Safeukui Innocent, Gomez Noé D, Adelani Aanuoluwa A, Burte Florence, Afolabi Nathaniel K, Akondy Rama, Velazquez Peter, Holder Anthony, Tewari Rita, Buffet Pierre, Brown Biobele J, Shokunbi Wuraola A, Olaleye David, Sodeinde Olugbemiro, Kazura James, Ahmed Rafi, Mohandas Narla, Fernandez-Reyes Delmiro, Haldar Kasturi
Division of Parasitology, MRC National Institute for Medical Research, London, United Kingdom.
Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Oyo, Nigeria.
mBio. 2015 Jan 20;6(1):e02493-14. doi: 10.1128/mBio.02493-14.
Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected erythrocytes and is a frequent fatal complication. It is proportional not to circulating parasitemia but total parasite mass (sequestered) in the organs. Thus, immune responses that clear parasites in organs may trigger changes leading to anemia. Here, we use an outbred-rat model where increasing parasite removal in the spleen escalated uninfected-erythrocyte removal. Splenic parasite clearance was associated with activated CD8(+) T cells, immunodepletion of which prevented parasite clearance. CD8(+) T cell repletion and concomitant reduction of the parasite load was associated with exacerbated (40 to 60%) hemoglobin loss and changes in properties of uninfected erythrocytes. Together, these data suggest that CD8(+) T cell-dependent parasite clearance causes erythrocyte removal in the spleen and thus anemia. In children infected with the human malaria parasite Plasmodium falciparum, elevation of parasite biomass (not the number of circulating parasites) increased the odds ratio for SMA by 3.5-fold (95% confidence intervals [CI95%], 1.8- to 7.5-fold). CD8(+) T cell expansion/activation independently increased the odds ratio by 2.4-fold (CI95%, 1.0- to 5.7-fold). Concomitant increases in both conferred a 7-fold (CI95%, 1.9- to 27.4-fold)-greater risk for SMA. Together, these data suggest that CD8(+)-dependent parasite clearance may predispose individuals to uninfected-erythrocyte loss and SMA, thus informing severe disease diagnosis and strategies for vaccine development.
Malaria is a major global health problem. Severe malaria anemia (SMA) is a complex disease associated with partial immunity. Rapid hemoglobin reductions of 20 to 50% are commonly observed and must be rescued by transfusion (which can carry a risk of HIV acquisition). The causes and risk factors of SMA remain poorly understood. Recent studies suggest that SMA is linked to parasite biomass sequestered in organs. This led us to investigate whether immune mechanisms that clear parasites in organs trigger anemia. In rats, erythropoiesis is largely restricted to the bone marrow, and critical aspects of the spleen expected to be important in anemia are similar to those in humans. Therefore, using a rat model, we show that severe anemia is caused through CD8(+) T cell-dependent parasite clearance and erythrocyte removal in the spleen. CD8 activation may also be a new risk factor for SMA in African children.
半免疫个体中的严重疟疾贫血（SMA）会清除感染和未感染的红细胞，是一种常见的致命并发症。它与循环中的寄生虫血症不成比例，而是与器官中总的寄生虫量（隐匿的）成比例。因此，清除器官中寄生虫的免疫反应可能会引发导致贫血的变化。在这里，我们使用了一个远交系大鼠模型，其中脾脏中寄生虫清除的增加会使未感染红细胞的清除增加。脾脏中的寄生虫清除与活化的CD8(+) T细胞有关，对其进行免疫耗竭可阻止寄生虫清除。CD8(+) T细胞的补充和寄生虫负荷的同时减少与加剧的（40%至60%）血红蛋白损失以及未感染红细胞特性的变化有关。总之，这些数据表明，CD8(+) T细胞依赖性的寄生虫清除会导致脾脏中红细胞的清除，从而导致贫血。在感染人类疟原虫恶性疟原虫的儿童中，寄生虫生物量的升高（而非循环寄生虫的数量）使SMA的优势比增加了3.5倍（95%置信区间[CI95%]，1.8至7.5倍）。CD8(+) T细胞的扩增/活化独立地使优势比增加了2.4倍（CI95%，1.0至5.7倍）。两者同时增加使患SMA的风险增加了7倍（CI95%，1.9至27.4倍）。总之，这些数据表明，CD8(+)依赖性的寄生虫清除可能使个体易患未感染红细胞的损失和SMA，从而为严重疾病的诊断和疫苗开发策略提供信息。
疟疾是一个主要的全球健康问题。严重疟疾贫血（SMA）是一种与部分免疫相关的复杂疾病。通常观察到血红蛋白会迅速降低20%至50%，必须通过输血来挽救（输血可能有感染艾滋病毒的风险）。SMA的病因和危险因素仍知之甚少。最近的研究表明，SMA与隐匿在器官中的寄生虫生物量有关。这促使我们研究清除器官中寄生虫的免疫机制是否会引发贫血。在大鼠中，红细胞生成主要局限于骨髓，脾脏中预期对贫血很重要的关键方面与人类相似。因此，使用大鼠模型，我们表明严重贫血是通过CD8(+) T细胞依赖性的寄生虫清除和脾脏中红细胞的清除引起的。CD8的活化也可能是非洲儿童患SMA的一个新的危险因素。
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