Mycobacterial Infection in TLR2 and TLR6 Knockout Mice

Sugawara, Isamu; Yamada, Hiroyuki; Li, Chuanyou; Mizuno, Satoru; Takeuchi, Osamu; Akira, Shizuo

doi:10.1111/j.1348-0421.2003.tb03404.x

Cited by 174 publications

(121 citation statements)

References 29 publications

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“…Further research into the innate immune response may elucidate pathological mechanisms underlying infectious morbidities such as tubal infertility and preterm labour, but as yet few studies have examined the functional effects of innate immune components such as NAPs and TLRs in the reproductive tract. While existing SLPI (Ashcroft et al 2000) and TLRnull (Sugawara et al 2003, Andersen-Nissen et al 2007) mutant mouse models show impaired wound healing and altered responses to infection, they have provided little information relating directly to the reproductive tract. In addition, fundamental differences in key physiological reproductive processes, such as implantation and placentation, exist between mouse and human limiting the relevance of these rodent models.…”

Section: Resultsmentioning

confidence: 99%

Innate immunity and disorders of the female reproductive tract

Horne¹,

Stock²,

King³

2008

Reproduction

137

129

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Sexually transmitted infections, and their associated sequelae, such as tubal infertility, ectopic pregnancy and preterm labour, are a major worldwide health problem. Chlamydia trachomatis infection is thought to be the leading global cause of tubal infertility and tubal ectopic pregnancy. Preterm birth occurs in around 10% of all deliveries, and nearly 30% of preterm deliveries are associated with intrauterine infection. The mucosal innate immune system of the female reproductive tract has evolved to eliminate such sexually transmitted pathogens whilst maintaining its ability to accommodate specialized physiological functions that include menstruation, fertilization, implantation, pregnancy and parturition. The aim of this review was to describe the role and distribution of key mediators of the innate immune system, the natural antimicrobial peptides (secretory leukocyte protease inhibitor, elafin and the defensins) and the pattern recognition toll-like receptors in the normal female reproductive tract and in the context of these pathological processes.

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Section: Resultsmentioning

confidence: 99%

Innate immunity and disorders of the female reproductive tract

Horne¹,

Stock²,

King³

2008

Reproduction

137

129

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“…Neutrophil depletion during early mycobacterial infection exacerbates disease and dysregulates granuloma formation (23)(24)(25)(26). However neutrophils are associated with tissue damage and necrosis in late disease and are a feature of granulomas in gene-deletion models associated with increased susceptibility to tuberculosis (27)(28)(29)(30)(31)(32)(33). Neutrophils release mediators that likely contributed to the angiogenesis in the trehalose mycolate-bearing matrices, evident at 4 days postinjection (34).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Activity of Released Cell Wall Lipids ofMycobacterium bovisBacillus Calmette-Guérin Is Due Principally to Trehalose Mycolates

Geisel

Sakamoto

Russell

et al. 2005

The Journal of Immunology

173

154

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The hallmark of Mycobacterium-induced pathology is granulomatous inflammation at the site of infection. Mycobacterial lipids are potent immunomodulators that contribute to the granulomatous response and are released in appreciable quantities by intracellular bacilli. Previously we investigated the granulomagenic nature of the peripheral cell wall lipids of Mycobacterium bovis bacillus Calmette-Guérin (BCG) by coating the lipids onto 90-μm diameter microspheres that were mixed into Matrigel matrix with syngeneic bone marrow-derived macrophages and injected i.p. into mice. These studies demonstrated that BCG lipids elicit proinflammatory cytokines and recruit leukocytes. In the current study we determined the lipids responsible for this proinflammatory effect. BCG-derived cell wall lipids were fractionated and purified by liquid chromatography and preparative TLC. The isolated fractions including phosphatidylinositol dimannosides, cardiolipin, phosphatidylglycerol, phosphatidylethanolamine, trehalose monomycolate, trehalose dimycolate, and mycoside B. Trehalose dimycolate, when delivered to bone marrow-derived murine macrophages, induced the greatest secretion of IL-1β, IL-6, and TNF-α in vitro. Trehalose dimycolate similarly induced the greatest secretion of these proinflammatory cytokines in ex vivo matrices over the course of 12 days. Trehalose monomycolate and dimycolate also induced profound neutrophil recruitment in vivo. Experiments with TLR2 or TLR4 gene-deficient mice revealed no defects in responses to trehalose mycolates, although MyD88-deficient mice manifested significantly reduced cell recruitment and cytokine production. These results demonstrate that the trehalose mycolates, particularly trehalose dimycolate, are the most bioactive lipids in the BCG extract, inducing a proinflammatory cascade that influences granuloma formation.

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“…While some groups found that TLR-mediated signalling is dispensable for protective immunity against M. tuberculosis [3][4][5][6], others suggested an essential contribution of TLR to protection [7][8][9]. The TLR contain a Toll/IL-1 receptor domain, which associates with the adaptor molecule MyD88.…”

Section: Introductionmentioning

confidence: 99%

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MU. IFN-c secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MU to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MU. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophildriven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.Key words: IFN-c . IL-18 . Mouse . Neutrophils . Tuberculosis IntroductionDespite more than 125 years of research and development, tuberculosis (TB) remains the most hazardous bacterial infection worldwide with approximately 2 million people dying of the disease annually [1]. The risk of disease is increased by immunocompromising conditions such as AIDS emphasizing that T-cell immunity protects latently infected individuals against active TB. The innate immune response to Mycobacterium tuberculosis instructs acquired immunity in the initial stage, and executes effector mechanisms in the chronic stage.M. tuberculosis is usually transmitted via aerosols and establishes stable infection in the lung. There, M. tuberculosis is engulfed by MF and DC, which serve as host cells for mycobacterial survival and propagation. Binding of mycobacterial ligands to TLR-2, -4 and -9 promotes release of chemokines and proinflammatory cytokines, expression of adhesion molecules and attraction of MF, DC and PMN. Two crucial MF-and DCderived cytokines, , induce NK-cell activity and bias immunity towards a Th1 cell response characterized by profound 396IFN-g production, which is considered critical for protection against M. tuberculosis [2]. Activated MF express anti-mycobacterial molecules such as nitric oxide synthase (NOS)-2 (also known as inducible NOS) and LRG47 as well as cytokines such as TNF-a, which promotes granuloma formation within the infected tissue to sequester the bacilli from dissemination [2].Despite the prevailing assumption that resistance to M. tuberculosis infection depends on microbe sensing through TLR, their importance for mounting a protective immune response against M. tuberculosis remains controversial. While some groups found that TLR-mediated...

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Mycobacterial Infection in TLR2 and TLR6 Knockout Mice

Cited by 174 publications

References 29 publications

Innate immunity and disorders of the female reproductive tract

Innate immunity and disorders of the female reproductive tract

In Vivo Activity of Released Cell Wall Lipids ofMycobacterium bovisBacillus Calmette-Guérin Is Due Principally to Trehalose Mycolates

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

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