Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections

Abstract

Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts.

Keywords: Cdc42; Rac1; Rho; chlamydia trachomatis; neisseria gonorrhoeae; pathogen-host cell interaction; pathogens; small GTPases; treponema pallidum; trichomonas vaginalis.

Figure 1.

Schematic comparison of Rho GTPases involved in Chlamydia trachomatis and Neisseria gonorrhoeae-host cell interplay. Bacterial proteins are shown in red boxes. Yellow arrows indicate Rho GTPase cycling. Phosphorylation events are shown in light blue. Putative roles of Rho GTPases are indicated in purple boxes. Bacterial exit processes are represented in green. (A) Rho GTPases and Chlamydia trachomatis. The bacterial infective form (Elementary Body, EB), through the injection of the bacterial factor TARP (Translocated Actin Recruitment Protein), triggers phosphorylation events and the recruitment of the guanine-nucleotide exchange factors (GEFs), Sos1 and Vav2, leading to Rac1 activation. Then, Rac1-GTP recruits WAVE2 and Abi-1, promoting Arp2/3 complex activation and actin polymerization at the bacterial entry site. After chlamydial differentiation into the replicative form (Reticulate Body, RB) and numerous rounds of multiplication, the Chlamydia-containing vacuole is extruded from the infected host cell by a mechanism that involves WASP, myosin II and RhoA. (B) Rho GTPases and Neisseria gonorrhoeae. Opa_CEA-expressing Neisseria gonorrhoeae (Ng), through Opa-CEACAM3 recognition, triggers Rac1 and Cdc42 activation, and the downstream recruitment of WAVE2 and the actin recruiting protein Arp2/3, which ends in actin cytoskeleton rearrangements and bacterial internalization. In contrast, Rho-mediated entry triggered by the bacterial porin PorB_IA drives actin polymerization that promotes the internalization of piliated gonococci into non-phagocytic cells. The release of Neisseria-containing phagosomes might involve Rho GTPases and actin reorganization.

Figure 2.

Schema depicting Rho GTPases involved in Trichomonas vaginalis-host cell interplay. Putative roles for Rho GTPases are indicated in purple boxes. Rho GTPase homologues are probably involved in the actin reorganization that occurs inside the parasite during the transition from the ovoid, free-swimming form to the amoeboid form, after its attachment to the host cell. In addition, Rho-related GTPases and actin polymerization apparently play a role in phagocytic processes that take place within the parasite.

Figure 3.

Schema depicting Rho GTPases involved in Treponema pallidum-host cell interplay. Putative roles for Rho GTPases are indicated in purple boxes. The bacterial adhesins Tp0136, Tp0155, Tp0483 and Tp0750, which binds to host fibronectin and/or laminin, are involved in the attachment to host cells. Treponema binding to cell surface might trigger actin polymerization that is regulated by Rho GTPases. The details of the events occurring at the plasma membrane are enlarged in the lower part of the panel.