Genetic analysis of cerebral malaria in the mouse model infected with Plasmodium berghei

Langlais, David; Gros, Philippe

doi:10.1007/s00335-018-9752-9

Cited by 16 publications

(34 citation statements)

References 211 publications

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“…2,5 Mutations that affect the number of function of these cells result in partial or complete protection against lethality in the P. berghei infection model. 4 As opposed to control ECM-susceptible B6 mice, the recruitment of proinflammatory myeloid cells (including DCs) to the CNS is not seen in ECM-resistant Ccdc88b mutants. 7 The impaired migratory properties of Ccdc88b Mut DCs established in the present study suggests a causal relationship with the ECM protection phenotype of mutant mice.…”

Section: Discussionmentioning

confidence: 96%

“…3 The mouse model of experimental cerebral malaria (ECM) induced by infection with Plasmodium berghei ANKA discovered a number of genes in which inactivation causes ECMresistance in PbA-infected mice. 6,7,4,8,9 One of these, Ccdc88b, encodes a poorly annotated protein (also known as Gipie, HkRP3), that belongs to the hook-related protein family shown to have a role in microtubuledependent organelle and endosomal vesicle movement. 10 Ccdc88b…”

Section: Introductionmentioning

confidence: 99%

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CCDC88B is required for mobility and inflammatory functions of dendritic cells

Olivier

Fodil

Habyan

et al. 2020

Journal of Leukocyte Biology

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The Coiled Coil Domain Containing Protein 88B (CCDC88B) gene is associated with susceptibility to several inflammatory diseases in humans and its inactivation in mice protects against acute neuroinflammation and models of intestinal colitis. We report that mice lacking functional CCDC88B (Ccdc88b Mut) are defective in several dendritic cells (DCs)-dependent inflammatory and immune reactions in vivo. In these mice, an inflammatory stimulus (LPS) fails to induce the recruitment of DCs into the draining lymph nodes (LNs). In addition, OVA-pulsed Ccdc88b Mut DCs injected in the footpad do not induce recruitment and activation of antigen-specific CD4 + and CD8 + T cells in their draining LN. Experiments in vitro indicate that this defect is independent of the ability of mutant DCs to capture and present peptide antigen to T cells. Rather, kinetic analyses in vivo of wild-type and Ccdc88b Mut DCs indicate a reduced migration capacity in the absence of the CCDC88B protein expression. Moreover, using time-lapse light microscopy imaging, we show that Ccdc88b Mut DCs have an intrinsic motility defect. Furthermore, in vivo studies reveal that these reduced migratory properties lead to dampened contact hypersensitivity reactions in Ccdc88b mutant mice. These findings establish a critical role of CCDC88B in regulating movement and migration of DCs. Thus, regulatory variants impacting Ccdc88b expression in myeloid cells may cause variable degrees of DC-dependent inflammatory response in situ, providing a rationale for the genetic association of CCDC88B with several inflammatory and autoimmune diseases in humans.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

CCDC88B is required for mobility and inflammatory functions of dendritic cells

Olivier

Fodil

Habyan

et al. 2020

Journal of Leukocyte Biology

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“…Given that ThPOK is a transcription factor expressed in thymocytes (29) and that the R367Q mutation is likely to affect DNA binding, we aimed to systematically identify the genes bound (cistrome) and possibly regulated by ThPOK and whose altered expression may underlie the altered inflammatory response phenotype of mutant mice. We prepared chromatin from Th1 polarized CD4 ϩ T cells, a cell type known to be a major driver of pathological neuroinflammation in the ECM model (8), and conducted ChIPseq. We found that ThPOK is recruited to 6,314 genomic sites and that ϳ73% of those sites are within 5 kb of a gene transcriptional start site ( Fig.…”

Section: Figmentioning

confidence: 99%

“…Although the P. berghei ANKA mouse model does not reproduce all facets of human CM, there are several aspects of disease pathogenesis and host immune response that are common to both. The shared features include (i) rapidly progressing neurological symptoms, such as convulsions, paralysis, seizures, and coma; (ii) histopathology, including vascular obstruction, parenchymal hemorrhage, and weakening of the blood-brain barrier; (iii) sequestration of parasitized erythrocytes (pRBCs); (iv) overlapping host immune and inflammatory responses, including a key role of infiltrating monocytes, T cells, and platelets at the site of injury, astroglial activation, and upregulation of antigen presentation molecules (e.g., major histocompatibility complex class 1 [MHC-I] and MHC-II) and of host endothelial adhesion molecules (e.g., ICAM-1) on cerebral vessels (8)(9)(10)(11)(12).…”

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confidence: 99%

“…During ECM, CD4 ϩ and CD8 ϩ T cells become activated in response to myeloid cytokines and other danger signals and migrate to the brain, where they drive immunopathology (3,15). This is exemplified by the observation that single gene mutations that affect the numbers, maturation, or activation of CD4 ϩ and CD8 ϩ T cells (Cd4, Cd8, Jak3, Themis, Ccdc88b, Mapk9, and Lck) (16)(17)(18)(19)(20)(21), including the production (Irf8, Irf1, Stat1, and Usp15) (22,23) of proinflammatory cytokines (Ifng, Ifnar1, and Il2) and their receptors (Ifngr1 and Il12rb2), as well as other T cell-specific cytotoxic molecules (Lta and Ltb), blunt neuroinflammation and protect mice against lethality in the ECM model (6,8,24).…”

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ZBTB7B (ThPOK) Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

et al. 2020

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We used a genome-wide screen in N-ethyl-N-nitrosourea (ENU)-mutagenized mice to identify genes in which recessive loss-of-function mutations protect against pathological neuroinflammation. We identified an R367Q mutation in the ZBTB7B (ThPOK) protein in which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Zbtb7bR367Q homozygous mice show a defect in the lymphoid compartment expressed as severe reduction in the number of single-positive CD4 T cells in the thymus and in the periphery, reduced brain infiltration of proinflammatory leukocytes in P. berghei ANKA-infected mice, and reduced production of proinflammatory cytokines by primary T cells ex vivo and in vivo. Dampening of proinflammatory immune responses in Zbtb7bR367Q mice is concomitant to increased susceptibility to infection with avirulent (Mycobacterium bovis BCG) and virulent (Mycobacterium tuberculosis H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK and causes loss of base contact by R367 in the major groove of the DNA, which is predicted to impair DNA binding. Global immunoprecipitation of ThPOK-containing chromatin complexes coupled to DNA sequencing (ChIP-seq) identified transcriptional networks and candidate genes likely to play key roles in CD4+ CD8+ T cell development and in the expression of lineage-specific functions of these cells. This study highlights ThPOK as a global regulator of immune function in which alterations may affect normal responses to infectious and inflammatory stimuli.

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