Activation of epidermal growth factor receptor is required for Chlamydia trachomatis development.

Achchhe L Patel,Snezana Petrovic,Scott T Wood,Elizabeth S Stuart,Cristina M Furdui,Allen W Tsang,Kathleen F Arcaro,Doris P Molina,Xiaofei Chen

doi:10.1186/s12866-014-0277-4

Abstract

BackgroundChlamydia trachomatis (C. trachomatis) is a clinically significant human pathogen and one of the leading causative agents of sexually transmitted diseases. As obligate intracellular bacteria, C. trachomatis has evolved strategies to redirect the host’s signaling and resources for its own survival and propagation. Despite the clinical notoriety of Chlamydia infections, the molecular interactions between C. trachomatis and its host cell proteins remain elusive.ResultsIn this study, we focused on the involvement of the host cell epidermal growth factor receptor (EGFR) in C. trachomatis attachment and development. A combination of molecular approaches, pharmacological agents and cell lines were used to demonstrate distinct functional requirements of EGFR in C. trachomatis infection. We show that C. trachomatis increases the phosphorylation of EGFR and of its downstream effectors PLCγ1, Akt and STAT5. While both EGFR and platelet-derived growth factor receptor-β (PDGFRβ) are partially involved in bacterial attachment to the host cell surface, it is only the knockdown of EGFR and not PDGFRβ that affects the formation of C. trachomatis inclusions in the host cells. Inhibition of EGFR results in small immature inclusions, and prevents C. trachomatis-induced intracellular calcium mobilization and the assembly of the characteristic F-actin ring at the inclusion periphery. By using complementary approaches, we demonstrate that the coordinated regulation of both calcium mobilization and F-actin assembly by EGFR are necessary for maturation of chlamydial inclusion within the host cells. A particularly important finding of this study is the co-localization of EGFR with the F-actin at the periphery of C. trachomatis inclusion where it may function to nucleate the assembly of signaling protein complexes for cytoskeletal remodeling required for C. trachomatis development.ConclusionCumulatively, the data reported here connect the function of EGFR to C. trachomatis attachment and development in the host cells, and this could lead to new venues for targeting C. trachomatis infections and associated diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-014-0277-4) contains supplementary material, which is available to authorized users.

Highlights

Chlamydia trachomatis (C. trachomatis) is a clinically significant human pathogen and one of the leading causative agents of sexually transmitted diseases
C. trachomatis induces epidermal growth factor receptor (EGFR) phosphorylation and activation of EGFR signaling pathways To assess the role of EGFR in C. trachomatis development, we initiated our studies by comparing the chlamydial inclusion formation between isogenic cell lines, Mouse embryonic fibroblast (MEF) EGFR+/+ and EGFR null MEFs (MEFs EGFR−/−)
The MEFs EGFR+/+ cells were infected with chlamydial elementary body (EB) and lysed at different time points ranging from 0.5 hpi to 5 hpi

Summary

Introduction

Chlamydia trachomatis (C. trachomatis) is a clinically significant human pathogen and one of the leading causative agents of sexually transmitted diseases. During the time course of RB replication, the early inclusions expand and fuse to form the early-mid inclusion, which further expands into the mid-late inclusion At this stage the RBs are converted back into EBs and are released from the host cells through extrusion or cell lysis [14]. In an elegant study performed by Kim et al, it was shown that C. muridarum recruits FGF2 signaling to enhance infection and bacterial spread [20]. In this case, FGF2 acts as a bridging molecule between the EBs and the receptor that results in the activation of FGFR and bacterial uptake in the host cells

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