The multiple functions of the numerous Chlamydia trachomatis secreted proteins: the tip of the iceberg

Abstract

Chlamydia trachomatis serovars are obligate intracellular bacterial pathogens mainly causing ocular and urogenital infections that affect millions of people worldwide and which can lead to blindness or sterility. They reside and multiply intracellularly within a membrane-bound vacuolar compartment, known as inclusion, and are characterized by a developmental cycle involving two morphologically and physiologically distinct chlamydial forms. Completion of the developmental cycle involves the secretion of > 70 C. trachomatis proteins that function in the host cell cytoplasm and nucleus, in the inclusion membrane and lumen, and in the extracellular milieu. These proteins can, for example, interfere with the host cell cytoskeleton, vesicular and non-vesicular transport, metabolism, and immune signalling. Generally, this promotes C. trachomatis invasion into, and escape from, host cells, the acquisition of nutrients by the chlamydiae, and evasion of cell-autonomous, humoral and cellular innate immunity. Here, we present an in-depth review on the current knowledge and outstanding questions about these C. trachomatis secreted proteins.

Eukaryotic Cell Permeabilisation to Identify New Putative Chlamydial Type III Secretion System Effectors Secreted within Host Cell Cytoplasm

“…The discrepancy between these results and our data could be due to different sensitivities of the technique used, MS analyses being far more sensitive than immunofluorescence. On this point, it is worth noting that in a list of 30 effector proteins of C. trachomatis published by Bugalhao and Mota [20], only one third were observed in the host cell cytoplasm using immunofluorescence [46,48,[59][60][61][62][63][64][65]. Alternatively, CT539 could also be a very abundant but not secreted protein contaminating our results as described above for ribosomal proteins.…”

“…It is first secreted in the inclusion lumen by the T2SS, and later reaches the host cell cytosol by a yet unclear mechanism. It modulates several host cell pathways to evade the innate immune response and promote bacterial survival (reviewed in [20]). CADD is secreted by the T3SS into the host cytoplasm, where it co-localises with tumour necrosis factor receptors and interacts with their death domains to modulate apoptosis pathways [45].…”

“…Chlamydial genomes encode several essential protein secretion systems such as the Sec system, which delivers proteins in the periplasmic space and can be coupled to Type II or Type V Secretion Systems for translocation in the lumen of the inclusion. Chlamydiales also possess a Type III Secretion System (T3SS) that spans the inclusion membrane and allows direct secretion into the host cell cytosol [20]. Structural components of the T3SS apparatus and chaperones required for maintenance of the effectors in a secretion-competent state are very well conserved between all known members of the Chlamydiales order [18].…”

“…Structural components of the T3SS apparatus and chaperones required for maintenance of the effectors in a secretion-competent state are very well conserved between all known members of the Chlamydiales order [18]. Effector proteins however are largely species-specific and likely contribute towards the differences in the host specificity and intracellular trafficking observed between the various members of this phylum [20,21]. Indeed, while C. trachomatis replication is mainly restricted to mammalian cells [22,23], W. chondrophila is able to multiply in a broad range of hosts including protists, insect, fish and mammalian cell lines [17,24,25].…”

“…Chlamydial T3SS effectors are divided in two subsets: (i) soluble effectors secreted within host cytosol, and (ii) effectors translocated and inserted in the inclusion membrane, also called Incs (reviewed in [20]). The latter share a specific feature, a hydrophobic bilobed domain that inserts the protein within the inclusion membrane, leaving the amino and carboxyl termini accessible on the host cell cytosol side (reviewed in [19]).…”