RTP4 inhibits IFN-I response and enhances experimental cerebral malaria and neuropathology

Xiao He, Alison W. Ashbrook, Yang Du, Jian Wu, Hans Heinrich Hoffmann, Cui Zhang, Lu Xia, Yu Chih Peng, Keyla C. Tumas, Brajesh K. Singh, Chen Feng Qi, Timothy G. Myers, Carole A. Long, Chengyu Liu, Rongfu Wang, Charles M. Rice, Xin Zhuan Su

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Infection by malaria parasites triggers dynamic immune responses leading to diverse symptoms and pathologies; however, the molecular mechanisms responsible for these reactions are largely unknown. We performed Trans-species Expression Quantitative Trait Locus analysis to identify a large number of host genes that respond to malaria parasite infections. Here we functionally characterize one of the host genes called receptor transporter protein 4 (RTP4) in responses to malaria parasite and virus infections. RTP4 is induced by type I IFN (IFN-I) and binds to the TANK-binding kinase (TBK1) complex where it negatively regulates TBK1 signaling by interfering with expression and phosphorylation of both TBK1 and IFN regulatory factor 3. Rtp4/ mice were generated and infected with malaria parasite Plasmodiun berghei ANKA. Significantly higher levels of IFN-I response in microglia, lower parasitemia, fewer neurologic symptoms, and better survival rates were observed in Rtp4/ than in wild-type mice. Similarly, RTP4 deficiency significantly reduced West Nile virus titers in the brain, but not in the heart and the spleen, of infected mice, suggesting a specific role for RTP4 in brain infection and pathology. This study reveals functions of RTP4 in IFN-I response and a potential target for therapy in diseases with neuropathology.

Original languageEnglish (US)
Pages (from-to)19465-19474
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number32
DOIs
StatePublished - Aug 11 2020

Keywords

  • Gene knockout
  • Interferon
  • Plasmodium berghei
  • Plasmodium yoelii
  • Signaling

ASJC Scopus subject areas

  • General

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