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

Infect Immun. 2020 Jan 22;88(2):e00845-19. doi: 10.1128/IAI.00845-19. Print 2020 Jan 22.


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.

Keywords: T cells; cerebral malaria; genetics; host response; immunity; immunology; infectious disease; malaria.

MeSH terms

  • Animals
  • Brain / microbiology
  • CD4-Positive T-Lymphocytes / microbiology
  • CD8-Positive T-Lymphocytes / microbiology
  • Cytokines / genetics
  • DNA-Binding Proteins / genetics*
  • Female
  • Inflammation / genetics
  • Inflammation / microbiology
  • Malaria, Cerebral / genetics*
  • Malaria, Cerebral / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / pathogenicity
  • Plasmodium berghei / pathogenicity
  • Transcription Factors / genetics*
  • Tuberculosis, Pulmonary / genetics*
  • Tuberculosis, Pulmonary / microbiology
  • Virulence / genetics


  • Cytokines
  • DNA-Binding Proteins
  • Transcription Factors
  • Zbtb7b protein, mouse