Research Alvaro Baeza Garcia

Abstract

African trypanosomiasis is a tsetse fly transmitted disease indigenous for the African continent. Millions of people in 36 sub-Saharan African countries are currently at risk of this fatal infection. The current drugs are faced with limitations of toxicity and drug resistance and to date not a single effective vaccine is available. For both vaccine development and elimination endeavours, an adequate understanding of the immunology of infection onset, disease progression and distribution of parasites to tissue sanctuary niches is crucial. Our recent work has identified the skin and lungs as overlooked tissue reservoirs. Immunological studies in mouse models unveiled the increased presence of γδ T cells in infected tissues and a profound importance of these cells in regulating parasite control and host survival. The current research initiative will investigate the complex dynamics of γδ T cells during Trypanosoma brucei infections. The project consists of three distinct work packages (WP1-3). WP1 focuses on characterizing tissue-specific γδ T cell subsets following a natural, tsetse fly-transmitted T. brucei infection, focussing on their tissue tropism and contribution to immune cell recruitment and pathology. WP2 aims to explore the molecular mechanisms underlying the immune response of γδ T cells against T. brucei parasites, including their interaction with the major variant-specific surface glycoprotein (VSG) of the parasite. In vitro studies will inform about the responsiveness and functional importance of gene expression patterns of γδ T cells to parasitic stimulation. WP3 investigates the role of γδ T cells in the development of antiparasitic adaptive immunity and post-treatment tissue repair. This research employs advanced techniques such as single-cell transcriptomics, multiparameter immunoprofiling, and histopathological examinations in unique infection models to unravel the intricate interplay between γδ T cells and T. brucei, offering unprecedented basic scientific insights and revealing opportunities for immunotherapeutic interventions against trypanosomiasis.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Baeza Garcia Alvaro
• Fellow: Jacobs Yentl

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

In the last decade, stem cells have been discovered to serve as a reservoir for many pathogenic organisms. Our recent research on visceral leishmaniasis (VL) revealed that hematopoietic stem cells (HSC) in the bone marrow underlie treatment failure and relapse. These cells exhibit a unique transcriptional signature (StemLeish) and provide an environment for the development of parasite quiescence, a metabolic state that is impervious to drug treatment. This project will build upon these cutting-edge findings in order to obtain (i) a thorough characterization of immunological processes in the HSC niche that are at the basis of treatment failure, and (ii) mechanistic insights in the possible trigger(s) of VL relapse and the particular role of Macrophage Migration Inhibitory Factor (MIF). From an applied research viewpoint, this project will (iii) establish the diagnostic value of HSC biomarkers using patient samples and (iv) install a novel drug screening platform based on the developed tools to predict and capture the risk of relapse. It is expected that this project will open new therapeutic avenues that may extend beyond leishmaniasis and be revolutionary in the precarious battle against treatment failure.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Baeza Garcia Alvaro
• Fellow: Dirkx Laura

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

The inability to acquire protective immunity against Plasmodium parasite infections is a significant obstacle to malaria control. Previous research has shown that Plasmodium parasites use an active mechanism to control the host immune response by expressing a molecule called PMIF, which is similar to the host macrophage migration inhibitory factor. Mutant parasites that lack PMIF have been shown to inhibit both cellular and humoral immune responses. However, the precise way in which parasite PMIF inhibits host MIF and host immune responses is not yet fully understood. This project aims to investigate the complex interplay between host and parasite-derived MIF molecules and their impact on the acquisition of protective immunity, as well as improving current and future therapeutic interventions. To achieve this, the following specific aims will be pursued: 1) Understanding the molecular basis of pro-inflammatory activation of T cell responses by host MIF and PMIF, 2) Determining the contribution of MIF molecules to the induction of Plasmodium antigen recognition and recall responses during liver and blood infection, and 3) Examining the impact of MIF functional polymorphism on the acquisition of sterile immunity against malaria. 1246

Researcher(s)

• Promoter: Baeza Garcia Alvaro
• Fellow: Bemelmans Britt

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

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)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

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)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project