Axis 1. Evaluation of the complex nature of immune mechanisms induced by protozoan parasite (co)infections
Project 1. Parasite virulence factors underlying severe disease in Leishmaniasis
L. guyanensis is infected with an endosymbiotic dsRNA virus (LRV1) conferring the parasite the ability to persist in the host and to form distant secondary lesions. The LRV1 is unable to infect vertebrates but is detected by the host innate immune system. By initiating an early anti-viral immune response following the engagement of the dsRNA by TLR3 receptor, the LRV subverts anti-parasite immune responses.
We intend to:
- Define the molecular mechanisms involved in this process thereby establishing if LRV infection is a virulence factor associated with severe metastatic leishmaniasis.
- Characterize the immune response from patients expressing various clinical forms of L. guyanensis and L. braziliensis (using a bank of clinical samples (skin biopsies, peripheral blood cells, and sera)).
- Identify cell modifications induced by the presence of LRV1 in macrophages infected with different Leishmania strains and in skin biopsies from infected patients.
- Undertake genetic profiling of L. guyanensis in patient isolates carrying LRV and correlate it with immune profiles and disease outcome
People involved in the project: Ghislaine Prévot, Pierre Couppié, Romain Blézot, Marine Ginouves.
Projet 2. Molecular and cellular host–parasite crosstalk underlying protection/ pathology during malaria
2.1 : Role of glial cells in Cerebral Malaria
Astrocytes and M1-like microglial cells play a prominent role for in the exacerbation of neuroinflammatory processes in cerebral malaria (CM) through parasite microvesicles transferred in Astrocytes.
Our workprogram is to:
- Define mechanisms of parasite microvesicle transfer to astrocytes (coll. F. Lafont and BICELL platform at CIIL).
- Characterize parasite microvesicles and the secretomes of glial cells (using differential metabolomics and proteomics (coll. S. Kamat, IISER Pune, India)) to identify immunoregulators.
- Examine how pro-inflammatory astrocytes and microglia interact with brain-infiltrating myeloid cells and CD8+ T cells to give rise to neuropathology.
People involved in the project: Sylviane Pied, Ines Leleu, Fatima Hellani, Jérémy Alloo, Pierre-André Cazenave, Jacques Roland.
2.2 : Role of IL-33 in Cerebral Malaria
Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is expressed in nuclei of cells and secreted as alarmin alerting the immune surrounding cells via its receptor ST2/IL1RL1. IL-33 is expressed in the developing and mature brain. However, its role in brain function and behavior remains unclear. The project aims to study the role of IL-33 in cerebral malaria (CM). CM is a lethal immunopatholological disorder induced by Plasmodium falciparum infection. It is characterized by i) the sequestration of infected red blood cells (iRBCs) in cerebral microvascular beds and ii) a strong neuroinflammation. The rationale of the project is based on our finding that in a mice model, upon Plasmodium berghei ANKA (PbA) infection, Interleukin-33 (IL-33) levels are higher in serum and brain of CM-sensitive compared to CM-resistant mice. However, the detrimental role of IL-33 during CM remains unexplored. IL-33 is known to increase expression of ICAM-1 and CD36, 2 mediators of the binding of iRBCs to endothelial cells (ECs) during CM, and to promote vascular permeability. We hypothetize that IL-33 could disrupt the blood–brain barrier (BBB) by favouring the binding of iRBCs to the brain ECs and the neuroinflammatory process.
IL-33 is also revealed as a crucial player for controlling Toxoplasma infection in the brain and preventing the development of encephalitis. However, its role in this infection resistance is not well understood. Therefore, a better understanding of the IL-33/ST2 signaling pathway could help find novel immunomodulatory therapies against cerebral malaria and toxoplasmosis.
People involved in the project: Corine Glineur, Ines Leleu, Capucine Picavet, Nasreddine Saidi, Sylviane Pied.
Project 3. Comprehensive analysis of immunopathological processes associated to Amazonian Toxoplasmosis
AT is characterized by severe clinical manifestations with pulmonary complications. In mice infected with T. gondii laboratory strains, chronic toxoplasmosis correlated with high levels of serum IFN-γ and MCP-1, and high lung infiltration by T cells, Innate lymphoid cells (ILCs), and NK1.1+CD27+ ILCs producing copious amounts of IFN-γ and TNF-α.
To understand the disease process in AT, comprehensive phenotyping studies are planned to characterize the immune cells induced in peripheral blood, spleen, and lungs of mice infected with T. gondii virulent strains and compare these with the reference strains. In addition, parasite genotyping and investigation of its association to the type of immune response are scheduled.
This should provide insights in the role of persistent or controlled inflammation in protection/pathology and pulmonary forms during T. gondii infection.
People involved in the project: Magalie Demar, Mona Saout, Félix Djossou, Maelys Doine, Kévin Néron.
Axis 2. Study how environmental factors influence immune responses and disease progression in the French Guiana Amazonian ecosystem
Project 4. Understanding natural immunity in populations exposed to multiple protozoan infections
We will take advantage of the high prevalence of malaria and toxoplasmosis in the Amazonian border of FG to analyze the intricate and complex mutualistic interactions between concomitant apicomplexan infections in exposed individuals. We will investigate if a concomitant chronic T. gondii infection in malaria patients modify the fine-tuning of the host immunity and trigger resistance to severe malarial disease. A multidisciplinary approach combining clinical field studies, molecular epidemiology, systems immunology, advanced bio-informatics, and multivariate statistical analysis will be implemented to search for functional innate and adaptive immune signatures contributing to asymptomatic disease in coinfections.
People involved in the project: Sylviane Pied, Magalie Demar, Félix Djossou, Mathieu Nacher, Narcisse Elenga, Loic Epelboin, Kévin Néron.