The Complex Mechanism of Antibody-Mediated Clearance of <i>Bordetella</i> from the Lungs Requires TLR4

Kirimanjeswara, Girish S.; Mann, Paul B.; Pilione, Mylisa; Kennett, Mary J.; Harvill, Eric T.

doi:10.4049/jimmunol.175.11.7504

Cited by 40 publications

(59 citation statements)

References 41 publications

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“…We have reported previously a defect in the immediate influx of neutrophils into the lungs of TLR4-defective mice following primary infection with B. pertussis (21). This is consistent with a report demonstrating that TLR4 is required for recruitment of neutrophils to the lungs, where they mediated Ab-mediated clearance of Bordetella bronchiseptica (40). IL-17 has already been shown to play a role in lung CXC chemokine production and neutrophil recruitment in host defense against K. pneumoniae infection (19,41).…”

Section: Discussionsupporting

confidence: 76%

TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells

Higgins

Jarnicki

Lavelle

et al. 2006

The Journal of Immunology

330

302

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Whole cell pertussis vaccines (Pw) induce Th1 responses and protect against Bordetella pertussis infection, whereas pertussis acellular vaccines (Pa) induce Ab and Th2-biased responses and also protect against severe disease. In this study, we show that Pw failed to generate protective immunity in TLR4-defective C3H/HeJ mice. In contrast, protection induced with Pa was compromised, but not completely abrogated, in C3H/HeJ mice. Immunization with Pw, but not Pa, induced a population of IL-17-producing T cells (Th-17), as well as Th1 cells. Ag-specific IL-17 and IFN-γ production was significantly lower in Pw-immunized TLR4-defective mice. Furthermore, treatment with neutralizing anti-IL-17 Ab immediately before and after B. pertussis challenge significantly reduced the protective efficacy of Pw. Stimulation of dendritic cells (DC) with Pw promoted IL-23, IL-12, IL-1β, and TNF-α production, which was impaired in DC from TLR4-defective mice. B. pertussis LPS, which is present in high concentrations in Pw, induced IL-23 production by DC, which enhanced IL-17 secretion by T cells, but the induction of Th-17 cells was also dependent on IL-1. In addition, we identified a new effector function for IL-17, activating macrophage killing of B. pertussis, and this bactericidal activity was less efficient in macrophages from TLR4-defective mice. These data provide the first definitive evidence of a role for TLRs in protective immunity induced by a human vaccine. Our findings also demonstrate that activation of innate immune cells through TLR4 helps to direct the induction of Th1 and Th-17 cells, which mediate protective cellular immunity to B. pertussis.

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Section: Discussionsupporting

confidence: 76%

TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells

Higgins

Jarnicki

Lavelle

et al. 2006

The Journal of Immunology

330

302

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“…Antibodies may clear bacteria by neutralization, complement-mediated lysis, or opsonization for FcγR-mediated phagocytosis. We have previously shown that serum antibodies rapidly clear B. bronchiseptica from the lungs of mice and that the mechanism involved both complement and FcγRs (25,26). Since B. pertussis is very closely related to B. bronchiseptica but is cleared much more slowly by serum antibodies, we predicted that B. pertussis has some mechanism to resist 1 or more of these antibody effector functions early in the infection.…”

Section: Serum Antibodies Do Not Rapidly Clear B Pertussismentioning

confidence: 99%

“…We have previously shown that FcγR-bearing neutrophils are the primary inflammatory cells recruited to the lungs following infection with B. bronchiseptica and are required for rapid antibodymediated bacterial clearance (26,36). Since B. pertussis clearance required FcγRs, we sought to determine whether neutrophils are required for antibody-mediated clearance of this organism.…”

Section: Neutrophils Are Required For Antibody-mediated Clearance Of mentioning

confidence: 99%

“…Interestingly, while both require B cells for their clearance from the respiratory tract, only B. bronchiseptica is rapidly (within 3 days) cleared by adoptively transferred serum antibodies (20). We previously elucidated the mechanism of antibody-mediated clearance of B. bronchiseptica in order to determine the pathway that is presumably inhibited by B. pertussis (25,26). Serum antibodymediated clearance of B. bronchiseptica requires a TLR4-induced early recruitment of neutrophils that phagocytose bacteria via Fcγ receptors (FcγRs) and CR3.…”

Section: Introductionmentioning

confidence: 99%

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Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of Bordetella pertussis

Kirimanjeswara¹

2005

Journal of Clinical Investigation

136

127

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Whooping cough is considered a childhood disease, although there is growing evidence that children are infected by adult carriers. Additionally, increasing numbers of vaccinated adults are being diagnosed with Bordetella pertussis disease. Thus it is critical to understand how B. pertussis remains endemic even in highly vaccinated or immune populations. Here we used the mouse model to examine the nature of sterilizing immunity to B. pertussis. Antibodies were necessary to control infection but did not rapidly clear B. pertussis from the lungs. However, antibodies affected B. pertussis after a delay of at least a week by a mechanism that involved neutrophils and Fc receptors, suggesting that neutrophils phagocytose and clear antibody-opsonized bacteria via Fc receptors. B. pertussis blocked migration of neutrophils and inhibited their recruitment to the lungs during the first week of infection by a pertussis toxin-dependent (PTx-dependent) mechanism; a PTx mutant of B. pertussis induced rapid neutrophil recruitment and was rapidly cleared from the lungs by adoptively transferred antibodies. Depletion of neutrophils abrogated the defects of the PTx mutant. Together these results indicate that PTx inhibits neutrophil recruitment, which consequently allows B. pertussis to avoid rapid antibody-mediated clearance and therefore successfully infect immune hosts.

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“…Furthermore, there is an increasing incidence of B. pertussis infections in adolescents and adults, possibly due to waning immunity following the introduction of acellular vaccines into most developed countries (2). Adaptive immunity generated by previous infection or immunization with the whole-cell vaccine is effective at preventing severe disease, and studies in a mouse model suggested that a combination of Abs and Th1 and Th17 cells are involved (3)(4)(5)(6)(7). Protection against a primary infection with B. pertussis is mediated by innate and adaptive immune responses, and IFN-g secreted by NK and Th1 cells seems to be critical (4,8,9).…”

mentioning

confidence: 99%

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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The Complex Mechanism of Antibody-Mediated Clearance of Bordetella from the Lungs Requires TLR4

Cited by 40 publications

References 41 publications

TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells

TLR4 Mediates Vaccine-Induced Protective Cellular Immunity to Bordetella pertussis: Role of IL-17-Producing T Cells

Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of Bordetella pertussis

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

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