Innate immune response to <i>Francisella tularensis</i> is mediated by TLR2 and caspase-1 activation

Li, Hanfen; Nookala, Suba; Bina, Xiaowen R.; Bina, James E.; Re, Fabio

doi:10.1189/jlb.0406294

Cited by 77 publications

(102 citation statements)

References 35 publications

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“…Host response to Francisella has been shown to be critically dependent on the expression of TLR2 [15][16][17][18]. Consistent with a lack of effect on the infection-induced signaling events, IFNc treatment did not alter TLR2 levels (Fig.…”

Section: Role Of Ifnc-priming During Infectionsupporting

confidence: 61%

IFNγ enhances IL‐23 production during Francisella infection of human monocytes

Butchar¹,

Parsa²,

Marsh³

et al. 2008

FEBS Letters

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We previously demonstrated that monocytes produce IL-23 during Francisella infection, and that IL-23 induces IFNc from NK cells. Here, we demonstrate that IFNc-priming of monocytes enhances IL-23 production during Francisella infection. This effect was seen on the IL12/23 p40 subunit. Induction of IL-12/23 p40 is reported to be enhanced by IRF-1 and IRF-8. Consistently, microarray analysis of IFNc-treated monocytes revealed a significant induction of the IRFs. Interestingly, IFNcprimed monocytes produced IL-12 p70, a more potent inducer of IFNc than IL-23. We propose that there exists an amplification loop between monocyte IL-23 and NK/T cell IFNc that leads to IL-12 p70 production.

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Section: Role Of Ifnc-priming During Infectionsupporting

confidence: 61%

IFNγ enhances IL‐23 production during Francisella infection of human monocytes

Butchar¹,

Parsa²,

Marsh³

et al. 2008

FEBS Letters

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“…The weak proinflammatory activity of LPS from F. tularensis has been well described [17,18], and mice deficient in TLR4 are as susceptible to lethal tularemia as are naïve mice of the same background [16,52]. In contrast, recent reports have indicated an important role for TLR2 in the pathogenesis of tularemia [21,22,25,26]. The fact that recombinant LpnA induced inflammation in human macrophages in a manner that was dependent on TLR2 implicates it and other F. tularensis lipoproteins as important mediators of the host response in tularemia.…”

Section: Discussionmentioning

confidence: 82%

“…Together, these data suggest that F. tularensis possesses components other than LPS that are capable of initiating inflammation and regulating virulence. Recent findings have implicated TLR2, a receptor for lipoproteins, as important in the host response to infection with Francisella [21,22,25,26]. Therefore, the lipoproteins of F. tularensis may be important in the pathogenesis of tularemia.…”

Section: Introductionmentioning

confidence: 99%

A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence

Forestal

Gil

Monfett

et al. 2008

Microbial Pathogenesis

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Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. A live vaccine strain (LVS) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. F. tularensis has been classified as a Category A agent of bioterrorism. Despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. Here, we report the deletion of a well-characterized lipoprotein of F. tularensis, designated LpnA (also known as Tul4), in the LVS. An LpnA deletion mutant was comparable to the wild-type strain in its ability to grow intracellularly and cause lethal disease in mice. Additionally, mice inoculated with a sublethal dose of the mutant strain were afforded the same protection against a subsequent lethal challenge with the LVS as were mice initially administered a sublethal dose of the wild-type bacterium. The LpnA-deficient strain showed an equivalent ability to promote secretion of chemokines by human monocyte-derived macrophages as its wild-type counterpart. However, recombinant LpnA potently stimulated primary cultures of human macrophages in a Toll-like receptor 2-dependent manner. Although human endothelial cells also were activated by recombinant LpnA, their response was relatively modest. LpnA is clearly unnecessary for multiple functions of the LVS, but its inflammatory capacity implicates it and other Francisella lipoproteins as potentially important to the pathogenesis of tularemia.

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“…TLR2 plays an essential role in innate immunity to F. tularensis LVS, and we have reported earlier that deficiency of TLR2 enhances murine susceptibility to infection (17). TLR2 forms heterodimers in association with TLR1 or TLR6 and plays a key role in the host defense against F. tularensis (18). In addition to TLRs, another family of pattern-recognition receptors, the Nod-like receptor (NLR) family, can detect bacterial products in the cytoplasm (19 -21).…”

mentioning

confidence: 99%