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 quantitative 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 inhibitors such as SOCS1, USP18, and TRIM24 and by altering immune cell populations. March1 deficiency increases CD86⁺DC (dendritic cell) populations and levels of IFN-γ and interleukin 10 (IL-10) at day 4 post infection, leading to improved host survival. T cell depletion reduces IFN-γ level and reverse the protective effects of March1 deficiency, which can also be achieved by antibody neutralization of IFN-γ. This study reveals functions of MARCH1 (membrane-associated ring-CH–type finger 1) in innate immune responses and provides potential avenues for activating antimalaria immunity and enhancing vaccine efficacy.

疟疾感染引起复杂而多样的免疫反应。为了阐明宿主与寄生虫相互作用的潜在机制，我们在小鼠约氏疟原虫感染的早期（24 h）期间进行了基因筛选，并在转基因表达定量性状基因座（Ts-eQTL）后鉴定出大量相互作用的宿主和寄生虫基因/基因座分析。接下来，我们基于赔率对数（LOD）得分（GPLS）的全基因组范围模式的相似性，研究了一个宿主E3泛素连接酶基因（March1），该基因与干扰素（IFN）刺激的基因（ISG）聚集在一起。March1在体内外均抑制MAVS / STING / TRIF诱导的I型IFN（IFN-I）信号传导。但是，在感染疟疾的寄主中，March1缺乏通过激活抑制剂（如SOCS1，USP18和TRIM24）和改变免疫细胞群来降低IFN-I的产生。在感染后第4天，March1缺乏症会增加CD86 ⁺ DC（树突状细胞）种群以及IFN-γ和白介素10（IL-10）的水平，从而改善宿主存活率。T细胞耗竭可降低IFN-γ水平并逆转March1缺乏症的保护作用，这也可以通过抗体中和IFN-γ来实现。这项研究揭示了MARCH1（膜相关的无环CH型手指1）在先天免疫应答中的功能，并提供了激活抗疟疾免疫和增强疫苗效力的潜在途径。