Our research projects at a glance
Protective and pathogenetic role of T cells in murine malaria
Malaria is characterized by two very distinct phases both of which with a unique interaction with immune system of the host. The liver phase is immunological silent i.e. no massive induction of the immune system occurs and no pathology is associated with this stage. However, during the liver stage CD8+ T cells that recognize malaria antigen on hepatocytes can mediate protection. Thus current vaccine strategies are concentrating on this stage. A major problem is the short duration of the liver stage. Therefore a vaccine-induced response must induce CD8+ T cells that persist in the liver and produce cytokines immediately after antigen encounter. This problem might be solved by using novel vaccine strategies that efficiently induce T effector/memory cells, which are known to persist in peripheral organs. Recently we have shown that fusion molecules of the adenylate cyclase toxin of Bordetella pertussis with liver stage specific antigens are potent tools to target antigen to dendritic cells in vivo, which is then followed by presentation on MHC class I. This, in combination with either a blockade of CTLA-4 or a heterologous boost immunization can confer a long-lasting and protective immune response.
The blood stage of malaria leads to a strong activation of cytokine-producing T cells, which are associated with inflammation and pathology in different organs e.g. the brain. Most of these T cells express negative costimulators like CTLA-4, PD-1 and BTLA. Ligands of these molecules were expressed in different organs upon inflammation and thus help to prevent an overwhelming pathology. Depending on the type of infection a blockade of these interactions lead to an increased parasite clearance or to an exacerbation of disease. However, the regulatory mechanisms that are induced during the blood stage are not only regulating the immune response that is triggered by the blood stage but they also influence liver stage immunity. Thus we are now concentrating on regulatory mechanisms at the interface between liver and blood stage immunity.
Trypanosoma cruzi and Chagas Disease
Infection with the obligate intracellular protozoan parasite Trypanosoma cruzi (T. cruzi) and the resulting Chagas disease remains the most important neglected vector-borne disease in Latin America. Chagas disease is an ancient affliction in this region, where nowadays more than 70 million people live in high-risk infection areas. Chagas is a chronic and a disabling infection with high social and economic impact, is highly stigmatizing, and promotes underdevelopment and poverty. Most infected people do not know that they are infected, as the disease does not show specific symptoms (e.g., fever, swollen at the biting site) in the acute stage. Infections then remain largely asymptomatic for years, or even decades (with few or no parasites detectable in the circulation). About 30-35 % of chronic infected cases develop clinical manifestations of Chagas Disease in cardiac or digestive forms. The major clinical manifestation is Chagas cardiomyopathy which leads to congestive heart failure, arrhythmia and even to death, while digestive Chagas disease leads to oesophageal or colonic mega syndromes. Because of this long asymptomatic phase, Chagas disease is often called “the silent killer”.
T. cruzi parasites have developed an intricate interaction with mammalian hosts. Like in chronic viral infections, these parasites persist throughout the host’s lifetime and have developed mechanisms to evade attack and elimination by the immune system. CD8+ T cells are crucial and highly effective in controlling this infection. Although strong CD8+ T cell responses, in concert with other immune effectors, control the acute phase of infection, they fail to completely clear all parasites and resolve the inflammation process, leading to parasite persistence and to chronic infection and inflammation. Our projects focus on the contribution of the co-inhibitory receptors and their pathways in the regulation of T cells during T. cruzi infection. Understanding the mechanistic and molecular basis of co-inhibitory receptor expression during T. cruzi infection is an important goal and is imperative for the development of new immunotherapeutic approaches against disease and for effective vaccine development.
In our current project we are investigating the role of T-cell immunoglobulin-3 (TIM-3) during infection. The up-regulation of Tim-3 has been associated with a negative regulation of the immune response in chronic viral infection and cancer models. We report a high percentage of CD8+TIM-3+ T cells during the acute phase of infection and and Tim-3 expression correlates with a significantly reduced function of these cytotoxic cells. Furthermore, Tim-3 expression has an adverse impact on the clearance of parasitic reservoirs, allowing persistence in the tissue. We are interested in understanding whether the expression of these co-inhibitory receptors is a natural mechanism to avoid immune pathology that has an adverse effect on disease progression.