<i>Yersinia pestis</i> Evades TLR4-dependent Induction of IL-12(p40)2 by Dendritic Cells and Subsequent Cell Migration

Robinson, Richard; Khader, Shabaana A.; Locksley, Richard M.; Lien, Egil; Smiley, Stephen T.; Cooper, Andrea

doi:10.4049/jimmunol.181.8.5560

Cited by 39 publications

(44 citation statements)

References 42 publications

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“…Transformation of Y. pestis with a plasmid encoding E. coli LpxL promotes constitutive production of hexa-acylated forms of LPS, thereby attenuating virulence by increasing Toll-like receptor 4 (TLR4)-activating ability (26). We transformed D27, a well-characterized Pgm-deficient variant of the Y. pestis KIM strain, with the same LpxL-producing plasmid described previously, thereby creating strain D27-pLpxL (35). To generate a control strain, we also transformed D27 with the parental plasmid, pBR322.…”

Section: Resultsmentioning

confidence: 99%

“…The intranasal median lethal dose (MLD) of strain D27, as calculated by the method of Reed and Muench (34), is approximately 1 ϫ 10 4 CFU when the strain is grown and administered as described above. The vaccine strain D27-pLpxL and control strain D27-pBR322 were prepared by transforming strain D27 with plasmid pLpxL or pBR322, respectively (26,35). These strains were stored and grown as described for D27 in culture medium supplemented with 100 g/ml ampicillin.…”

Section: Methodsmentioning

confidence: 99%

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D27-pLpxL, an Avirulent Strain of Yersinia pestis , Primes T Cells That Protect against Pneumonic Plague

et al. 2009

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

D27-pLpxL, an Avirulent Strain of Yersinia pestis , Primes T Cells That Protect against Pneumonic Plague

et al. 2009

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“…The change from hexa-acylated to tetra-acylated lipid A upon temperature upshift from 21°C to 37°C is essential for pathogenesis, because Y. pestis mutants unable to switch to the tetra-acylated form stimulate a protective inflammatory response in the host and are unable to cause systemic disease even at high challenge doses (34). Robinson et al (44) showed that Y. pestis producing tetra-acylated lipid A evades early dendritic cell activation. Y. pestis expressing the E. coli LpxL acyltransferase produced hexa-acylated lipid A at 37°C and stimulated dendritic cell activation and migration.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Innate Immune Response to Yersinia pestis after Intradermal Infection in a Mouse Model

et al. 2012

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A hallmark of Yersinia pestis infection is a delayed inflammatory response early in infection. In this study, we use an intradermal model of infection to study early innate immune cell recruitment. Mice were injected intradermally in the ear with wild-type (WT) or attenuated Y. pestis lacking the pYV virulence plasmid (pYV ؊ ). The inflammatory responses in ear and draining lymph node samples were evaluated by flow cytometry and immunohistochemistry. As measured by flow cytometry, total neutrophil and macrophage recruitment to the ear in WT-infected mice did not differ from phosphate-buffered saline (PBS) controls or mice infected with pYV ؊ , except for a transient increase in macrophages at 6 h compared to the PBS control. Limited inflammation was apparent even in animals with high bacterial loads (10 5 to 10 6 CFU). In addition, activation of inflammatory cells was significantly reduced in WT-infected mice as measured by CD11b and major histocompatibility complex class II (MHC-II) expression. When mice infected with WT were injected 12 h later at the same intradermal site with purified LPS, Y. pestis did not prevent recruitment of neutrophils. However, significant reduction in neutrophil activation remained compared to that of PBS and pYV ؊ controls. Immunohistochemistry revealed qualitative differences in neutrophil recruitment to the skin and draining lymph node, with WT-infected mice producing a diffuse inflammatory response. In contrast, focal sites of neutrophil recruitment were sustained through 48 h postinfection in pYV ؊ -infected mice. Thus, an important feature of Y. pestis infection is reduced activation and organization of inflammatory cells that is at least partially dependent on the pYV virulence plasmid.Y ersinia pestis, the bacterial agent of plague, is an international public health concern from the perspective of both natural transmission and its potential use as a bioterrorist weapon (20,41). Two other pathogenic Yersinia species, Yersinia pseudotuberculosis and Yersinia enterocolitica, cause a mild, self-limiting enteric disease. However, Y. pestis is unique among the yersiniae as a flea-borne pathogen of rodents (17). Yersinia pestis is highly invasive, causing severe septicemia which, if untreated, is usually fatal to its host. This high bacteremia is necessary to infect fleas feeding on the host and to propagate the transmission cycle (15,32).Transmission of Y. pestis by fleas typically results in bubonic plague, characterized by painful swelling of the lymph node proximal to the feeding site. A critical first step in determining the outcome of bubonic plague occurs in the dermis of the host, where Y. pestis is deposited by the flea vector. If the bacterium is contained and killed by the innate inflammatory response in the skin, the disease cannot progress. These events occur very early after transmission. Within about 12 to 24 h, Y. pestis has colonized the draining lymph node and from there can disseminate to other target organs in the host, such as the spleen and liver.All three path...

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“…For example, the flagellin expressed by Campylobacter jejuni lacks a TLR5 binding site and is a poor activator of this signaling pathway (13,14). Likewise, Yersinia pestis can evade TLR4 signaling by producing a tetra-acylated form of lipid A when grown at a temperature that resembles that of the mammalian host (15,16). Although strategies designed to avoid recognition of PAMPs by their respective PRRs have been described extensively, it is unclear how bacterial pathogens can evade inflammasome activation, a critical host defense pathways poised to detect manipulation of host cells by bacterial pathogens.…”

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confidence: 99%

The Flagellar Regulator TviA Reduces Pyroptosis by Salmonella enterica Serovar Typhi

Winter

Atluri

et al. 2015

Infect Immun

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To discern virulent from innocuous microbes, the innate immune system senses events associated with bacterial access to immunoprivileged sites such as the host cell cytosol. One such pathway is triggered by the cytosolic delivery of flagellin, the major subunit of the flagellum, by bacterial secretion systems. This leads to inflammasome activation and subsequent proinflammatory cell death (pyroptosis) of the infected phagocyte. In this study, we demonstrate that the causative agent of typhoid fever, Salmonella enterica serovar Typhi, can partially subvert this critical innate immune recognition event. The transcriptional regulator TviA, which is absent from Salmonella serovars associated with human gastroenteritis, repressed the expression of flagellin during infection of human macrophage-like (THP-1) cells. This mechanism allowed S. Typhi to dampen inflammasome activation, leading to reduced interleukin-1␤ (IL-1␤) secretion and diminished cell death. Likewise, the introduction of the tviA gene in nontyphoidal Salmonella enterica serovar Typhimurium reduced flagellin-induced pyroptosis. These data suggest that gene regulation of virulence factors enables S. Typhi to evade innate immune recognition by concealing a pathogen-induced process from being sensed by the inflammasome. To distinguish between self and nonself, the host employs a multitude of innate pattern recognition receptors (PRRs) to initiate adequate host responses aimed at eradicating invading microbes. Activation of PRRs can be achieved by two conceptually different types of events: recognition of conserved microbial structures (pathogen-associated molecular patterns [PAMPs]) (1) and recognition of virulence-associated strategies aimed at manipulating host cells (patterns of pathogenesis) (2, 3). PAMPs are specific for certain groups of microbes regardless of their pathogenic potential, while host cell manipulation is a trait found exclusively in pathogens (2, 3).PAMPs are typically detected by Toll-like receptors (TLRs), resulting in the activation of the NF-B pathway (4). For example, flagellin, the major component of the flagellum, is recognized by TLR5, which enables the innate immune system to detect flagellated bacteria, regardless of their pathogenic potential (5, 6). In contrast, detection of host cell manipulation events allows the host to discern virulent from commensal microbes and scale the host defenses commensurate with the threat (2, 3). A prime example is the translocation of bacterial flagellin into the host cell cytosol through virulence-associated type III secretion system or type IV secretion system, which triggers a proinflammatory form of cell death termed pyroptosis (7-9). Pyroptotic cell death is characterized by the assembly and activation of the inflammasome (10, 11). In the center of this multiprotein complex, active caspase-1 processes pro-interleukin-1␤ (IL-1␤) as well as pro-IL-18 into the biologically active forms by proteolytic cleavage. IL-1␤ and IL-18 are highly proinflammatory cytokines that are critical for coordi...

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Yersinia pestis Evades TLR4-dependent Induction of IL-12(p40)2 by Dendritic Cells and Subsequent Cell Migration

Cited by 39 publications

References 42 publications

D27-pLpxL, an Avirulent Strain of Yersinia pestis , Primes T Cells That Protect against Pneumonic Plague

D27-pLpxL, an Avirulent Strain of Yersinia pestis , Primes T Cells That Protect against Pneumonic Plague

Kinetics of Innate Immune Response to Yersinia pestis after Intradermal Infection in a Mouse Model

The Flagellar Regulator TviA Reduces Pyroptosis by Salmonella enterica Serovar Typhi

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