The protein family TcTASV-C is a novel Trypanosoma cruzi virulence factor secreted in extracellular vesicles by trypomastigotes and highly expressed in bloodstream forms
| Autor: | Lucas D. Caeiro, Mariana Rizzi, Matias Exequiel Rodriguez, María Elisa Solana, Agustina Chidichimo, Valeria Tekiel, Daniel O. Sánchez, Giselle Rodriguez, Gabriela V. Levy, Catalina D. Alba-Soto |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Life Cycles Physiology Protozoan Proteins Protozoology Virulence factor Epitope purl.org/becyt/ford/1 [https] Database and Informatics Methods Mice Medicine and Health Sciences Immune Response Protozoans Mice Inbred C3H biology lcsh:Public aspects of medicine Eukaryota Hematology Protein Transport Infectious Diseases Blood PARASITIC DISEASE Multigene Family Protozoan Life Cycles Cellular Structures and Organelles SEQUENCE MOTIF ANALYSIS Sequence Analysis CIENCIAS NATURALES Y EXACTAS BLOODSTREAM INFECTION Research Article Chagas disease Trypanosoma lcsh:Arctic medicine. Tropical medicine Protein family lcsh:RC955-962 Bioinformatics Virulence Factors Trypanosoma cruzi Immunology Virulence Research and Analysis Methods Microbiology Ciencias Biológicas 03 medical and health sciences Extracellular Vesicles Biología Celular Microbiología Sequence Motif Analysis IMMUNE RESPONSE parasitic diseases TRYPOMASTIGOTES medicine Parasitic Diseases Animals Humans Secretion Chagas Disease Vesicles purl.org/becyt/ford/1.6 [https] Public Health Environmental and Occupational Health Organisms Biology and Life Sciences lcsh:RA1-1270 Bloodstream Infections Cell Biology Trypomastigotes biology.organism_classification medicine.disease Parasitic Protozoans 030104 developmental biology Humoral immunity Physiological Processes Developmental Biology |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 12, Iss 5, p e0006475 (2018) |
| Popis: | TcTASV-C is a protein family of about 15 members that is expressed only in the trypomastigote stage of Trypanosoma cruzi. We have previously shown that TcTASV-C is located at the parasite surface and secreted to the medium. Here we report that the expression of different TcTASV-C genes occurs simultaneously at the trypomastigote stage and while some secreted and parasite-associated products are found in both fractions, others are different. Secreted TcTASV-C are mainly shedded through trypomastigote extracellular vesicles, of which they are an abundant constituent, despite its scarce expression on culture-derived trypomastigotes. In contrast, TcTASV-C is highly expressed in bloodstream trypomastigotes; its upregulation in bloodstream parasites was observed in different T. cruzi strains and was specific for TcTASV-C, suggesting that some host-molecules trigger TcTASV-C expression. TcTASV-C is also strongly secreted by bloodstream parasites. A DNA prime—protein boost immunization scheme with TcTASV-C was only partially effective to control the infection in mice challenged with a highly virulent T. cruzi strain. Vaccination triggered a strong humoral response that delayed the appearance of bloodstream trypomastigotes at the early phase of the infection. Linear epitopes recognized by vaccinated mice were mapped within the TcTASV-C family motif, suggesting that blockade of secreted TcTASV-C impacts on the settlement of infection. Furthermore, although experimental and naturally T. cruzi-infected hosts did not react with antigens from extracellular vesicles, vaccinated and challenged mice recognized not only TcTASV-C but also other vesicle-antigens. We hypothesize that TcTASV-C is involved in the establishment of the initial T. cruzi infection in the mammalian host. Altogether, these results point towards TcTASV-C as a novel secreted virulence factor of T. cruzi trypomastigotes. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|