Global epithelial cell transcriptional responses reveal Streptococcus pyogenes Fas regulator activity association with bacterial aggressiveness

Abstract

SummaryThe bacterial human pathogen Streptococcus pyogenes (group A streptococci, GAS) is able to adhere to, internalize into and cross-talk on multiple levels with its host cells. To gain insight into the Fas function in pathogenesis we used Affymetrix human genome DNA-arrays to measure temporal and global transcriptional responses of HEp-2 cells infected with M49 S. pyogenes wild-type bacteria and D D D D fas X, an isogenic S. pyogenes two-component-signal-transduction system mutant. A modified stringent statistical analysis method identified a total of 86 HEp-2 cell genes as differentially transcribed upon infection over the investigated time course. Increased expression of genes encoding proteins involved in GAS host cell adherence and internalization (fibronectin, integrin-a a a a 5) was found as a common response. In contrast to earlier reports investigating other GAS serotype strains, Ras superfamily and RhoA pathways are exploited by M49 GAS, suggesting serotype specific interactions with the host cell cytoskeleton. Despite transcriptional induction, secreted IL-8 levels of D fasX mutant infected cells were below those of non-infected cells, indicating an absence of Fas expression could be important for GAS tissue colonization and long-term intracellular persistence. Oppositely, activity of the S. pyogenes Fas-system apparently promotes high adherence and internalization rates, massive cytokine gene transcription and cytokine release, host cell apoptosis via a caspase-2 activation pathway, and cytotoxicity. Thus, the S. pyogenes Fas two-component signal transduction system could be involved in local tissue destruction and general bacterial aggressiveness towards host cells.

Response of corneal epithelial cells toStaphylococcus aureus

“…68 Klenk et al 68 observed increased abundance of transcripts for CSF2, CXCL1, CXCL2, CXCL3, CCL20, IL6 and IL8, as well as transcription factors Jun and FosB. They also observed stimulation of release of IFNγ, corroborating for another Gram positive bacterial species the release of IFNγ by epithelial cells of the wet mucosa.…”

Small RNAs in streptococci

“…42,48 The positive effect of FasX on streptokinase activity was also reported in a strain of M1T1 serotype (MGAS2221). 18 In host response studies performed with strain CS101, FasX was shown to control positively the interaction of S. pyogenes with laryngeal cells by affecting adherence and internalization rates, massive cytokine gene transcription and release, host cell apoptosis via a caspase-2 activation pathway and cytotoxicity.…”

“…18 In host response studies performed with strain CS101, FasX was shown to control positively the interaction of S. pyogenes with laryngeal cells by affecting adherence and internalization rates, massive cytokine gene transcription and release, host cell apoptosis via a caspase-2 activation pathway and cytotoxicity. 48 The authors of the study suggested that by mediating these functions FasX may influence local tissue destruction and general bacterial aggressiveness towards epithelial cells during the infection process. 48 In Streptococcus dysgalactiae subsp.…”

“…48 The authors of the study suggested that by mediating these functions FasX may influence local tissue destruction and general bacterial aggressiveness towards epithelial cells during the infection process. 48 In Streptococcus dysgalactiae subsp. equisimilis, also called Group C streptococcus, the orthologue of S. pyogenes FasX is also part of a fasBCAX operon.…”

Systems Biology Approach to Identifying Host Interactive Pathways Modulating the Severity of Streptococcal Sepsis

“…Apoptosis in streptococcal pathogenesis is affected by interacting factors including, context of infection (Marriott and Dockrell, 2006), cells undergoing apoptosis (Kobayashi et al, 2003;Nakagawa et al, 2004;Miyoshi-Akiyama et al, 2005), for example, apoptosis aids in the clearing of infection if macrophages are undergoing apoptosis, while it would be harmful to the host if lymphocytes are undergoing apoptosis. Other factors include, whether the bacteria is internalized or extracellular (Cywes Bentley et al, 2005) and accordingly the type of apoptosis pathways activated (Klenk et al, 2005). In our murine GAS sepsis model, we have measured expression levels in whole spleens, which involved the response of various cells including macrophages, T and B lymphocytes, dendritic and endothelial cells etc.…”