br Concluding remarks br Conflict

Concluding remarks
Conflict of interest statement
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Acknowledgements We thank all the present and former members in our laboratory for their contributions to the original and ongoing research. Work in our laboratory is funded by the Intramural Program on the National Institute on Aging (NIA, NIH).
Introduction Chlamydia trachomatis is an obligate intracellular pathogen responsible for a variety of serious human diseases. C. trachomatis serovars A–C are the leading cause of noncongential blindness worldwide (Satpathy et al., 2017), whereas serovars D–K are the etiological agents of one of the most common sexually transmitted infections (Menon et al., 2015). In women, 15%–40% of untreated infections can progress to pelvic inflammatory disease (PID), resulting in ectopic pregnancy and sterility (Menon et al., 2015). C. trachomatis serovars L1–L3 cause invasive urogenital or anorectal infections, known as lymphogranuloma venerum (LGV) (Stoner and Cohen, 2015). There is no vaccine, and, in total, over 100 million new C. trachomatis cases are reported annually (Menon et al., 2015). Furthermore, wh4 receptor fail to clear the infection in approximately 10% of cases (Afrakhteh et al., 2013, Geisler et al., 2015). All chlamydiae share a biphasic developmental cycle in which they alternate between an infectious, environmentally stable elementary body (EB) and a noninfectious, replicative form termed the “reticulate body” (RB) (Elwell et al., 2016). During infection, the EB is internalized into a membrane-bound compartment, termed “the inclusion,” that deviates from the endo-lysosomal pathway (Scidmore et al., 2003) and traffics along microtubules to the peri-Golgi region (Grieshaber et al., 2003). As obligate intracellular bacteria, chlamydiae must scavenge essential nutrients, such as amino acids, lipids, and iron from the host, all while avoiding detection by the host innate immune system (Elwell et al., 2016, Finethy and Coers, 2016, Pokorzynski et al., 2017). To achieve this, the chlamydial inclusion maintains intimate interactions with select host organelles, such as mitochondria (Chowdhury et al., 2017), the Golgi apparatus (Carabeo et al., 2003, Heuer et al., 2009), the endoplasmic reticulum (Derré et al., 2011), and endosomes (Saka et al., 2015). However, the precise mechanisms by which chlamydiae control these diverse interactions are largely unknown, but likely involve bacterial effector proteins capable of redirecting and intercepting host vesicles. C. trachomatis encodes a type III secretion system (T3SS) that is predicted to translocate over 100 proteins into the host cell (Muschiol et al., 2011, Scidmore-Carlson et al., 1999, Subtil et al., 2005, Weber et al., 2015). A subset of proteins, termed inclusion membrane proteins (Incs), possess a bilobed hydrophobic domain of ∼30–40 amino acids and are inserted in the inclusion membrane such that their N and C termini are oriented into the host cell cytosol (Hackstadt et al., 1999). Given their positioning at the host-pathogen interface, Incs likely mediate crucial interactions with the host cell. The importance of the Inc protein CT229 in forming and maintaining the unique intracellular niche of C. trachomatis is underscored by our recent study demonstrating that the absence of CT229 triggers premature inclusion lysis and host cell death (Weber et al., 2017). CT229 (CpoS) binds several Rab GTPases (Mirrashidi et al., 2015, Rzomp et al., 2006, Sixt et al., 2017). However, the physiological effects of CT229 targeting Rab GTPases and the necessity of this interaction for C. trachomatis infection is largely unknown. To acquire key nutrients from the host and membrane for the growing inclusion, chlamydiae interact with and modulate aspects of intracellular trafficking and fusogenicity with the inclusion membrane. Movement and fusion of eukaryotic membrane bound vesicles is tightly regulated by soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptors (SNARE) (Kim and Gadila, 2016), and small guanosine triphosphate (GTP) binding proteins, such as ADP-ribosylating factors (ARFs) (Donaldson and Jackson, 2011) and Rab GTPases (Hutagalung and Novick, 2011, Hammer and Wu, 2002). Rab GTPases localize to distinct organelles and regulate vesicle budding, transport, docking, and fusion (Hutagalung and Novick, 2011). Therefore, components of the eukaryotic vesicle trafficking apparatus are likely targeted by C. trachomatis effector proteins. Rab GTPases associated with both early endosomes (Rab4 and Rab11) and the Golgi apparatus (Rab1, Rab6, and Rab10) are recruited to the chlamydial inclusion membrane (Rzomp et al., 2003), suggesting that chlamydia diverts and interacts with Rab GTPases to hijack host vesicular trafficking.