Study of immune responses to infection by T. cruzi, the parasite responsible for Chagas disease, has led Paola MINOPRIO's team, in the Immunology Department of the Institut Pasteur in Paris (Team associated with CNRS URA 1960) to a totally new approach for vaccine research, based on neutralization of non specific immunity which is observed at the early stages of infection. Scientists have shown that abbrogation of this non specific responses leads to the induction of an effective immunity against T. cruzi parasite. This work has been done in collaboration with Antonio COUTINHO, Instituto Gulbenkian de Ciência and Mario ARALA CHAVES, Instituto de Ciencias Biomedicas Abel Salazar, Portugal. It is published in "Nature Medicine ", August 1st, 2000.
Attempts to provoke effective immunity to parasites are limited by poor specific immune responses to parasite antigenic molecules in early phases of infection, thus, allowing for immune evasion. Infectious processes are characterized by non specific immune responses associated with immunosuppression and autoimmunity in the infected host. These non specific responses are due to polyclonal lymphocyte activation.
In the 80s', using the murine model of T.cruzi infection, Paola MINOPRIO's team had shown that 98% of the immune responses triggered at the early stages of infection are non specific. These non specific responses had also been observed following different infections by viruses, bacteria, parasites and fungi. The pasteurian team has therefore, decided to study the mechanisms underlying such lymphocyte non specific responses. The better understanding of these mechanisms may open the way for their neutralization and thus, allow for effective immunity against infectious agents.
Scientists have studied immune mechanisms during infection by T.cruzi, the etiological agent of Chagas' disease. In this model, parasite evasion owes at least in part from the release of mitogenic or superantigenic molecules that subvert host specific responses by triggering non specific lymphocyte activation.
In collaboration with Antonio COUTINHO and Mario ARALA CHAVES, the team of Paola MINOPRIO has tried to isolate T.cruzi molecules involved in the induction of such non specific immunity. The scientists have identified and characterized a parasite gene (TcPA45) and demonstrated that its product is a mitogenic protein. In addition, they have shown that this protein is in fact a novel eukaryotic racemase, enzyme whose activity is fundamental for mitogenicity.
Using this experimental model, the scientists have shown that the abbrogation or reduction of these B and T cell non specific responses leads to an increased resistance to infection and to the control of chronic pathology : intramuscular DNA " vaccination " containing the TcPA45 gene is able to induce 85% decrease in parasitemia levels after challenge with infective forms of the parasite. Moreover, even higher levels of parasitemia control have been observed when sub-mitogenic doses of the protein were injected.
These results suggest that mitogenic proteins can be used as 'vaccines' or 'drug targets' : neutralization of these proteins could abort parasite strategy to deviate immune responses into a non specific activation on the immune system and immunosuppression.
This work open the way to new vaccination and therapeutics strategies and may contribute to stimulate further research on the biological role of mitogenic molecules and their implications in immune phenomena.
This new approach, pursued since several years by these teams, is in contrast with classic trends in vaccine research that have focused on the search for immunity against immunodominant and highly antigenic molecules. By developping this approach, scientists have anticipated the emergent interest for non specific immunity.