CFTR is required for cellular entry and internalization of Chlamydia trachomatis

Abstract

Chlamydia trachomatis is an obligate intracellular Gram-negative pathogen affecting over 600 million people worldwide with 92 million new cases occurring globally each year. C. trachomatis enter the cells and replicate to infect different tissues/organs, giving rise to a spectrum of pathological conditions; however, the exact mechanism or receptor(s) for their entry is not well understood. Here we report that CFTR (cystic fibrosis transmembrane conductance regulator), an apical epithelial anion channel, is required for cellular entry and internalization of C. trachomatis. Human epithelial cell lines expressing functional CFTR internalized more C. trachomatis than the cells expressing mutant Delta508 CFTR. The in vitro cellular uptake of C. trachomatis can be blocked by CFTR inhibitors or antibody, and the in vivo cellular uptake of C. trachomatis in CFTR mutant (CFTR(-/-)) mice was significantly less compared with that in the wild-type. Direct interaction between CFTR and C. trachomatis LPS (lipopolysaccharide) is demonstrated by their immune-co-localization and co-immunoprecipitation. Despite an increase in CFTR expression observed upon C. trachomatis LPS challenge, a reduction in its ion channel activity is observed, consistent with the notion that CFTR functions as a receptor for cellular entry and internationization of C. trachomatis, with compromised ion-channel function. These findings, for the first time, demonstrate that CFTR functions as a cell-surface receptor for epithelial cell entry, and internalization of C. trachomatis and these findings may lead to the development of new treatment strategies to curtail the spread of chlamydial infections.

Chlamydia cell biology and pathogenesis

“…The level and position of sulfation in HSPGs have important roles in the binding of C. muridarum and C. trachomatis L2 (REFS 17,28,29) and may contribute to tissue tropism. Other adhesins include lipopolysaccharide (LPS) in C. trachomatis , which is proposed to bind to the cystic fibrosis transmembrane conductance regulator 17,30 , major outer membrane protein (MOMP; also known as CT681), which binds to the mannose receptor and the mannose 6-phosphate receptor 18 , and CT017 (also known as Ctad1) in C. trachomatis , which binds to β1 integrin 31 . The polymorphic membrane protein (Pmp) family in C. trachomatis and C. pneumoniae also mediates adhesion 32 .…”

Chlamydia exploits filopodial capture and a macropinocytosis-like pathway for host cell entry

“…However, there are also striking parallels with viral entry mechanisms. The small size of EBs, their association with filopodia [ 2 ], entry-associated phosphorylation and signaling [ 16 , 18 , 19 ], and also the requirement for protein disulphide isomerase-associated reduction [ 20 ] and promiscuous receptor interactions [ 21 – 23 ] are all factors common to viral entry mechanisms [ 24 – 28 ]. In this study we have quantified the cytoskeletal rearrangements and membrane reorganisation at C .…”

Host-pathogen reorganisation during host cell entry by Chlamydia trachomatis

“…In addition to the action of the T3SS, the role of receptors in C. trachomatis entry is less clear. Mannose receptor enhances C. trachomatis adhesion [29] , the cystic fibrosis transmembrane conductance regulator (CFTR) binds chlamydial LPS [30] , and most recently Ephrin A2 has been linked to C. trachomatis adhesion and entry, although invasion was only reduced by 30% upon receptor silencing [31] . EGFR activity is also important for the progression of the C. trachomatis lifecycle [32] .…”