Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 32, Pages 19465-19474Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2006492117
Keywords
Plasmodium yoelii; Plasmodium berghei; interferon; gene knockout; signaling
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Funding
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH
- Public Health Service Awards [F32 AI133910, R01 AI091707]
- National Cancer Institute, the NIH [R01CA101795, 1U54CA210181]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZICHL005907] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001020, ZIAAI000892, ZICAI001051] Funding Source: NIH RePORTER
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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 rateswere 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.
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