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

Abstract

Relatively little is understood about the dynamics of global hostpathogen 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.epithelial growth factor receptor | host pathogen | microarray | Streptococcus pyogenes | transcriptome

Smooth Muscle Cells Relay Acute Pulmonary Inflammation via Distinct ADAM17/ErbB Axes

“…The use of different transactivating ligands and receptors by SMC could provide a means to adapt inflammatory responses to the type of injury. EGFR/ErbB1 sensing could be more important to the binding and clearance of bacteria (31), whereas the initiation of inflammation after acid exposure might require ErbB4 signaling, which is important for surfactant production and proliferation of lung epithelial cells (32). Moreover, we found that IL-1b induced CXCL8 release by htSMC in an ADAM17-NRG1-dependent manner.…”

Virulence of serotype M3 Group AStreptococcusstrains in wax worms (Galleria mellonellalarvae)

“…As a consequence, we have extensively used non-human primates, the most human-relevant animal model possible, as the preferred host for testing hypotheses bearing on GAS molecular pathogenesis. 13,14,34,[37][38][39] However, high cost and substantial…”

“…A growing body of evidence suggests an increased interest in performing GAS gene expression studies under human-relevant in vitro conditions or during in vivo infections. 14,37,[46][47][48][49] Infected hemolymph is easy to manipulate and enriched in GAS cells relative to host cells. This helps to overcome the challenges associated with extracting a sufficient quantity of high quality GAS RNA from infected animal tissues for TaqMan or expression microarray analyses.…”

IL-17-induced NF-κB Activation via CIKS/Act1

“…Genechip Experiment-RNAs were extracted and DNA microarray targets were prepared as described previously (27). Gene expression was measured using the Affymetrix 430 2.0 Genechip containing the mouse genome and data analysis were carried out as described previously (28) with the following modifications.…”