ArticlePloS one2012
An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- CCDC88B interacts with RASAL3 and ARHGEF2 and regulates dendritic cell function in neuroinflammation and colitis.Communications biology · 2024Article
- Pathogenetic mechanisms and treatment targets in cerebral malaria.Nature reviews. Neurology · 2023Review
- Forward Genetics in Apicomplexa Biology: The Host Side of the Story.Frontiers in cellular and infection microbiology · 2022Review
- ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis.Infection and immunity · 2020Article
- Expression of CD300lf by microglia contributes to resistance to cerebral malaria by impeding the neuroinflammation.Genes and immunity · 2020Article
- KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria.Scientific reports · 2019Article
- NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Host genetics in malaria: lessons from mouse studies.Mammalian genome : official journal of the International Mammalian Genome Society · 2018Review
- Genetic analysis of cerebral malaria in the mouse model infected with Plasmodium berghei.Mammalian genome : official journal of the International Mammalian Genome Society · 2018Review
- USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.Nature immunology · 2017Article
- Mapping of a quantitative trait locus controlling susceptibility to Coxsackievirus B3-induced viral hepatitis.Genes and immunity · 2015Article
- THEMIS is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis.Infection and immunity · 2015Article
- CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation.The Journal of experimental medicine · 2014Article
- Mouse ENU Mutagenesis to Understand Immunity to Infection: Methods, Selected Examples, and Perspectives.Genes · 2014Review
- Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1.PLoS pathogens · 2013Article
- Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice.Genes and immunity · 2013Article
- Irf8-regulated genomic responses drive pathological inflammation during cerebral malaria.PLoS pathogens · 2013Article
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.
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Registered trials
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