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Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner.

ABSTRACT: Viral spread is considered a promising target for antiviral therapeutics, but the associated mechanisms remain unclear for gallid alpha herpesvirus 1 (ILTV). We previously identified proto-oncogene tyrosine-protein kinase Src (Src) as a crucial host determinant of ILTV infection. The present study revealed accelerated spread of ILTV upon Src inhibition. This phenomenon was independent of either viral replication or the proliferation of infected cells and could not be compromised by neutralizing antibody. Neither extracellular vesicles nor the direct cytosol-to-cytosol connections between adjacent cells contributed to the enhanced spread of ILTV upon Src inhibition. Further genome-wide transcriptional profile analyses in combination with functional validation identified fatty acid metabolism as an essential molecular event during modulation of the intercellular spread and subsequent cytopathic effect of ILTV by Src. Overall, these data suggest that Src controls the cell-to-cell spread of ILTV in a cellular fatty acid metabolism-dependent manner, which determines the virus's cytopathic effect.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7172859 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner.

Wang Zhitao Z Sun Bangyao B Gao Qi Q Ma Yong Y Liang Yumeng Y Chen Zhijie Z Wu Hanguang H Cui Lu L Shao Yuhao Y Wei Ping P Li Hai H Liu Shengwang S

Virology 20190813

Viral spread is considered a promising target for antiviral therapeutics, but the associated mechanisms remain unclear for gallid alpha herpesvirus 1 (ILTV). We previously identified proto-oncogene tyrosine-protein kinase Src (Src) as a crucial host determinant of ILTV infection. The present study revealed accelerated spread of ILTV upon Src inhibition. This phenomenon was independent of either viral replication or the proliferation of infected cells and could not be compromised by neutralizing ...[more]

PMID: 31425969

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Project description:The intracellular human pathogen Shigella flexneri invades the colon epithelium, replicates to high cell density within the host cell, and then spreads to adjacent epithelial cells. When S. flexneri gains access to the host cytosol, the bacteria metabolize host cytosolic carbon using glycolysis and mixed acid fermentation, producing formate as a by-product. We show that S. flexneri infection results in the accumulation of formate within the host cell. Loss of pyruvate formate lyase (PFL; ?pflB), which converts pyruvate to acetyl coenzyme A (CoA) and formate, eliminates S. flexneri formate production and reduces the ability of S. flexneri to form plaques in epithelial cell monolayers. This defect in PFL does not decrease the intracellular growth rate of S. flexneri; rather, it affects cell-to-cell spread. The S. flexneri ?pflB mutant plaque defect is complemented by supplying exogenous formate; conversely, deletion of the S. flexneri formate dehydrogenase gene fdnG increases host cell formate accumulation and S. flexneri plaque size. Furthermore, exogenous formate increases plaque size of the wild-type (WT) S. flexneri strain and promotes S. flexneri cell-to-cell spread. We also demonstrate that formate increases the expression of S. flexneri virulence genes icsA and ipaJ Intracellular S. flexneriicsA and ipaJ expression is dependent on the presence of formate, and ipaJ expression correlates with S. flexneri intracellular density during infection. Finally, consistent with elevated ipaJ, we show that formate alters S. flexneri-infected host interferon- and tumor necrosis factor (TNF)-stimulated gene expression. We propose that Shigella-derived formate is an intracellular signal that modulates virulence in response to bacterial metabolism.IMPORTANCEShigella is an intracellular pathogen that invades the human host cell cytosol and exploits intracellular nutrients for growth, enabling the bacterium to create its own metabolic niche. For Shigella to effectively invade and replicate within the host cytoplasm, it must sense and adapt to changing environmental conditions; however, the mechanisms and signals sensed by S. flexneri are largely unknown. We have found that the secreted Shigella metabolism by-product formate regulates Shigella intracellular virulence gene expression and its ability to spread among epithelial cells. We propose that Shigella senses formate accumulation in the host cytosol as a way to determine intracellular Shigella density and regulate secreted virulence factors accordingly, enabling spatiotemporal regulation of effectors important for dampening the host immune response.

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Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner.

Publications

Host Src controls gallid alpha herpesvirus 1 intercellular spread in a cellular fatty acid metabolism-dependent manner.

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