A metabolite-based resistance mechanism against malaria

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-06-12

Ana Figueiredo, Sonia Trikha Rastogi, Susana Ramos, Fátima Nogueira, Katherine De Villiers, António G. Gonçalves de Sousa, Lasse Votborg-Novél, Cäcilie von Wedel, Pinkus Tober-Lau, Elisa Jentho, Sara Pagnotta, Miguel Mesquita, Silvia Cardoso, Giulia Bortolussi, Andrés F. Muro, Erin M. Tranfield, Jessica Thibaud, Denise Duarte, Ana Laura Sousa, Sandra N. Pinto, Jamil Kitoko, Ghyslain Mombo-Ngoma, Johannes Mischlinger, Sini Junttila, Marta Alenquer, Maria João Amorim, Chirag Vasavda, Piter J. Bosma, Sara Violante, Bernhard Drotleff, Tiago Paixão, Silvia Portugal, Florian Kurth, Laura L. Elo, Bindu D. Paul, Rui Martins, Miguel P. Soares

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Abstract

Jaundice is a common presentation of Plasmodium falciparum malaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response to Plasmodium spp. infection. We found that asymptomatic P. falciparum infection in humans was associated with a higher ratio of unconjugated over conjugated bilirubin and parasite burden compared with symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, through genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells by a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin crystallization and compromised the parasite’s food vacuole. Hence, jaundice appears to represent a metabolic response to Plasmodium spp. infection that limits malaria severity.

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一种基于代谢物的疟疾抗性机制

黄疸是恶性疟原虫疟疾的常见表现，由循环胆红素积累引起。目前尚不清楚这是否代表了对疟原虫感染的适应性或非适应性反应。我们发现，与有症状的疟疾相比，人类无症状恶性疟原虫感染与较高的非共轭过共轭胆红素比例和寄生虫负担相关。胆红素还原酶A （BVRA）对胆红素合成的遗传抑制增加了寄生虫毒力和小鼠疟疾死亡率。血浆中未偶联胆红素的积累，通过基因抑制UDP葡萄糖醛酸糖基转移酶家族1成员A1 （UGT1A1）的肝偶联，对小鼠的疟疾有保护作用。未结合的胆红素通过抑制线粒体嘧啶合成的机制抑制恶性疟原虫在红细胞中的增殖。此外，未结合的胆红素抑制血色素结晶并损害寄生虫的食物液泡。因此，黄疸似乎代表了对疟原虫感染的代谢反应，从而限制了疟疾的严重程度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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