QIMR Berghofer Medical Research Institute , Herston, Brisbane, Queensland, Australia.
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne , Parkville, Victoria, Australia.
mBio. 2023 Aug 31;14(4):e0112923. doi: 10.1128/mbio.01129-23. Epub 2023 Jul 14.
Maturation rates of malaria parasites within red blood cells (RBCs) can be influenced by host nutrient status and circadian rhythm; whether host inflammatory responses can also influence maturation remains less clear. Here, we observed that systemic host inflammation induced in mice by an innate immune stimulus, lipopolysaccharide (LPS), or by ongoing acute infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. Importantly, plasma from LPS-conditioned or acutely infected mice directly inhibited parasite maturation during in vitro culture, which was not rescued by supplementation, suggesting the emergence of inhibitory factors in plasma. Metabolomic assessments confirmed substantial alterations to the plasma of LPS-conditioned and acutely infected mice, and identified a small number of candidate inhibitory metabolites. Finally, we confirmed rapid parasite responses to systemic host inflammation using parasite scRNA-seq, noting broad impairment in transcriptional activity and translational capacity specifically in trophozoites but not rings or schizonts. Thus, we provide evidence that systemic host inflammation rapidly triggered transcriptional alterations in circulating blood-stage Plasmodium trophozoites and predict candidate inhibitory metabolites in the plasma that may impair parasite maturation . IMPORTANCE Malaria parasites cyclically invade, multiply, and burst out of red blood cells. We found that a strong inflammatory response can cause changes to the composition of host plasma, which directly slows down parasite maturation. Thus, our work highlights a new mechanism that limits malaria parasite growth in the bloodstream.
疟原虫在红细胞（RBC）内的成熟速度可受到宿主营养状况和昼夜节律的影响；宿主炎症反应是否也会影响成熟尚不清楚。在这里，我们观察到，内毒素（LPS）等先天免疫刺激物或持续的急性感染引起的宿主全身性炎症，会减缓单个疟原虫种群从一代 RBC 到下一代的发育进程。重要的是，LPS 调理或急性感染小鼠的血浆可直接抑制体外培养中的寄生虫成熟，补充营养物质并不能挽救这种抑制作用，这表明血浆中出现了抑制因子。代谢组学评估证实 LPS 调理和急性感染小鼠的血浆发生了实质性改变，并鉴定出少数候选抑制性代谢物。最后，我们通过寄生虫单细胞 RNA 测序（scRNA-seq）证实了宿主全身性炎症对寄生虫的快速反应，注意到在滋养体中广泛损害转录活性和翻译能力，但在环状体和裂殖体中没有这种情况。因此，我们提供的证据表明，宿主全身性炎症可迅速触发循环血液期疟原虫滋养体中的转录改变，并预测血浆中可能会损害寄生虫成熟的候选抑制性代谢物。意义疟原虫周期性地入侵、增殖并从红细胞中爆发。我们发现，强烈的炎症反应会导致宿主血浆成分发生变化，这直接减缓了寄生虫的成熟速度。因此，我们的工作强调了一种新的机制，该机制限制了疟原虫在血液中的生长。
