[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: A century after its discovery, Chagas disease (CD) is still considered a public health problem. Mortality caused by CD between 2000 and 2010 was described according to the specific underlying cause, year of occurrence, gender, age range, and region of Brazil. The standardized mortality rate decreased 32.4%, from 3.4% in 2000 to 2.3% in 2010. Most of the deaths (85.9%) occurred in male patients who were > 60 years of age caused by cardiac involvement. The mortality rate caused by cardiac involvement decreased in all regions of Brazil, except in the North region, where it increased by 1.6%. The Northeast had the smallest and the Central-West had the largest decrease. The mortality rate caused by a compromised digestive tract increased in all regions. Despite the control of transmission by vector and blood transfusions, CD should remain on the list of priority diseases for the public health service in Brazil, and surveillance actions cannot be interrupted.
The American journal of tropical medicine and hygiene 07/2014; 91(3). DOI:10.4269/ajtmh.13-0574 · 2.74 Impact Factor
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