Dennison Nathan J, BenMarzouk-Hidalgo Omar J, Dimopoulos George
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Dev Comp Immunol. 2015 Mar;49(1):170-8. doi: 10.1016/j.dci.2014.10.016. Epub 2014 Nov 10.
Invasion of the malaria vector Anopheles gambiae midgut by Plasmodium parasites triggers transcriptional changes of immune genes that mediate the antiparasitic defense. This response is largely regulated by the Toll and Immune deficiency (IMD) pathways. To determine whether A. gambiae microRNAs (miRNAs) are involved in regulating the anti-Plasmodium defense, we showed that suppression of miRNA biogenesis results in increased resistance to Plasmodium falciparum infection. In silico analysis of A. gambiae immune effector genes identified multiple transcripts with miRNA binding sites. A comparative miRNA microarray abundance analysis of P. falciparum infected and naïve mosquito midgut tissues showed elevated abundance of miRNAs aga-miR-989 and aga-miR-305 in infected midguts. Antagomir inhibition of aga-miR-305 increased resistance to P. falciparum infection and suppressed the midgut microbiota. Conversely, treatment of mosquitoes with an artificial aga-miR-305 mimic increased susceptibility to P. falciparum infection and resulted in expansion of midgut microbiota, suggesting that aga-miR-305 acts as a P. falciparum and gut microbiota agonist by negatively regulating the mosquito immune response. In silico prediction of aga-miR-305 target genes identified several anti-Plasmodium effectors. Our study shows that A. gambiae aga-miR-305 regulates the anti-Plasmodium response and midgut microbiota, likely through post-transcriptional modification of immune effector genes.
疟原虫对冈比亚按蚊中肠的入侵会引发免疫基因的转录变化，这些免疫基因介导抗寄生虫防御。这种反应很大程度上受Toll和免疫缺陷（IMD）途径调控。为了确定冈比亚按蚊微小RNA（miRNA）是否参与调节抗疟防御，我们发现抑制miRNA生物合成会增强对恶性疟原虫感染的抗性。对冈比亚按蚊免疫效应基因的计算机分析鉴定出多个带有miRNA结合位点的转录本。对感染了恶性疟原虫和未感染的蚊子中肠组织进行的比较性miRNA微阵列丰度分析显示，感染的中肠中miRNA aga-miR-989和aga-miR-305的丰度升高。用抗miR抑制aga-miR-305可增强对恶性疟原虫感染的抗性并抑制中肠微生物群。相反，用人工合成的aga-miR-305模拟物处理蚊子会增加对恶性疟原虫感染的易感性，并导致中肠微生物群扩张，这表明aga-miR-305通过负向调节蚊子的免疫反应，充当恶性疟原虫和肠道微生物群的激动剂。对aga-miR-305靶基因的计算机预测鉴定出几种抗疟效应因子。我们的研究表明，冈比亚按蚊的aga-miR-305可能通过对免疫效应基因的转录后修饰来调节抗疟反应和中肠微生物群。
