Format

Send to

Choose Destination
Infect Immun. 2019 Dec 2. pii: IAI.00845-19. doi: 10.1128/IAI.00845-19. [Epub ahead of print]

ZBTB7B (ThPOK) IS REQUIRED FOR PATHOGENESIS OF CEREBRAL MALARIA AND PROTECTION AGAINST PULMONARY TUBERCULOSIS.

Author information

1
Department of Biochemistry, McGill University, Montreal, Canada.
2
McGill Center for Complex Traits, McGill University, Montreal, Canada.
3
Department of Human Genetics, McGill University, Montreal, Canada.
4
Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
5
Department of Medicine, McGill University, Montreal, Canada.
6
Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montreal, Canada.
7
Department of Biochemistry, McGill University, Montreal, Canada philippe.gros@mcgill.ca.

Abstract

We have 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 which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA (PbA). 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 pro-inflammatory leukocytes in PbA infected mice and reduced production of pro-inflammatory 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 (Mycobatcerium bovis, BCG) and virulent (M. tuberculosis, H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK, and causes a loss of base contact by R367 in the major groove of 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 a key role 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.

PMID:
31792077
DOI:
10.1128/IAI.00845-19

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center