of IL-17 production. These findings are consistent with the well-established role of IFN-g (4, 36) and other effector cells and molecules, such as those induced through TLR4-activation (5,42,43), in protection against B. pertussis and suggest that Th1 and Th17 cells may cooperate to mediate bacterial clearance. Consistent with previous reports on other toxins (22,23), we found that the pore-forming activity of CyaA was essential for promoting IL-1b via activation of the inflammasome in a process that involves a reduction in intracellular potassium The Journal of Immunologylevels.…”

Section: Discussionsupporting

confidence: 89%

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Dunne

Ross

Pospíšilová

et al. 2010

The Journal of Immunology

158

161

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Inflammasome-mediated IL-1β production is central to the innate immune defects that give rise to certain autoinflammatory diseases and may also be associated with the generation of IL-17–producing CD4+ T (Th17) cells that mediate autoimmunity. However, the role of the inflammasome in driving adaptive immunity to infection has not been addressed. In this article, we demonstrate that inflammasome-mediated IL-1β plays a critical role in promoting Ag-specific Th17 cells and in generating protective immunity against Bordetella pertussis infection. Using a murine respiratory challenge model, we demonstrated that the course of B. pertussis infection was significantly exacerbated in IL-1R type I-defective (IL-1RI−/−) mice. We found that adenylate cyclase toxin (CyaA), a key virulence factor secreted by B. pertussis, induced robust IL-1β production by dendritic cells through activation of caspase-1 and the NALP3-containing inflammasome complex. Using mutant toxins, we demonstrate that CyaA-mediated activation of caspase-1 was not dependent on adenylate cyclase enzyme activity but was dependent on the pore-forming capacity of CyaA. In addition, CyaA promoted the induction of Ag-specific Th17 cells in wild-type but not IL-1RI−/− mice. Furthermore, the bacterial load was enhanced in IL-17–defective mice. Our findings demonstrate that CyaA, a virulence factor from B. pertussis, promotes innate IL-1β production via activation of the NALP3 inflammasome and, thereby, polarizes T cell responses toward the Th17 subtype. In addition to its known role in subverting host immunity, our findings suggest that CyaA can promote IL-1β–mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.

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Section: Discussionsupporting

confidence: 89%

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Dunne

Ross

Pospíšilová

et al. 2010

The Journal of Immunology

158

161

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“…Our findings show that CyaA induces DC maturation through TLR4 signaling and that the CTL induction by CyaA-OVA is strongly affected in TLR4-deficient mice, supporting a critical role for this pathway in the efficiency of this vector. Interestingly, it has been shown that TLR4 is a central player in orchestration of very early innate defense against B. pertussis (29) and is required for the induction and effector phases of adaptive immunity to B. pertussis (30)(31)(32). However, in these studies, TLR4 signaling was attributed to the presence of B. pertussis LPS.…”

Section: Discussionmentioning

confidence: 98%

Antigen Targeting to CD11b+ Dendritic Cells in Association with TLR4/TRIF Signaling Promotes Strong CD8+ T Cell Responses

Dadaglio

Fayolle

Zhang

et al. 2014

The Journal of Immunology

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Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant. Two therapeutic vaccine candidates against human papilloma viruses and melanoma have been developed recently, based on the CyaA vector, and are currently in clinical trials. We took advantage of one of these highly purified vaccines, produced under good manufacturing practice–like conditions, to decipher the mechanisms by which CyaA induces immune responses. In this study, we demonstrate that CyaA binds both human and mouse CD11b+ dendritic cells (DCs) and induces their maturation, as shown by the upregulation of costimulatory and MHC molecules and the production of proinflammatory cytokines. Importantly, we show that DCs sense CyaA through the TLR4/Toll/IL-1R domain–containing adapter-inducing IFN-β pathway, independent of the presence of LPS. These findings show that CyaA possesses the intrinsic ability to not only target DCs but also to activate them, leading to the induction of strong immune responses. Overall, this study demonstrates that Ag delivery to CD11b+ DCs in association with TLR4/Toll/IL-1R domain–containing adapter-inducing IFN-β activation is an efficient strategy to promote strong specific CD8+ T cell responses.

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“…Our data also suggest that plrS mutants are more susceptible to innate immune mechanisms that function at early stages of infection, perhaps by enhanced clearance by phagocytic cells. Bordetella can interact directly with macrophages (26,28), and previous work using B. bronchiseptica infection of murine lungs has shown that bacterial clearance involves activation of Tolllike receptor 4 and CD11b immune cell signaling pathways (39,50). An important next step in characterization of plrS function will include an evaluation of its contribution to immune cell activity, and toward this end, we have observed that the levels of adherence of plrS mutants to J774 macrophage-like cells in culture are similar to those of wild-type B. bronchiseptica (K. T. Cochran and S. M. Julio, unpublished observations), suggesting that the defect present in plrS strains may exist at a level other than direct interactions with immune cells.…”

Section: Discussionmentioning

confidence: 99%

A Novel Sensor Kinase Is Required for Bordetella bronchiseptica To Colonize the Lower Respiratory Tract

Kaut¹,

Duncan

Kim³

et al. 2011

Infect Immun

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Bacterial virulence is influenced by the activity of two-component regulator systems (TCSs), which consist of membrane-bound sensor kinases that allow bacteria to sense the external environment and cytoplasmic, DNA-binding response regulator proteins that control appropriate gene expression. Respiratory pathogens of the Bordetella genus require the well-studied TCS BvgAS to control the expression of many genes required for colonization of the mammalian respiratory tract. Here we describe the identification of a novel gene in Bordetella bronchiseptica, plrS, the product of which shares sequence homology to several NtrY-family sensor kinases and is required for B. bronchiseptica to colonize and persist in the lower, but not upper, respiratory tract in rats and mice. The plrS gene is located immediately 5 to and presumably cotranscribed with a gene encoding a putative response regulator, supporting the idea that PlrS and the product of the downstream gene may compose a TCS. Consistent with this hypothesis, the PlrS-dependent colonization phenotype requires a conserved histidine that serves as the site of autophosphorylation in other sensor kinases, and in strains lacking plrS, the production and/or cellular localization of several immune-recognized proteins is altered in comparison to that in the wild-type strain. Because plrS is required for colonization and persistence only in the lower respiratory tract, a site where innate and adaptive immune mechanisms actively target infectious agents, we hypothesize that its role may be to allow Bordetella to resist the host immune response.

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Toll‐Like Receptor 4 Is Critical to Innate Host Defense in a Murine Model of Bordetellosis

Cited by 49 publications

References 15 publications

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Antigen Targeting to CD11b+ Dendritic Cells in Association with TLR4/TRIF Signaling Promotes Strong CD8+ T Cell Responses

A Novel Sensor Kinase Is Required for Bordetella bronchiseptica To Colonize the Lower Respiratory Tract

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