title: 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 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 gammadelta 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.
authors.affiliation: Department of Pathology, Center for Molecular and Translational Human Infectious Diseases Research, Methodist Hospital Research Institute, Houston, TX 77030, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Shea
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.forename: John J
authors.initials: JJ
authors.lastname: Kupko
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kobayashi
authors.forename: Aaron
authors.initials: A
authors.lastname: Carmody
authors.forename: Robin M
authors.initials: RM
authors.lastname: Ireland
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Sturdevant
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ricklefs
authors.forename: Imran
authors.initials: I
authors.lastname: Babar
authors.forename: Claire A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Morag R
authors.initials: MR
authors.lastname: Graham
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Gardner
authors.forename: John R
authors.initials: JR
authors.lastname: Bailey
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnell
authors.forename: Frank R
authors.initials: FR
authors.lastname: Deleo
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006820:Hyaluronic Acid / Q000378:metabolism; D008252:Macaca fascicularis / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology; D009504:Neutrophils / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010612:Pharyngitis / Q000235:genetics / Q000382:microbiology; D010614:Pharynx / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D006820:Hyaluronic Acid; D020558:GTP Phosphohydrolases