Dr. Manuel Fresno's group at the Severo Ochoa Molecular Biology Centre (CSIC-UAM) studies the immune response and inflammatory processes that are triggered by Trypanosoma cruziinfection, the causative agent of Chagas Disease, which is endemic in South and Central America. This disease is characterised by presenting with high parasitaemia in the acute stage of the disease, which can be fatal in a small percentage of patients. After overcoming the acute stage, patients present with a chronic asymptomatic stage that may last for decades and is characterised by absence of parasitaemia and a highly reduced presence of parasites in tissue. In the chronic symptomatic stage, there is marked cardiac pathology with abundant mononuclear cell infiltrate in approximately 30% of patients, accompanied, at times, by cardiomegalia. In a lower percentage of patients, pathology may also be present in the digestive tract, giving rise to mega-oesophagus or megacolon.
The laboratory has experience in the study of different aspects of in vitro infection and the experimental mouse model, as well as studies on patients in endemic areas. We have analysed the pathogenic mechanisms underlying T. cruzi infection, especially this parasite's contribution to the infection, as well as autoimmune phenomena, with these taking concrete form in the following lines of research:
we identified the Cha autoantigen, recognised as a disease progression marker by antibodies present in the serum of infected patients. In addition, during infection in mice, T-cells are generated with cross-reaction between Cha and repetitions of the carboxyl terminal of the shed acute-phase antigen (SAPA)/trans-sialidase of T. cruzi, which are capable of generating heart disease. These results indicate that both the parasite's persistence and autoimmunity are implicated in the generation of heart disease.
We analysed T. cruzi phagocytosis and escape mechanisms in macrophages and subversion of the immune response. The results indicated that T .cruzi alters the 2 macrophage infection phases (interaction with the macrophage and intracellular replication), interfering with macrophage activation mechanisms in order to enable intracellular replication.
We analysed the inflammatory infiltrate present during the acute infection phase in the heart of infected mice, and characterised a new type of macrophage that expresses arginase I, which may influence the survival of the parasite and at the same time regulate inflammatory cellular response in the heart during infection.
Furthermore, the laboratory collaborates with Latin American and Spanish blood banks and hospitals for the purpose of: detecting cases that test positive for Chagas Disease among the immigrant population from Latin America; and studying prognostic markers.
Note should be taken of the fact that, within the RICET framework, we have recently had access to new tools, such as telemetry, which enables electrocardiograms to be recorded in conscious rats, and in vivo images, which allow for sequential follow-up of parasite infections in mice, with both techniques rendering it possible for the number of experimental animals to be reduced. Moreover, new cell population purification techniques and bioluminiscent techniques allow for innovative approaches to the respective study topics. At a molecular level, we also have probes for studying gene expression or determining parasite burden quantitatively in different tissue types.
Severo Ochoa Molecular Biology Centre, Autonomous University of Madrid