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A Monoallelic Deletion of the TcCRT Gene Increases the Attenuation of a Cultured Trypanosoma cruzi Strain, Protecting against an In Vivo Virulent Challenge.
- Source :
- PLoS Neglected Tropical Diseases; Feb2014, Vol. 8 Issue 2, p1-9, 9p
- Publication Year :
- 2014
-
Abstract
- Trypanosoma cruzi calreticulin (TcCRT) is a virulence factor that binds complement C1, thus inhibiting the activation of the classical complement pathway and generating pro-phagocytic signals that increase parasite infectivity. In a previous work, we characterized a clonal cell line lacking one TcCRT allele (TcCRT+/−) and another overexpressing it (TcCRT+), both derived from the attenuated TCC T. cruzi strain. The TcCRT+/− mutant was highly susceptible to killing by the complement machinery and presented a remarkable reduced propagation and differentiation rate both in vitro and in vivo. In this report, we have extended these studies to assess, in a mouse model of disease, the virulence, immunogenicity and safety of the mutant as an experimental vaccine. Balb/c mice were inoculated with TcCRT+/− parasites and followed-up during a 6-month period. Mutant parasites were not detected by sensitive techniques, even after mice immune suppression. Total anti-T. cruzi IgG levels were undetectable in TcCRT+/− inoculated mice and the genetic alteration was stable after long-term infection and it did not revert back to wild type form. Most importantly, immunization with TcCRT+/− parasites induces a highly protective response after challenge with a virulent T. cruzi strain, as evidenced by lower parasite density, mortality, spleen index and tissue inflammatory response. TcCRT+/− clones are restricted in two important properties conferred by TcCRT and indirectly by C1q: their ability to evade the host immune response and their virulence. Therefore, deletion of one copy of the TcCRT gene in the attenuated TCC strain generated a safe and irreversibly gene-deleted live attenuated parasite with high immunoprotective properties. Our results also contribute to endorse the important role of TcCRT as a T. cruzi virulence factor. [ABSTRACT FROM AUTHOR]
- Subjects :
- TRYPANOSOMA cruzi
MICE
VACCINATION
DEATH (Biology)
IMMUNE response
Subjects
Details
- Language :
- English
- ISSN :
- 19352727
- Volume :
- 8
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- PLoS Neglected Tropical Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 94728894
- Full Text :
- https://doi.org/10.1371/journal.pntd.0002696