Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 28, Pages 16567-16578Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2004332117
Keywords
Plasmodium; host-parasite interaction; innate response; interferons
Categories
Funding
- Division of Intramural Research, NIAID, NIH
- NCI, NIH [R01CA101795, U54CA210181]
- Department of Defense Congressionally Directed Medical Research Programs, Breast Cancer Research Program [BC151081]
- Houston Methodist Research Institute
- University of Southern California
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [ZIATR000040] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZICAI001051, ZIAAI001125, ZIAAI000912, ZIAAI000892, ZIAAI001020] Funding Source: NIH RePORTER
- CDMRP [BC151081, 893187] Funding Source: Federal RePORTER
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Malaria infection induces complex and diverse immune responses. To elucidate the mechanisms underlying host-parasite interaction, we performed a genetic screen during early (24 h) Plasmodium yoelii infection in mice and identified a large number of interacting host and parasite genes/loci after transspecies expression quanti-tative trait locus (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene (March1) that was clustered with interferon (IFN)-stimulated genes (ISGs) based on the similarity of the genome-wide pattern of logarithm of the odds (LOD) scores (GPLS). March1 inhibits MAVS/STING/TRIF-induced type I IFN (IFN-I) signaling in vitro and in vivo. However, in malaria-infected hosts, deficiency of March1 reduces IFN-I production by activating inhib-itors such as SOCS1, USP18, and TRIM24 and by altering immune cell populations. March1 deficiency increases CD86+DC (dendritic cell) populations and levels of IFN-gamma and interleukin 10 (IL-10) at day 4 post infection, leading to improved host survival. T cell depletion reduces IFN-gamma level and reverse the protective effects of March1 deficiency, which can also be achieved by antibody neu-tralization of IFN-gamma. This study reveals functions of MARCH1 (membrane-associated ring-CH-type finger 1) in innate immune responses and provides potential avenues for activating antima-laria immunity and enhancing vaccine efficacy.
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