A Role for CD300f Gene in Resistance to Cerebral Malaria Revealed in B6.WLA-Berr2 Congenic Mice
48 Pages Posted: 1 Aug 2019More...
Background: Malaria is a complex pathological disease. Genetic mapping and genome-wide studies provide evidence for the association of several genetic polymorphisms with malaria severity degrees. However, the genetic factors that predispose to CM remain poorly understood. We previously studied the genetic determinism of experimental CM (ECM) using the mouse malaria parasite P. berghei ANKA (PbA). We described two loci, Berr1WLA and Berr1WLA, associated with resistance to ECM (CMR) in WLA/Pas mice. In this study, we analyzed the consequences induced by PbA infection in these new congenic mouse strains.
Methods: We derived two congenic strains on the C57BL/6JR background for Berr1WLA and Berr1WLA alleles, which were partially and highly CMR, respectively compared to C57BL/6JR CMS mice. The mechanisms associated with the CMR phenotype were studied by combining genotype, transcriptomic and immune response analyses.
Findings: Upon P. berghei ANKA infection, mice bearing the Berr1WLA allele showed reduced parasite load, blood brain barrier disruption and diminished CXCR3+ T cell infiltration in the brain along with altered astrocyte, microglia, and monocyte response and decreased pro-inflammatory factors production. We have identified the CD300f as a potential candidate gene associated with CM resistance. We found that brain monocytes and microglial cells from B6.W-Berr2 compared to B6 mice highly expressed the CD300f receptors upon PbA infection.
Interpretation: This report underlines the value of using congenic mouse strains to identify novel genetic factors in the etiology of CM and provides a unique model for studying the immunopathological processes associated to severe malaria.
Fundaing Statement: 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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Declaration of Interests: The authors declare no competing interests.
Ethics Approval Statement: 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.
Keywords: Cerebral malaria, Genetics, P. berghei ANKA, neuroinflammation, neuroprotection, congenic mouse, CD300, Immunophenotyping
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