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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 32 Pg. 19465-19474 (08 11 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32709745 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• IRF3 protein, human
• Interferon Regulatory Factor-3
• Interferon Type I
• Membrane Proteins
• Molecular Chaperones
• Rtp4 protein, mouse
• STING1 protein, human
• Protein Serine-Threonine Kinases
• TBK1 protein, human

Topics

• Animals
• Brain (parasitology, pathology, virology)
• HEK293 Cells
• Host-Pathogen Interactions
• Humans
• Interferon Regulatory Factor-3
• Interferon Type I (metabolism)
• Malaria, Cerebral (metabolism, parasitology, pathology)
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (metabolism)
• Molecular Chaperones (genetics, metabolism)
• Phosphorylation
• Plasmodium berghei (physiology)
• Plasmodium yoelii (physiology)
• Protein Binding
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• West Nile Fever (metabolism, pathology, virology)
• West Nile virus (physiology)