THE ROLE OF THE INFLAMMATORY RESPONSE IN MALARIA PATHOGENESIS AND IN PROTECTIVE IMMUNE RESPONSE
The work we are doing is aimed at exploring the immunological mechanisms involved in malaria. In recent years, using a mouse model of experimental cerebral malaria (ECM), we have demonstrated that a new histamine signaling pathway and a FceRI+ neutrophil population are crucial for the disease. Interestingly, a pro-inflammatory gene of the parasite, called the histamine releasing factor (HRF), has been identified as essential for the pre-erythrocytic development of the PbANKA parasite responsible for ECM. More recently, it has been demonstrated that another mutant strain, PbNK65 deficient in HRF (PbHRFD)), provided effective protection against parasite infection and led to the establishment of a durable immune memory against the erythrocyte stage. It prompted us to develop vaccine strains of Plasmodium falciparum (Pf), a parasite that infects humans, by designing HRF mutant parasites, in collaboration with Sylvie Garcia who joined the BIHP Unit headed by Artur Scherf and who is developing a project to design humanized mice. Most recently, we began working with a Weizmann Institute team to analyze a new mode of parasite-parasite and parasite-host interactions through vesicles called exosomes. In particular, we are working on the hypothesis that these exosomes modulate the immune response of the host in favor of parasite development. Indeed, we found that these vesicles are endowed with immunosuppressive properties with T cells as target cells. We have also initiated a project on immunity against hepatic stages of parasite development. This project consists in studying the effect of hepatic inflammation on the immune response against the parasite. For this, mice deficient for the MDR2 gene, a flippase which allows the translocation of phospholipids from the hepatic cells to the biliary canaliculi so that micelles are formed with bile acids which render them nontoxic to the hepatic parenchyma. As a result, MDR2-KO mice develop chronic inflammation. Preliminary results show that these mice do not become infected following the inoculation of sporozoites thus proving that the hepatic inflammatory response is deleterious for the parasite development. We will develop our projects in the following directions:
- The characterization of the mechanisms by which the liver inflammation controls the development of pre-erythrocytic stages of the parasite.
- We will establish whether virally-induced hepatic inflammation will have an impact on the Plasmodium parasite development in the liver.
- Based on our model, we will develop new vaccine strategies against hepatic stages of the parasite.
