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Group A Streptococcus M1T1 Intracellular Infection of Primary Tonsil Epithelial Cells Dampens Levels of Secreted IL-8 Through the Action of SpyCEP

ABSTRACT: Streptococcus pyogenes (Group A Streptococcus; GAS) commonly causes pharyngitis in children and adults, with severe invasive disease and immune sequelae being an infrequent consequence. The ability of GAS to invade the host and establish infection likely involves subversion of host immune defenses. However, the signaling pathways and innate immune responses of epithelial cells to GAS are not well understood. In this study, we utilized RNAseq to characterize the inflammatory responses of primary human tonsil epithelial (TEpi) cells to infection with the laboratory-adapted M6 strain JRS4 and the M1T1 clinical isolate 5448. Both strains induced the expression of genes encoding a wide range of inflammatory mediators, including IL-8. Pathway analysis revealed differentially expressed genes between mock and JRS4 or 5448-infected TEpi cells, were enriched in transcription factor networks that regulate IL-8 expression, such as AP-1, ATF-2 and NFAT. While JRS4 infection resulted in high levels of secreted IL-8, 5448 infection did not, suggesting that 5448 may post-transcriptionally dampen IL-8 production. Infection with 5448ΔcepA, an isogenic mutant lacking the IL-8 protease SpyCEP, resulted in IL-8 secretion levels comparable to JRS4 infection. Complementation of 5448ΔcepA and JRS4 with a plasmid encoding 5448-derived SpyCEP significantly reduced IL-8 secretion by TEpi cells. Our results suggest that intracellular infection with the pathogenic GAS M1T1 clone induces a strong pro-inflammatory response in primary tonsil epithelial cells, but modulates this host response by selectively degrading the neutrophil-recruiting chemokine IL-8 to benefit infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107001 | GEO | 2018/05/08

REPOSITORIES: GEO

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Project description:Relatively little is understood about the dynamics of global hostâpathogen transcriptome changes that occur during bacterial infection of mucosal surfaces. To test the hypothesis that group A Streptococcus (GAS) infection of the oropharynx provokes a host transcriptome response, we performed genome-wide transcriptome analysis using a nonhuman primate model of experimental pharyngitis. We also identified host and pathogen biological processes and individual host and pathogen gene pairs with correlated patterns of expression, suggesting interaction. For this study, 509 host genes and seven biological pathways were differentially expressed throughout the entire 32-day infection cycle. GAS infection produced an initial widespread significant decrease in expression of many host genes, including those involved in cytokine production, vesicle formation, metabolism, and signal transduction. This repression lasted until day 4, at which time a large increase in expression of host genes was observed, including those involved in protein translation, antigen presentation, and GTP-mediated signaling. The interactome analysis identified 73 host and pathogen gene pairs with correlated expression levels. We discovered significant correlations between transcripts of GAS genes involved in hyaluronic capsule production and host endocytic vesicle formation, GAS GTPases and host fibrinolytic genes, and GAS response to interaction with neutrophils. We also identified a strong signal, suggesting interaction between host Î³Î´ T cells and genes in the GAS mevalonic acid synthesis pathway responsible for production of isopentenyl-pyrophosphate, a short-chain phospholipid that stimulates these T cells. Taken together, our Q:2 results are unique in providing a comprehensive understanding of the hostâpathogen interactome during mucosal infection by a bacterial pathogen. Longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus Briefly, animals were GAS-culture negative and had negligible antistreptolysin O titers, indicating no recent history of GAS exposure. Twenty animals were subjected to a mock-inoculation protocol (PBS only) for 5 weeks, rested for 4 weeks, and inoculated in the upper respiratory tract with 107 CFUsMGAS5005. Blood, saliva, and throat swabs were collected on days 0, 1, 2, 4, 7, 9, 16, 23, 32, 45, 58, 72, and 86. Only the first nine time-points were studied because specimens collected during days 0 to 32 had matching comparator specimens from the mock-infection protocol. Thirty-two clinical and laboratory parameters were measured by the same veterinarian during mock and infection periods. Array data was only for the tonsil swabs, while blood and saliva used for other tests.

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Group A Streptococcus M1T1 Intracellular Infection of Primary Tonsil Epithelial Cells Dampens Levels of Secreted IL-8 Through the Action of SpyCEP

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