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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-03, Vol.107 (10), p.4693-4698
• Main Authors: Shea, Patrick R, Virtaneva, Kimmo, Kupko, John J. 3rd, Porcella, Stephen F, Barry, William T, Wright, Fred A, Kobayashi, Scott D, Carmody, Aaron, Ireland, Robin M, Sturdevant, Daniel E, Ricklefs, Stacy M, Babar, Imran, Johnson, Claire A, Graham, Morag R, Gardner, Donald J, Bailey, John R, Parnell, Michael J, DeLeo, Frank R, Musser, James M
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antigen presentation; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biological Sciences; Cells; Clathrin-Coated Vesicles - metabolism; Correlations; Cynomolgus; Cytokines; Cytokines - metabolism; fibrin; Gene expression; Gene Expression Profiling; Genes; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Guanosinetriphosphatase; Host pathogen relationships; Host-Pathogen Interactions; Hyaluronic Acid - metabolism; Infection; Infections; Leukocytes (neutrophilic); Lymphocytes T; Macaca; Macaca fascicularis - genetics; Macaca fascicularis - metabolism; Macaca fascicularis - microbiology; Metabolism; mevalonic acid; Monkeys & apes; Mucosa; Neutrophils; Neutrophils - metabolism; Neutrophils - microbiology; Neutrophils - pathology; Oligonucleotide Array Sequence Analysis; Oropharynx; Pathogens; Pharyngitis; Pharyngitis - genetics; Pharyngitis - microbiology; Pharynx; Pharynx - metabolism; Pharynx - microbiology; Pharynx - pathology; Phospholipids; Primates; Proteins; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Streptococcus; Streptococcus infections; Streptococcus pyogenes - genetics; Streptococcus pyogenes - metabolism; Streptococcus pyogenes - physiology; T lymphocytes; Throat; Transcriptomes; Translation; Vesicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0906384107

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 distinct 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 results are unique in providing a comprehensive understanding of the host-pathogen interactome during mucosal infection by a bacterial pathogen.