Klebsiella pneumoniae subverts the activation of inflammatory responses in a NOD1-dependent manner

Regueiro, Verónica; Moranta, David; Frank, Christian; Larrarte, Eider; Margareto, Javier; March, Catalina; Garmendia, Junkal; Bengoechea, José A.

doi:10.1111/j.1462-5822.2010.01526.x

Cited by 62 publications

(124 citation statements)

References 58 publications

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“…Therefore, targeting p65 subunit in the host cell cytoplasm and preventing its nuclear translocation may represent an efficient strategy that F. tularensis adopts to inhibit NF-B transactivating activity. A similar role has recently been reported for OmpA protein of Klebsiella pneumoniae (66,67). Collectively, these results demonstrate that FTT0831c of F. tularensis SchuS4 offers this pathogen a selective advantage by allowing immune evasion that is independent of any other Francisella protein.…”

Section: Discussionsupporting

confidence: 56%

Identification of a Novel Francisella tularensis Factor Required for Intramacrophage Survival and Subversion of Innate Immune Response

Mahawar

Atianand

Dotson

et al. 2012

Journal of Biological Chemistry

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Background:The mechanism of immune suppression caused by Francisella tularensis SchuS4 strain, a category A agent, are yet unknown. Results: FTL_0325/FTT0831c genes of F. tularensis suppress proinflammatory cytokines by preventing activation of NF-B signaling. Conclusion: FTL_0325/FTT0831c of Francisella is a key virulence factor and functions as an immunosuppressant. Significance: Understanding of such pathogenic mechanisms will define vaccine candidates to prevent tularemia acquired naturally or through an act of bioterrorism.

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Section: Discussionsupporting

confidence: 56%

Identification of a Novel Francisella tularensis Factor Required for Intramacrophage Survival and Subversion of Innate Immune Response

Mahawar

Atianand

Dotson

et al. 2012

Journal of Biological Chemistry

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“…A transcriptome analysis of Klebsiella in different tissues is warranted to shed light into tissue-induced Klebsiella adaptations. Here, we demonstrate that the LpxO-dependent lipid A modification acts as a shield against innate immunity recognition thereby contributing to the panoply of K. pneumoniae systems involved in the attenuation of inflammatory responses in vitro and in vivo (33)(34)(35)(36)(37)(38). This lipid A modification also helps K. pneumoniae to counteract the bactericidal action of APs, including colistin, which is one of the few remaining therapeutic options available to treat infections caused by multidrug-resistant Klebsiella isolates.…”

Section: Discussionmentioning

confidence: 96%

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

Llobet

Martínez-Moliner

Moranta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The outcome of an infection depends on host recognition of the pathogen, hence leading to the activation of signaling pathways controlling defense responses. A long-held belief is that the modification of the lipid A moiety of the lipopolysaccharide could help Gram-negative pathogens to evade innate immunity. However, direct evidence that this happens in vivo is lacking. Here we report the lipid A expressed in the tissues of infected mice by the human pathogen Klebsiella pneumoniae. Our findings demonstrate that Klebsiella remodels its lipid A in a tissue-dependent manner. Lipid A species found in the lungs are consistent with a 2-hydroxyacyl-modified lipid A dependent on the PhoPQ-regulated oxygenase LpxO. The in vivo lipid A pattern is lost in minimally passaged bacteria isolated from the tissues. LpxO-dependent modification reduces the activation of inflammatory responses and mediates resistance to antimicrobial peptides. An lpxO mutant is attenuated in vivo thereby highlighting the importance of this lipid A modification in Klebsiella infection biology. Colistin, one of the last options to treat multidrug-resistant Klebsiella infections, triggers the in vivo lipid A pattern. Moreover, colistin-resistant isolates already express the in vivo lipid A pattern. In these isolates, LpxO-dependent lipid A modification mediates resistance to colistin. Deciphering the lipid A expressed in vivo opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern.

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“…Our new immunoblot data indicate that the previously observed effect of T2S on cytokine gene transcription (16) is due, at least partly, to a dampening of the macrophage's MAPK and NF-B pathways. Although it is possible that proteins secreted via T2S act directly on components of the MAPK and NF-B pathways, as has been documented following exposure to various pathogens (21,(74)(75)(76), we focused this study on discerning whether T2S diminishes the upstream event of PAMP recognition. By generating a set of human knockdown cell lines, we determined that the NLR, RLR, TRIF, and PKR pathways as well as ASC-and caspase-4-dependent inflammasomes are not required for the T2S dampening effect.…”

Section: Discussionmentioning

confidence: 99%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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Previously, we reported that mutants of Legionella pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-B) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)-or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the L. pneumophila T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during L. pneumophila infection of macrophages.KEYWORDS Legionella pneumophila, TLR2, cytokine, innate immunity, macrophage, type II secretion L egionella pneumophila, a Gram-negative bacterium that is widespread in aquatic habitats, is the principal agent of Legionnaires' disease pneumonia (1-6). In the lungs, Legionella bacteria invade and grow in resident macrophages and then trigger severe inflammation (2). In macrophages, L. pneumophila evades the degradative lysosomal pathway and replicates to large numbers within a membrane-bound vacuole, the Legionella-containing vacuole (LCV) (7,8). Two protein secretion systems, Lsp type II secretion (T2S) and Dot/Icm type IV secretion (T4S), play major roles in the pathogenesis of L. pneumophila (9, 10). In T2S, protein substrates are first translocated across the inner membrane, and upon the action of the T2S pilus-like apparatus, they then exit the bacterial cell through a specific outer membrane pore (11). Using proteomics and enzymatic assays, we have shown that the T2S system of L. pneumo-

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Klebsiella pneumoniae subverts the activation of inflammatory responses in a NOD1-dependent manner

Abstract: SummaryKlebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia.

Cited by 62 publications

References 58 publications

Identification of a Novel Francisella tularensis Factor Required for Intramacrophage Survival and Subversion of Innate Immune Response

Identification of a Novel Francisella tularensis Factor Required for Intramacrophage Survival and Subversion of Innate Immune Response

Deciphering tissue-induced Klebsiella pneumoniae lipid A structure

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

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