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Identification of host cytosolic sensors and bacterial factors regulating the type I interferon response to Legionella pneumophila.

ABSTRACT: Legionella pneumophila is a gram-negative bacterial pathogen that replicates in host macrophages and causes a severe pneumonia called Legionnaires' Disease. The innate immune response to L. pneumophila remains poorly understood. Here we focused on identifying host and bacterial factors involved in the production of type I interferons (IFN) in response to L. pneumophila. It was previously suggested that the delivery of L. pneumophila DNA to the host cell cytosol is the primary signal that induces the type I IFN response. However, our data are not easily reconciled with this model. We provide genetic evidence that two RNA-sensing proteins, RIG-I and MDA5, participate in the IFN response to L. pneumophila. Importantly, these sensors do not seem to be required for the IFN response to L. pneumophila DNA, whereas we found that RIG-I was required for the response to L. pneumophila RNA. Thus, we hypothesize that bacterial RNA, or perhaps an induced host RNA, is the primary stimulus inducing the IFN response to L. pneumophila. Our study also identified a secreted effector protein, SdhA, as a key suppressor of the IFN response to L. pneumophila. Although viral suppressors of cytosolic RNA-sensing pathways have been previously identified, analogous bacterial factors have not been described. Thus, our results provide new insights into the molecular mechanisms by which an intracellular bacterial pathogen activates and also represses innate immune responses.

SUBMITTER: Monroe KM

PROVIDER: S-EPMC2773930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Legionella pneumophila usurps host cell lipids for vacuole expansion and bacterial growth.

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| S-EPMC10883544 | biostudies-literature

Identification of two Legionella pneumophila effectors that manipulate host phospholipids biosynthesis.

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<i>Legionella pneumophila</i> inhibits type I interferon signaling to avoid cell-intrinsic host cell defense.

Project description:The host type I interferon (IFN) response protects against Legionella pneumophila infections. Other bacterial pathogens inhibit type I IFN-mediated cell signaling; however, the interaction between this signaling pathway and L. pneumophila has not been well described. Here, we demonstrate that L. pneumophila inhibits the IFN-β signaling pathway but does not inhibit IFN-γ-mediated cell signaling. The addition of IFN-β to L. pneumophila-infected macrophages limited bacterial growth independently of NOS2 and reactive nitrogen species. The type IV secretion system of L. pneumophila is required to inhibit IFN-β-mediated cell signaling. Finally, we show that the inhibition of the IFN-β signaling pathway occurs downstream of STAT1 and STAT2 phosphorylation. In conclusion, our findings describe a novel host cell signaling pathway inhibited by L. pneumophila via its type IV secretion system.

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Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection.

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Legionella pneumophila glucosyltransferase inhibits host elongation factor 1A.

Project description:Legionella pneumophila, the causal agent of Legionnaires' disease, is an intracellular parasite and invades and proliferates within different eukaryotic cells, including human alveolar macrophages. After several 100-fold multiplication within host cells, the pathogens are released for new invasion by induction of apoptosis or necrosis. Here we report that L. pneumophila produces a glucosyltransferase, which selectively modifies an approximately 50-kDa mammalian protein by using UDP-glucose as a cosubstrate. MS analysis identified the protein substrate as the mammalian elongation factor (EF)1A. Legionella glucosyltransferase modifies its eukaryotic protein substrate at serine-53, which is located in the GTPase domain of the EF. Glucosylation of EF1A results in inhibition of eukaryotic protein synthesis and death of target cells. Our findings show a mode of inhibition of protein synthesis by microbial pathogens and offer a perspective for understanding of the host-pathogen interaction of L. pneumophila.

| S-EPMC1636560 | biostudies-literature

Shuttle mutagenesis of Legionella pneumophila: identification of a gene associated with host cell cytopathicity.

Project description:We performed shuttle mutagenesis of Legionella pneumophila. Mutants were screened for reduced cellular infectivity. Approximately 10% of the mutants had decreased cytopathicity. The DNA sequence of one locus was determined; the inferred amino acid sequence revealed homology with transport proteins including Escherichia coli TolC, Bordetella pertussis CyaE, and Alcaligenes eutrophus CzcC and CnrC.

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Allosteric regulation and substrate activation in cytosolic nucleotidase II from Legionella pneumophila.

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| S-EPMC3982195 | biostudies-literature

Use of partial 16S rRNA gene sequencing for identification of Legionella pneumophila and non-pneumophila Legionella spp.

Project description:We examined 49 Legionella species, 26 L. pneumophila and 23 non-pneumophila Legionella spp., using partial 16S rRNA gene sequencing. This approach accurately identified all the L. pneumophila isolates, characterized all non-pneumophila Legionella isolates as such within this genus, and classified most (20/23; 87%) of the non-pneumophila Legionella isolates to the species level.

| S-EPMC1828979 | biostudies-literature

Screening for eukaryotic motives in Legionella pneumophila reveals bacterial LPC_1677 as functional host histone de-acetylase

Project description:Purpose: The interaction between Legionella pneumophila and its host cell is not completly understood. The aim of this study was to identify eukaryotic-like bacterial factors which manipulate the host cell. Method: A stable overexpression of LPC_1677 was performed in THP-1 cells. The LPC_1677 overexpressing cells were infected with L.p. and RNA sequencing was performed. Key pro-inflammatory markers were validated via qPCR and ELISA. Results: Bioinformatic screening for eukaryotic-like motives in L.p. took us to LPC_1677 which deacetylates host histones and thereby attenuating gene transcription. Conclusion: This study demonstrated that the eukaryotic-like bacterial factor LPC_1677 de-acetylates Histones in the host cell.

2023-01-01 | GSE185936 | GEO

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