Trypanosoma cruzi is the causative agent of Chagas disease or American Trypanosomiasis. Chagas Disease continues to be a relevant infectious cause of death in Latin America where at least 50,000 people dies every year and many young men became disabled to rural work with high economic impact to their families. It is estimated that 18,000,000 persons are already infected and 100,000,000 are at risk of infection with 200,000 new cases/year. The disease is also transmitted in uterus and by contaminated blood extending the risk of infection out of the endemic regions. Even though this parasite is unable to synthesize sialic acids de novo, its attachment to, and invasion of host cell as well as its physical protection against serum lytic factors depend upon the sialylation of its membrane-anchored components. To circumvent this gap, the parasite expresses a novel trans-sialidase (TS) activity on its surface, which scavenges sialyl residues from host glycoconjugates and use them to trans- glycosylate its own acceptor molecules. No similar mammal enzyme is described. In addition to the parasite surface-associated role TS is shed into the bloodstream. The systemically distributed enzyme triggers several of the pathologic findings associated to the acute phase of the disease by inducing apoptosis on different cells of the immune system, thrombocytopenia and erythropenia. The control of this virulence factor by neutralizing antibodies results in prevention of all those abnormalities then suggesting a target for chemotherapy This Application points to get novel cellular and molecular insights into the multiple pathogenic roles played by TS during infection and to obtain clues for the rational design of inhibitors that might be used in chemotherapy. The immune cells glycoconjugates involved as targets of the TS will be identified by tagged sugars and mass spectra to gain knowledge on the cellular mechanisms involved. The interaction of the modified surface molecules with the endogenous ligands that leads to the associated mechanisms of death will be also searched. The extent to which the immune system damage induced by the TS is reflected on the ongoing immune response will be determined by using ovalbumin specific TCR transgenic mice. The structural basis of the TS inhibition will be analyzed by the 3D resolution of the binary complex with a high affinity neutralizing monoclonal antibody.
Chagas disease, the American trypanosomiasis, is a chronic parasitic illness that represents a major health, social and economic problem in Latin America. The prevalence of Trypanosoma cruzi infection has been estimated as about 18 million cases, with about 100 million more people at risk and 200,000 new cases/year with about 5 million people having clinical changes attributable to Chagas disease. Treatment is unsatisfactory mainly because dubious outcome and serious adverse effects of the few available drugs. ? ? ?
