Research team
Expertise
In vitro and In vivo models for the assessment of T cell responses- In vitro and in vivo models of cancer and parasitic infectious diseases- Orthotopic and non orthotopic models in cancer- Natural transmission models of parasites using insect vectors and assessment of immune responses. Drug discovery and vaccines development against parasitic diseases.
The molecular mechanisms leading to the onset of severe malaria.
Abstract
In his research plan for the next five years, the researcher focuses on the following questions. He wants to define the molecular basis of proinflammatory activation of immune responses by host and PMIF. In addition, he wants to investigate the physiological relevance of MIF-driven modulation of T cell function in advanced malaria. Finally, the researchers aims to improve current therapeutic approaches targeting binding of CD74-MIF by pharmacological or vaccine approaches. The proposal combines the modulation of immune responses by MIF and T cell biology immunology to improve current knowledge and development of parasitic diseases. Although this project focuses on malaria the knowledge gained will also be extrapolable to other parasites that express a MIF orthologue, such as Leishmania.Researcher(s)
- Promoter: Baeza Garcia Alvaro
- Fellow: Baeza Garcia Alvaro
Research team(s)
Project type(s)
- Research Project
Targeting an endogenous Plasmodium-expressed immunosuppressive pathway for new malaria therapeutics.
Abstract
We have described a mechanism by which the Plasmodium expressed cytokine Macrophage Migration inhibitory Factor (PMIF) acts to prevent the acquisition of immunologic memory by activating the host MIF receptor CD74 to establish severe malaria and parasite replication. Immunoneutralization or genetic deletion of PMIF, strictly conserved in all Plasmodium species, improves malaria immunologic memory, reduces parasite burden, and protects from severe malaria. Moreover, we have shown in genetic PMIF deficiency experiments that malaria protection and development can be recapitulated with a small-molecule antagonist developed by our group. This novel molecule, called 26k, was identified by leveraging the unique features of PMIF structural biology. It specifically blocks PMIF interaction with its host receptor CD74, inhibiting parasite replication in the host liver and protecting from severe malaria. We hypothesize that such a PMIF inhibitor provides a unique approach for interfering with a parasite-specific mechanism for suppressing host immunity and offers a new tool for combating Plasmodium infection. This project aims to identify better quality and pharmacologically tractable PMIF antagonists for lead optimization programs and will provide a proof-of-concept that PMIF pharmacological inhibition increases memory immunity to Plasmodium infection. We will accomplish our objective by pursuing the following Specific Aims: Aim 1: Identification and optimization of novel PMIF inhibitors. Aim 2: Evaluation of lead PMIF inhibitors in experimental models of Plasmodium infection. Aim 3: Evaluation of the full therapeutic potential of PMIF inhibitors.Researcher(s)
- Promoter: Baeza Garcia Alvaro
Research team(s)
Project type(s)
- Research Project