Chagas disease
Manager: Manuel Fresno Escudero UAM-A
Chagas Disease is an infectious disease that affects over 15 million people and is endemic to Central and South America. This disease, which is due to infection by the parasite protozoa Trypanosoma cruzi, registers high indices of morbidity and mortality. Although it is traditionally transmitted by a haematophagous insect vector, current inflows of immigration towards cities mean that vertical transmission, and transmission by blood transfusion in particular, have now come to be regarded as the prevalent routes of contagion. Spain's present intense influx of immigrants from Latin America has made this a "local" disease, which has in turn generated new needs in terms of clinical diagnosis, treatment and control. A serious problem nowadays is the absence of markers of disease severity and of progress after drug treatment, especialy where the latter is relatively ineffective and toxic.
Immune control of T. cruzi requires the action of multiple mechanisms, in which both the innate and adaptative immune responses to parasite-specific antigens play an important role. Experimental infection system studies have made it possible to ascertain important aspects of the nature of the immune response required to achieve immune control of the infection. Although many of the parasite's antigens have been characterised and examined in order to study their immune system stimulation capacity, only a few have been shown to possess the ability to induce a protective immune response to T. cruzi infection.
Recent results, obtained in the context of the RICET's collaborative project (Ref. C03-04) have enabled an immunodominant A2 epitope, recognised by CTLs of transgenic A"0201 mice immunised with the PFR2 protein, to be identified in the PFR2 antigen. Furthermore, immunisation of mice with DNA vectors that carry the PFR2 gene fused to the HSP70-encoding gene, induces an increase in type-Th1 cytokine expression, an IgG2a subtype humoral response, and activation of specific CD8+ CTLs that correlate with protective activity against T. cruzi infection.
Subprogram: Pathogenic Mechanisms of Chagas Disease
Manager: Manuel Fresno Escudero UAM-A
Chagasic pathology is the result of multiple effector mechanisms, which include processes that entail autoimmunity as well as the possible persistence of the parasite. Late appearance of myocardiopathy in relation with acute infection and absence of the parasite, particularly at sites of intense inflammation, led to the proposal that chronic pathology was the result of a response against antigens specific to the host. The induction of myocarditis in normal mice adoptively transferred with purified T-cells from the spleen of mice chronically infected with Trypanosoma cruzi, is one of the most recent and strongest items of evidence that support autoimmunity as a pathogenic process. In contrast, the presence of T. cruzi antigens would act as a stimulus for a delayed-type hypersensitivity process mediated by specific T-cells, leading to host-tissue damage. In recent years, the recognition of the parasite's genetic diversity (at least two clearly-differentiated evolutionary lineages) has suggested that there may be a causal relationship between the diversity of clinical forms (asymptomatic, cardiopathies, megaviscera) and the diversity of T. cruzi populations. Currently, these populations have been grouped into two lineages, namely, T. cruzi-I (linked to the wild transmission cycle) and T. cruzi-II (linked to human transmission).
Goal
This programme's main goal is the study of the molecular bases of the generation and maintenance of the pathology of Chagas Disease.
Subprogram: Immune intervention in Chagas Disease
Manager: Maria del Carmen Thomas Carazo IPBLN-A
Immunotherapy emerges as a fundamental tool for the control of Chagas Disease, and must be able to induce a specific response, both cellular and humoral, with the balance shifted towards subtype Th1. DNA vaccines combine the advantages of expressing the cloned antigen in situ, the presence of sequences that tip the balance of the response towards subtype Th1 and their ease of handling, all of which allows for the construction of chimerae and the introduction of coding sequences for stimulator/modulator molecules of the immune response. They would thus appear to be extremely suitable vehicles for inducing protection against this parasitosis, and should therefore be designated a research priority. Moreover, the use of genetically modified animals represents a useful tool for determining the immunological mechanism whereby protection is induced and, in particular, the role played in this by certain cytokines.
Goal
This programme's main goal is the rational selection of molecules with effective immunoprotective capacity against Trypanosoma cruzi infection and the study of the immunological mechanisms involved in the induction of the above protection.
