Glycosylation-dependent galectin-receptor interactions promote Chlamydia trachomatis infection.

Chlamydia trachomatis (Ct) constitutes the most prevalent sexually transmitted bacterium worldwide. Chlamydial infections can lead to severe clinical sequelae including pelvic inflammatory disease, ectopic pregnancy, and tubal infertility. As an obligate intracellular pathogen, Ct has evolved multiple strategies to promote adhesion and invasion of host cells, including those involving both bacterial and host glycans. Here, we show that galectin-1 (Gal1), an endogenous lectin widely expressed in female and male genital tracts, promotes Ct infection. Through glycosylation-dependent mechanisms involving recognition of bacterial glycoproteins and N-glycosylated host cell receptors, Gal1 enhanced Ct attachment to cervical epithelial cells. Exposure to Gal1, mainly in its dimeric form, facilitated bacterial entry and increased the number of infected cells by favoring Ct-Ct and Ct-host cell interactions. These effects were substantiated in vivo in mice lacking Gal1 or complex ß1-6-branched N-glycans. Thus, disrupting Gal1-N-glycan interactions may limit the severity of chlamydial infection by inhibiting bacterial invasion of host cells.

Galectins as potential therapeutic targets in STIs in the female genital tract.

Every day, more than one million people worldwide acquire a sexually transmitted infection (STI). This public health problem has a direct effect on women's reproductive and sexual health as STIs can cause irreversible damage to fertility and can have negative consequences associated with discrimination and social exclusion. Infection with one sexually transmitted pathogen predisposes to co-infection with others, suggesting the existence of shared pathways that serve as molecular links between these diseases. Galectins, a family of ß-galactoside-binding proteins, have emerged as endogenous mediators that facilitate cell-surface binding, internalization and cell invasion of many sexually transmitted pathogens, including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Candida albicans, HIV and herpes simplex virus. The ability of certain galectins to dimerize or form multimeric complexes confers the capacity to interact simultaneously with glycosylated ligands on both the pathogen and the cervico-vaginal tissue on these proteins. Galectins can act as a bridge by engaging glycans from the pathogen surface and glycosylated receptors from host cells, which is a mechanism that has been shown to be shared by several sexually transmitted pathogens. In the case of viruses and obligate intracellular bacteria, binding to the cell surface promotes pathogen internalization and cell invasion. Inflammatory responses that occur in cervico-vaginal tissue might trigger secretion of galectins, which in turn control the establishment, evolution and severity of STIs. Thus, galectin-targeted therapies could potentially prevent or decrease STIs caused by a diverse array of pathogenic microorganisms; furthermore, anti-galectin agents might reduce treatment costs of STIs and reach the most vulnerable populations.

Ptr/CTL0175 Is Required for the Efficient Recovery of Chlamydia trachomatis From Stress Induced by Gamma-Interferon.

Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen in humans and a frequent cause of asymptomatic, persistent infections leading to serious complications, particularly in young women. Chlamydia displays a unique obligate intracellular lifestyle involving the infectious elementary body and the replicative reticulate body. In the presence of stressors such as gamma-interferon (IFNγ) or beta-lactam antibiotics, C. trachomatis undergoes an interruption in its replication cycle and enters a viable but non-cultivable state. Upon removal of the stressors, surviving C. trachomatis resume cell division and developmental transitions. In this report, we describe a genetic screen to identify C. trachomatis mutants with defects in recovery from IFNγ- and/or penicillin-induced stress and characterized a chemically derived C. trachomatis mutant strain that exhibited a significant decrease in recovery from IFNγ- but not penicillin-induced stress. Through lateral gene transfer and targeted insertional gene inactivation we identified ptr, encoding a predicted protease, as a gene required for recovery from IFNγ-induced stress. A C. trachomatis LGV-L2 ptr-null strain displayed reduced generation of infectious progeny and impaired genome replication upon removal of IFNγ. This defect was restored by introducing a wild type copy of ptr on a plasmid, indicating that Ptr is required for a rapid growth upon removal of IFNγ. Ptr was expressed throughout the developmental cycle and localized to the inclusion lumen. Overall, our findings indicate that the putative secreted protease Ptr is required for C. trachomatis to specifically recover from IFNγ- but not penicillin-induced stress.