Toll-Like Receptor 2 Is Required for Control of Pulmonary Infection with<i>Francisella tularensis</i>

Malik, Meenakshi; Bakshi, Chandra Shekhar; Sahay, Bikash; Shah, Aaloki; Lotz, Steven A.; Sellati, Timothy J.

doi:10.1128/iai.02030-05

Cited by 104 publications

(156 citation statements)

References 34 publications

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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%

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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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Section: Discussionmentioning

confidence: 82%

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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“…Bacteria were cultured on modified Mueller-Hinton (MH) agar plates or in modified MH broth (Difco) with ferric pyrophosphate and IsoVitalex (BD Biosciences) and maintained as described (19). For invasion assays, 2.5 ϫ 10 5 THP-1 or 293T cells were seeded in 24-well plates and infected with LVS or U112 (100 m.o.i.)…”

Section: Methodsmentioning

confidence: 99%

“…Because of its importance in controlling bacterial infection and promoting adaptive immunity, the innate immune response to F. tularensis has been an area of recent interest. In mouse models of tularemia, the macrophage response to F. tularensis LVS is heavily reliant upon TLR2 as TLR2-deficient macrophages fail to produce TNF␣, IL-6, and other NF-B dependent proinflammatory cytokines (19,20). Mouse macrophages infected with U112 produce IL-1␤ in an ASC and caspase-1-dependent fashion, indicating the likely involvement of an NLRP inflammasome (21, 22).…”

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confidence: 99%

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Atianand

Duffy

Shah

et al. 2011

Journal of Biological Chemistry

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Pathogen-triggered activation of the inflammasome complex leading to caspase-1 activation and IL-1␤ production involves similar sensor proteins between mouse and human. However, the specific sensors used may differ between infectious agents and host species. In mice, Francisella infection leads to seemingly exclusive activation of the Aim2 inflammasome with no apparent role for Nlrp3. Here we examine the IL-1␤ response of human cells to Francisella infection. Francisella strains exhibit differences in IL-1␤ production by influencing induction of IL-1␤ and ASC transcripts. Unexpectedly, our results demonstrate that Francisella activates the NLRP3 inflammasome in human cells. Innate immune responses to pathogens are initiated by recognition of pathogen-associated molecular patterns by both extracellular and intracellular sensors (1-3). Pathogen-associated molecular pattern recognition by members of the Toll-like receptor (TLR) 3 family result in the activation of the NF-B, MAPK, and/or interferon regulatory factor signaling pathways depending on the specific TLR engaged (1, 4 -8). Intracellular receptors of the MAVS/RIG-I family act similarly and are involved in recognition of viral nucleic acids (9, 10). Thus, production of inflammatory cytokines and chemokines such as TNF␣, IL-6, and MCP-1 in response to infection generally follows activation via these receptors. The inflammatory cytokines IL-1␤ and IL-18, however, require processing by caspase-1 to produce their active forms (11). Pathogen-associated molecular patterns and danger-associated molecular patterns activate various members of the nucleotide binding leucine-rich receptor (NLR) family in the cytoplasm, resulting in the assembly of an NLR containing, multiprotein complex (the inflammasome) that recruits and activates caspase-1 leading to IL-1␤ processing (12, 13). Although CARD domain-containing NLRs (e.g. Ipaf) can directly interact with caspase-1, most inflammasomes are assembled by Pyrin domain containing NLRs (NLRPs), which recruit caspase-1 indirectly through the adapter molecule ASC (14).Francisella tularensis is the causative agent of tularemia and a potential bioweapon (15). Pulmonary infection with even a single, virulent F. tularensis bacterium is potentially lethal if untreated (16,17). For humans, the type A strain, SchuS4 (F. tularensis sp. tularensis) results in the highest mortality, whereas neither the attenuated type B live vaccine strain LVS (F. tularensis sp. holarctica) or the U112 strain (Francisella tularensis sp. novicida) are virulent. In mice however, the SchuS4, LVS and U112 strains are lethal (18). Because of its importance in controlling bacterial infection and promoting adaptive immunity, the innate immune response to F. tularensis has been an area of recent interest. In mouse models of tularemia, the macrophage response to F. tularensis LVS is heavily reliant upon TLR2 as TLR2-deficient macrophages fail to produce TNF␣, IL-6, and other NF-B dependent proinflammatory cytokines (19,20). Mouse macrophages infected with U112 ...

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“…F. tularensis LPS is inert, lacks endotoxin-like inflammatory properties, and is not sensed by TLR4. 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).…”

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confidence: 99%

Repression of Inflammasome by Francisella tularensis during Early Stages of Infection

Dotson

Rabadi

Westcott

et al. 2013

Journal of Biological Chemistry

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Toll-Like Receptor 2 Is Required for Control of Pulmonary Infection withFrancisella tularensis

Cited by 104 publications

References 34 publications

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

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

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Repression of Inflammasome by Francisella tularensis during Early Stages of Infection

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