The protein family TcTASV-C is a novel Trypanosoma cruzi virulence factor secreted in extracellular vesicles by trypomastigotes and highly expressed in bloodstream forms

摘要

Author summary Trypanosoma cruzi is the kinetoplastid parasite that causes Chagas’ disease, a neglected infection endemic in Latin America and emerging worldwide. Being vaccines currently unavailable and treatments not completely effective, identification and characterization of parasite molecules that can be target for these interventions are urgently needed. Of particular interest are surface anchored and secreted proteins involved in parasite—host interplay. Recently, extracellular vesicles released from protozoan pathogens have been shown to alter host cell function favoring the establishment of infection. Trypomastigotes are the disseminating stage of T. cruzi, being their presence in peripheral blood a hallmark of early acute infection in mammals. While the most abundant proteins of the trypomastigote surface are fairly well characterized, little is known about other, less abundant and more recently discovered multigenic families, which could have critical functions in the parasite—host interaction. The T. cruzi Trypomastigote Alanine, Valine and Serine rich proteins (TcTASV) belong to a medium-size multigene family of ~40 members that remained unobserved until a few years ago when it was identified through a trypomastigote-enriched cDNA library. Almost simultaneously, an expression library immunization approach designed to discover novel vaccine antigens in T. cruzi, spotlighted the TcTASV-C subfamily, as a fragment of a TcTASV-C gene was identified in a pool of protective clones. A distinctive feature that characterizes TcTASV proteins–and particularly the TcTASV-C subfamily- is their predominant expression in trypomastigotes. Recent transcriptomic and proteomic studies uphold our previous observations that the TcTASV family is over-represented in the trypomastigote stage, and therefore could represent an interesting target for rational intervention against T. cruzi infection. Here show that TcTASV-C is mainly secreted through extracellular vesicles (EVs) of trypomastigotes, and is a major cargo of its content. We have also shown that TcTASV-C is much more expressed in trypomastigotes purified from blood from infected mice than in trypomastigotes harvested from in vitro cultures, suggesting that host molecules should trigger TcTASV-C expression in vivo during the infection. The immunization of mice with TcTASV-C interfered with the early acute phase of T. cruzi infection through a strong humoral immune response. TcTASV-C should be considered as a novel secreted virulence factor of T. cruzi trypomastigotes and -although its biological function is still unknown- we hypothesize its participation in the early steps of T cruzi infection in the mammalian host.