Dataset Information

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3

ABSTRACT: Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs. Further analyses identified EhaF as a secreted autotransporter—a type of bacterial secretion system with no known innate immune-modulatory function—that translocates into host cell cytosol and inhibit IFN response to EHEC. Mechanistically, EhaF interacts with and inhibits the MiT/TFE family transcription factor TFE3 resulting in impaired TANK phosphorylation and consequently, reduced IRF3 activation and type I IFN expression. Notably, EhaF-mediated innate immune suppression promotes EHEC colonization and pathogenesis in vivo. Overall, this study has uncovered a previously unknown autotransporter-based bacterial strategy that targets a specific transcription factor to subvert innate host defense.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Escherichia Coli Mus Musculus (mouse)

TISSUE(S): Macrophage

DISEASE(S): Disease Free

SUBMITTER: Jeremy Balsbaugh

LAB HEAD: Jeremy Balsbaugh

PROVIDER: PXD041070 | Pride | 2023-04-13

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20220106_jcl_ATa_Vanaja_ctrl1_300ng_60min_Wat25cmBEH_1.raw	Raw
	20220106_jcl_ATa_Vanaja_ctrl2_300ng_60min_Wat25cmBEH_1.raw	Raw
	20220106_jcl_ATa_Vanaja_ctrl3_300ng_60min_Wat25cmBEH_1.raw	Raw
	20220106_jcl_ATa_Vanaja_treatment_300ng_60min_Wat25cmBEH_1.raw	Raw
	Custom_jcl20220112_EColi_BL21DE3_withZ0390_UP000002032_updated12Feb21.fasta	Fasta

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Publications

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3.

Ta Atri A Ricci-Azevedo Rafael R Vasudevan Swathy O SO Wright Skylar S SS Kumari Puja P Havira Morena S MS Surendran Nair Meera M Rathinam Vijay A VA Vanaja Sivapriya Kailasan SK

Nature communications 20230411 1

Type I interferons (IFNs) are consequential cytokines in antibacterial defense. Whether and how bacterial pathogens inhibit innate immune receptor-driven type I IFN expression remains mostly unknown. By screening a library of enterohemorrhagic Escherichia coli (EHEC) mutants, we uncovered EhaF, an uncharacterized protein, as an inhibitor of innate immune responses including IFNs. Further analyses identified EhaF as a secreted autotransporter-a type of bacterial secretion system with no known inn ...[more]

PMID: 37041208

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Project description:Although mast cells elicit proinflammatory and type I IFN responses upon VSV infection, in response to L.monocytogenes (L.m) or S. Typhimurium (S.t), such cells elicit a transcriptional program devoid of type I IFN response. Balanced induction of proinflamatory and type I interferon (IFN) responses upon activation of Toll like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmune syndromes. However, their potential role in anti-microbial host defenses is increasingly being acknowledged. How mast cells interact with microbes and the nature of responses triggered thereof is not well characterized. Here we show that in response to TLR activation by Gram-positive and negative bacteria or their components like LPS, unlike macrophages, mast cells elicit pro-inflammatory but not type I IFN responses. We demonstrate that in mast cells, the bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization - a prerequisite for type I IFN induction. Such cells could, however, elicit type I IFNs in response to vesicular stomatitis virus (VSV), which accesses the cytosolic RIG-I receptor. Although important for anti-viral immunity, a strong type I IFN response is known to contribute to pathogenesis during bacterial infection. Thus, while endowed with the capacity to elicit type I IFNs in response to viral infection, the fact that mast cells only elicit pro-inflammatory responses upon bacterial infection illustrates that mast cells, key effector cells of the innate immune system, are well adjusted for optimal anti-bacterial and anti-viral responses. Wild type control (cntr) or interferon receptor (IFNAR)-deficient mast cells (MC) or macrophages (MAC) were infected with L.m. and S.t. (MOIs 50 and 5 for MC and MAC, respectively). MC and MAC were exposed to VSV-AV2 (MOI: 2). Samples were analyzed after 6 hours. Uninfected/unstimulated cells were used as reference samples for calculating fold change in gene expression. Gene Expression levels were determined by the Affymetrix MOE 430 2.0 GeneChips. Signal Intensities were calculated using the RMA algorithm and for statistical analysis we applied GeneSpring GX 10 software suite (Agilent Technologies, Waldbronn, Germany). MultiExperiment Viewer (MEV) software version 4.4 of the Institute for Genomic Research was used for clustering algorithm data analysis and visualization.