Trypanosoma cruzitrans-sialidase inducesSTAT3andERKactivation by prokineticin receptor 2 binding

Tc85, as other members of trans-sialidase family, is involved inTrypanosoma cruziparasite adhesion to mammalian cells. Particularly, Tc85 acts through specific interactions with prokineticin receptor 2, a G-protein coupled receptor involved in diverse physiological and pathological processes. In this manuscript, through biochemical analyses, we demonstrated that LamG, a Tc85 domain, physically interacts with the prokineticin receptor 2. Moreover, expressing prokineticin receptor 1 and 2 we demonstrated that LamG specifically activates prokineticin receptor 2 through a strong coupling with G(alpha i)or G(alpha q)proteins in yeast strains and inducing ERK and NFAT phosphorylation in CHO mammalian cells. To demonstrate a Tc85 physiological role inT.cruziinfection of the nervous system, we evidenced a strong STAT3 and ERK activation by LamG in mice Dorsal Root Ganglia. L173R is the most common prokineticin receptor 2 mutation reported in Kallmann syndrome and it is a founder mutation. Our results demonstrated that in cells co-expressing prokineticin receptor 2 mutant (L173R) and wild-type, LamG is unable to induce signal transduction. The L173R mutation in heterozygosity may allow for a selective advantage due to increased protection fromT.cruziinfection. Significance of the study The Chagas' disease affecting millions of people worldwide is caused by an eukaryotic microorganism calledT.cruzi. Pharmacological treatment for patients with Chagas' disease is still limited. Indeed, the small number of drugs available shows important side effects that can be debilitating for patient health. In order to replicate and produce new parasitesT.cruziuses a complex of different proteins produced by both the parasite and the human host cells. So, understanding the molecular details used byT.cruzito be internalised by different types of human cells is an important step towards the development of new drugs for this disease. Prokineticin receptors are relevant for host-parasite interaction. To characterise the signal transduction cascade induced by their activation may help to understand the molecular details of cell infection, leading to novel therapeutic alternative for this debilitating disease.

Automated summary

Tc85, a member of trans-sialidase family, plays a crucial role in Trypanosoma cruzi parasite adhesion to mammalian cells by interacting with prokineticin receptor 2. LamG, a Tc85 domain, activates prokineticin receptor 2 and contributes to nervous system infection. The study also sheds light on the implications of the L173R mutation in Kallmann syndrome and its potential impact on parasite infection.