Human Toll-like receptor 4 recognizes host-specific LPS modifications

Hajjar, Adeline M.; Ernst, Robert K.; Tsai, Jeff H.; Wilson, Christopher; Miller, Samuel I.

doi:10.1038/ni777

Cited by 537 publications

(495 citation statements)

References 35 publications

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“…These results are consistent with a previous study showing that TLR5 is essential to the recognition of P. aeruginosa flagellin both in vivo and ex vivo [38]. P. aeruginosa possesses other virulence factors such as LPS, which is recognized either by TLR2 or TLR4 depending on its structure [23,50]. It has been suggested that the most important system involved in the recognition of P. aeruginosa could be TLR and that TLR4 and TLR5 were redundant for the recognition of P. aeruginosa [38].…”

Section: Discussionsupporting

confidence: 92%

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

Garcia

Morello

Garnier³

et al. 2018

Virulence

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Pseudomonas aeruginosa, an opportunistic pathogen involved in skin and lung diseases, possesses numerous virulence factors, including type 2 and 3 secretion systems (T2SS and T3SS) and its flagellum, whose functions remain poorly known during cutaneous infection. Using isogenic mutants deleted from genes encoding each or all of these three virulence factors, we investigated their role in induction of inflammatory response and in tissue invasiveness in human primary keratinocytes and reconstructed epidermis. Our results showed that flagellum, but not T2SS and T3SS, is involved in induction of a large panel of cytokine, chemokine, and antimicrobial peptide (AMP) mRNA in the infected keratinocytes. Chemokine secretion and AMP tissular production were also dependent on the presence of the bacterial flagellum. This pro-inflammatory effect was significantly reduced in keratinocytes infected in presence of anti-toll-like receptor 5 (TLR5) neutralizing antibody. Bacterial invasion of human epidermis and persistence in a mouse model of sub-cutaneous infection were dependent on the P. aeruginosa flagellum. We demonstrated that flagellum constitutes the main virulence factor of P. aeruginosa involved not only in early induction of the epidermis inflammatory response but also in bacterial invasion and cutaneous persistence. P. aeruginosa is mainly sensed by TLR5 during the early innate immune response of human primary keratinocytes.

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Section: Discussionsupporting

confidence: 92%

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

Garcia

Morello

Garnier³

et al. 2018

Virulence

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“…This suggests that the lipid A acylation state may influence outer membrane permeability. In addition, changes in lipid A acylation have been shown to affect complement activation and opsonization, as well as TLR-4 recognition in vitro (1,7,13,21). Despite these compelling data, the influence of lipid A acylation on in vivo host-pathogen interactions is not well understood.…”

mentioning

confidence: 99%

pagPIs Required for Resistance to Antibody-Mediated Complement Lysis duringBordetella bronchisepticaRespiratory Infection

Pilione

Pishko²,

Preston

et al. 2004

Infect Immun

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To efficiently colonize and persist in the lower respiratory tract, bacteria must survive multiple host immune mechanisms. Bordetella bronchiseptica is a gram-negative respiratory pathogen that naturally infects mice and persists in the lower respiratory tract for up to 49 days postinoculation. In this work, we examined the effect of mutation of the pagP gene on the persistence of B. bronchiseptica in the lower respiratory tract of mice. The pagP gene encodes a palmitoyl transferase that is responsible for the addition of a palmitoyl group to the lipid A region of B. bronchiseptica lipopolysaccharide. Data presented here confirm that a B. bronchiseptica ⌬pagP mutant demonstrates defective persistence in the lower respiratory tract of wild-type mice. We hypothesized that the defective persistence of the B. bronchiseptica ⌬pagP mutant was due to an increased susceptibility of this mutant to a host immune response. In vivo data indicate that both B cells and the complement component C3 are required for the reduced bacterial numbers of the ⌬pagP mutant on day 14 postinoculation. In addition, an in vitro complement killing assay demonstrated that B. bronchiseptica exhibits pagP-dependent resistance to antibody-mediated complement killing at low concentrations of immune serum. Taken together, these results suggest that pagP is required for B. bronchiseptica to resist antibody-mediated complement lysis during respiratory infection.

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“…MD-2 binds LPS with high affinity (17), and it is required for Tlr4 signaling (11). Although normal expression of the Tlr4 and MD-2 are too low for direct measurements of LPS binding to the receptor complex, indirect evidence of ligandreceptor binding has been provided by the ability of structurally different forms of Tlr4 (18,19) or MD-2 (20,21) to discriminate between differences in lipid A structure. Direct evidence of LPS binding to Tlr4/MD-2 was provided by LPS cross-linking experiments in cells that overexpressed these proteins (22).…”

mentioning

confidence: 99%

Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS

Thompson

Tobias

Viriyakosol

et al. 2003

Journal of Biological Chemistry

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Lipopolysaccharide (LPS)-binding protein (LBP) is an acute phase reactant that may play a dual role in vivo,both potentiating and decreasing cell responses to bacterial LPS. Whereas low concentrations of LBP potentiate cell stimulation by transferring LPS to CD14, high LBP concentrations inhibit cell responses to LPS. One inhibitory mechanism involves the ability of LBP to neutralize LPS by transferring it to plasma lipoproteins, whereas other inhibitory mechanisms, such as the one described here, do not require exogenous lipoproteins. Here we show that LBP can inhibit monocyte responses to LPS that has already bound to membrane-bound CD14 (mCD14) on the cell surface. LBP caused rapid dissociation of LPS from mCD14 as measured by the ability of LBP to inhibit cross-linking of a radioiodinated, photoactivatable LPS derivative to mCD14. Whereas LBP removed up to 75% of the mCD14-bound LPS in 10 min, this was not accompanied by extensive release of the LPS from the cells. The cross-linking data suggest that much of the LPS that remained bound to the cells was associated with LBP. The ability of LBP to inhibit cell responses could not be explained by its effect on LPS internalization, because LBP did not significantly increase the internalization of the cell-bound LPS. In cell-free LPS cross-linking experiments, LBP inhibited the transfer of LPS from soluble CD14 to soluble MD-2. Our data support the hypothesis that LBP can inhibit cell responses to LPS by inhibiting LPS transfer from mCD14 to the Toll-like receptor 4-MD-2 signaling receptor.Lipopolysaccharide (LPS 1 ; endotoxin), an abundant component of the outer membrane of Gram-negative bacteria, is one of the most potent of the known bacterial agonists in animal host cells. Whereas LPS recognition benefits the host by sensing the presence of bacteria and mobilizing defense mechanisms, an exaggerated response to LPS may contribute to the harmful sequelae of severe sepsis, which include coagulation disorders, organ failure, shock, and death. The host, therefore, has numerous mechanisms that down-regulate responses to LPS and remove it from the circulation and tissues (1-7).The potency of LPS is due to the sensitivity of the host recognition system, which requires the Toll-like receptor 4 (Tlr4) (8) signaling receptor. At least three LPS-binding proteins (LBP (9), CD14 (10), and MD-2 (11)) are required for sensitive Tlr4-mediated LPS recognition. Plasma LBP potentiates LPS recognition by transferring it from bacterial membranes (6) to CD14 (12, 13), which is expressed as a glycosylphosphatidylinositol-anchored protein on the surfaces of myeloid lineage cells (mCD14) and as an anchorless plasma protein, soluble CD14 (sCD14) (14, 15). CD14 presents LPS to Tlr4, presumably by transferring the LPS to MD-2, an accessory protein that is constitutively associated with the extracellular domain of Tlr4 (16). MD-2 binds LPS with high affinity (17), and it is required for Tlr4 signaling (11). Although normal expression of the Tlr4 and MD-2 are too low for direct measurements...

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Human Toll-like receptor 4 recognizes host-specific LPS modifications

Cited by 537 publications

References 35 publications

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis

pagPIs Required for Resistance to Antibody-Mediated Complement Lysis duringBordetella bronchisepticaRespiratory Infection

Lipopolysaccharide (LPS)-binding Protein Inhibits Responses to Cell-bound LPS

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