Genetic mapping and genome-wide studies provide evidence for the association of several genetic polymorphisms with malaria, a complex pathological disease with multiple severity degrees. We have previously described Berr1and Berr2 as candidate genes identified in the WLA/Pas inbreed mouse strain predisposing to resistance to cerebral malaria (CM) induced by P. berghei ANKA. We report in this study the phenotypic and functional characteristics of a congenic strain we have derived for Berr2WLA allele on the C57BL/6JR (B6) background. B6.WLA-Berr2 was found highly resistant to CM compared to C57BL/6JR susceptible mice. The mechanisms associated with CM resistance were analyzed by combining genotype, transcriptomic and immune response studies. We found that B6.WLA-Berr2 mice showed a reduced parasite sequestration and blood–brain barrier disruption with low CXCR3+ T cell infiltration in the brain along with altered glial cell response upon P. berghei ANKA infection compared to B6. In addition, we have identified the CD300f, belonging to a family of Ig-like encoding genes, as a potential candidate associated with CM resistance. Microglia cells isolated from the brain of infected B6.WLA-Berr2 mice significantly expressed higher level of CD300f compared to CMS mice and were associated with inhibition of inflammatory response.
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We gratefully acknowledge Dr. Sulabha Pathak for fruitful discussions, Dr. Xavier Montagutelli, Institut Pasteur Paris for the gift of WLA mice, and Oliver Gorgette for assistance in the generation of the recombinant B6xWLA mouse strains. Thanks are also due to Philippe Persoons and the staff of the animal facility of Institute Pasteur of Lille for maintenance and preservation of the mouse strains. We also thank Florent Auger and Nicolas Durieux from Platform of Biology and Health, CHRU Lille for MRI acquisition and analysis, Marine Swiathon for administrative support, and Shabdda Communication for scientific and language editing.
This work was supported by ARCir “Dynamique” Région Nord-Pas de Calais and the LabEx PARAFRAP: ANR-11-LABX-0024. TK is a recipient of PRESTIGE (Sanction No.2014-1-0043: Marie Curie Actions/FP7/PCOFUND-GA-2013-609102) and Région Haut-de-France (CNRS - Sanction No.147894) Post-doctoral Fellowship and Fondation des Treilles (Young Rresearcher Prize 2016)— “La Fondation des Treilles, créée par Anne Gruner Schlumberger, a notamment pour vocation d’ouvrir et de nourrir le dialogue entre les sciences et les arts afin de faire progresser la création et la recherche contemporaines. Elle accueille également des chercheurs et des écrivains dans le domaine des Treilles (Var) www.les-treilles.com”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
All animal work was conducted in strict accordance with the Directive 2010/63/EU of the European Parliament and Council “On the protection of animals used for scientific purposes.” All protocols were approved by the Ethical Committee of Institute Pasteur of Lille and the French Ministry of Agriculture (permit number A 75-15-28) and performed in compliance with the NIH Animal Welfare Assurance #A5476-01 issued on 02/07/2007. All efforts were taken to minimize animal suffering.
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Keswani, T., Roland, J., Herbert, F. et al. Expression of CD300lf by microglia contributes to resistance to cerebral malaria by impeding the neuroinflammation. Genes Immun 21, 45–62 (2020). https://doi.org/10.1038/s41435-019-0085-9