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Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

ABSTRACT: Relatively little is understood about the dynamics of global host–pathogen 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 γδ 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 host–pathogen interactome during mucosal infection by a bacterial pathogen.

ORGANISM(S): Macaca fascicularis Homo sapiens

PROVIDER: GSE20262 | GEO | 2010/03/18

SECONDARY ACCESSION(S): PRJNA124227

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.

Project description:The interaction between Aspergillus flavus and Zea mays is complex, and the identification of plant genes and pathways conferring resistance to the fungus has been challenging. Therefore authors undertook a systems biology approach involving dual RNA-seq to determine simultaneous response from the host and pathogen. What was dramatically highlighted in the analysis was upon infection there is uniformity in the development of the host and pathogen. This led to the development of host-pathogen index which was able to categorize the samples for down-stream system biology analysis. Additionally we were able to determine key genes in the pathways such as jasmonate, ethylene and ROS which were up-regulated in the studyThe stage of infection index used for the transcriptomic analysis revealed that A. flavus does not produce many transcripts initially during pathogenesis. It was found that when A. flavus was producing an abundance of transcripts, pathways involved the endosomal transport, aflatoxin production, sugar production and many others were up-regulated. In tandem, Z. mays had multiple resistance pathways, such as the phenylpropaniod, jasmonic acid and ethylene pathways that were up-regulated. The analysis of the gene regulatory networks revealed that multiple WRKY genes were targeting the activation of the resistance pathways. The analysis also revealed, for the first time, the activation of Z. mays resistance genes targeting A. flavus genes. Our results show that the plant-microbe interaction has multiple layers and that A. flavus transcriptionally reacts to the hostile environment of Z. mays. The interaction between Aspergillus flavus and Zea mays is complex, and the identification of plant genes and pathways conferring resistance to the fungus has been challenging. Therefore authors undertook a systems biology approach involving dual RNA-seq to determine simultaneous response from the host and pathogen. What was dramatically highlighted in the analysis was upon infection there is uniformity in the development of the host and pathogen. This led to the development of host-pathogen index which was able to categorize the samples for down-stream system biology analysis. Additionally we were able to determine key genes in the pathways such as jasmonate, ethylene and ROS which were up-regulated in the studyThe stage of infection index used for the transcriptomic analysis revealed that A. flavus does not produce many transcripts initially during pathogenesis. It was found that when A. flavus was producing an abundance of transcripts, pathways involved the endosomal transport, aflatoxin production, sugar production and many others were up-regulated. In tandem, Z. mays had multiple resistance pathways, such as the phenylpropaniod, jasmonic acid and ethylene pathways that were up-regulated. The analysis of the gene regulatory networks revealed that multiple WRKY genes were targeting the activation of the resistance pathways. The analysis also revealed, for the first time, the activation of Z. mays resistance genes targeting A. flavus genes. Our results show that the plant-microbe interaction has multiple layers and that A. flavus transcriptionally reacts to the hostile environment of Z. mays. The interaction between Aspergillus flavus and Zea mays is complex, and the identification of plant genes and pathways conferring resistance to the fungus has been challenging. Therefore authors undertook a systems biology approach involving dual RNA-seq to determine simultaneous response from the host and pathogen. What was dramatically highlighted in the analysis was upon infection there is uniformity in the development of the host and pathogen. This led to the development of host-pathogen index which was able to categorize the samples for down-stream system biology analysis. Additionally we were able to determine key genes in the pathways such as jasmonate, ethylene and ROS which were up-regulated in the studyThe stage of infection index used for the transcriptomic analysis revealed that A. flavus does not produce many transcripts initially during pathogenesis. It was found that when A. flavus was producing an abundance of transcripts, pathways involved the endosomal transport, aflatoxin production, sugar production and many others were up-regulated. In tandem, Z. mays had multiple resistance pathways, such as the phenylpropaniod, jasmonic acid and ethylene pathways that were up-regulated. The analysis of the gene regulatory networks revealed that multiple WRKY genes were targeting the activation of the resistance pathways. The analysis also revealed, for the first time, the activation of Z. mays resistance genes targeting A. flavus genes. Our results show that the plant-microbe interaction has multiple layers and that A. flavus transcriptionally reacts to the hostile environment of Z. mays.

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Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

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