Charactering mucosal parasitism by Trichomonas vaginalis and Trichomonas gallinae through comparative genomics, transcriptomics, molecular and biochem

Species of the genus Trichomonas are parasitic protozoa of vertebrates that include important pathogens inflicting morbidity and in some contexts significant mortality rates in infected populations. Trichomonas vaginalis (TV) is the most common human cellular STD worldwide - 277 millions new cases in 2008 (WHO). TV induces significant health sequelae including facilitating the spread of HIV, preterm birth and is associated with cervical and aggressive prostate cancers. Other Trichomonas species are known to infect birds and Trichomonas gallinae (TG), common in Columbiformes (e.g. pigeons), emerged as a novel fatal disease of finches (death of 1.5 million greenfinches, 35% of population) in 2005/6 in the UK.
In this project we propose to exploit three sets of important new data to characterise Trichomonas virulence factors targeting host glycoproteins: (i) identification of a novel TV cell surface metallopeptidase mediating human cell cytolysis via binding to proteoglycans, (ii) phylogenetics supporting close relationships between human and bird Trichomonas species suggesting zoonotic origins for human parasites and (iii) novel genome sequence data for several Trichomonas species from birds and humans. Recent data (PhD student, supervisors Hirt and Bolam, collaborator Johnson, UCLA) indicate that TV is adhering to and degrading human surface proteoglycans of both vaginal epithelial cell (VEC) and prostate cells (PC) using a surface metalloprotease (M60-like) possessing two carbohydrate-binding modules (CBMs) binding heparan sulphate (HS). Significantly TV overexpressing the M60-like protein leads to an increase of VEC and PC cytolysis. In contrast, human cell cytolysis was significantly reduced when interfering with either TV binding to HS or the M60-like protease activity. Investigation of the initial genome sequence data for one UK bird isolate of TG, implicated in UK finch population decline, identified 16 M60-like homologues with the same structural configuration as the aforementioned TV M60-like protein.
The PhD student will investigate candidate virulence factors from Trichomonas spp. potentially targeting bird and human glycoproteins by combining comparative genomics, transcriptomics, biochemistry and cell biology. Comparative genomics and transcriptomics (from both in vitro and in vivo complementary experiments) will be exploited to identify common and highly expressed genes encoding CBMs, CAZymes (carbohydrate active enzymes) and proteases of bird and human pathogens to gain a global picture of how Trichomonas targets host glycans and glycoproteins. The gene annotations and transcriptomics data will be integrated to select a handful of TV and TG proteins for their functional characterisation focusing on peptidases associated with CBMs to test their glycan binding and protease specificity and their impact on host cells.