Host control of malaria infections: constraints on immune and erythropoeitic response kinetics.
Host control of malaria infections: constraints on immune and erythropoeitic response kinetics.
复制标题
疟疾感染的宿主控制：对免疫和红细胞反应动力学的限制。
DOI：
10.1371/journal.pcbi.1000149
复制
发表时间：
2008-08-22
影响因子：
4.3
通讯作者：
McKenzie, F. Ellis
中科院分区：
文献类型：
--
作者：
McQueen, Philip G.;McKenzie, F. Ellis
人类疟疾的两种主要病原体间日疟原虫和恶性疟原虫可引起严重贫血并引起强烈、复杂的免疫反应。宿主免疫和红细胞生成反应的哪些动力学行为将促进感染的控制，哪些将导致失控的寄生虫血症和/或严重贫血？为了回答这些问题，我们开发了微分方程模型的相互作用寄生虫和红细胞（RBC）群体调节宿主免疫和红细胞生成反应。模型免疫反应包括快速反应的先天性组分和反应较慢的长期抗体组分，其中几个寄生虫发育阶段被认为是每种类型免疫反应的靶点。我们发现，即使存在抗体，寄生虫血症最高的模拟感染往往是先天免疫无效的感染。我们还比较了红细胞生成障碍（感染期间红细胞生成减少）与代偿性红细胞生成（红细胞生成增加）或固定基础红细胞生成率的感染。红细胞生成不良倾向于轻微减少寄生虫血症，但以加重贫血为代价。另一方面，代偿性红细胞生成倾向于降低贫血的严重程度，但如果先天反应无效，则会增强寄生虫血症。对于这两种寄生虫物种，发育的裂殖体和裂殖子阶段之间的急剧转变（即，红细胞内发育时间的标准差≤2.4小时）与较低的寄生虫血症和较轻的贫血有关。因此，无性寄生虫发育的紧密同步可能有助于控制寄生虫血症。最后，我们的模拟表明，间日疟原虫可以像恶性疟原虫一样容易地诱导严重的贫血，尽管间日疟原虫攻击的红细胞亚群要小得多。由于大多数间日疟原虫感染在临床上是非致命的（如果使人衰弱），这表明恶性疟原虫对抗或逃避免疫应答的适应性比间日疟原虫更有效。在寄生于人类红细胞并诱发疟疾的四种疟原虫中，恶性疟原虫和间日疟原虫造成了大部分公共卫生负担。恶性疟原虫感染通常被描述为“恶性”（由于严重的，有时是致命的后果，特别是在免疫初治的个体中），而间日疟原虫疟疾被描述为（相对）“良性”。利用Beowulf集群的能力，我们通过模拟108.4 ×104种寄生虫物种、宿主免疫反应和对感染的红细胞生成反应的组合来检验关于疟疾宿主控制的假设。我们根据这两个物种生命周期的具体细节定制了模型，这两个物种侵入了不同的红细胞亚类。我们的研究结果挑战了一些标准假设。例如，我们表明，疟疾寄生虫的无性繁殖的紧密同步实际上可能有利于宿主减少寄生虫血症。我们还证明，宿主免疫或红细胞生成的属性，有助于高寄生虫血症和严重贫血的恶性疟原虫疟疾将这样做，以及在间日疟原虫感染，在最近的报告表明，间日疟原虫确实可以导致“恶性”疾病的一些患者。这表明恶性疟原虫在免疫逃避或抑制方面总体上比间日疟原虫更有效。
The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time ≤2.4 h) were associated with lower parasitemia and less severe anemia. Thus tight synchronization in asexual parasite development might help control parasitemia. Finally, our simulations suggest that P. vivax can induce severe anemia as readily as P. falciparum for the same type of immune response, though P. vivax attacks a much smaller subset of RBCs. Since most P. vivax infections are nonlethal (if debilitating) clinically, this suggests that P. falciparum adaptations for countering or evading immune responses are more effective than those of P. vivax. Of the four Plasmodium species that parasitize human erythrocytes and induce malaria, Plasmodium falciparum and Plasmodium vivax cause most of the public health burden. P. falciparum infection is typically characterized as “malignant” (due to severe, sometimes lethal consequences, particularly in immune-naïve individuals), and P. vivax malaria as (relatively) “benign.” Using the power of a Beowulf cluster, we tested hypotheses about host control of malaria by simulating ∼8.4×104 combinations of parasite species, host immune response, and erythropoietic response to infection. We tailored the models to specific details of the life cycles of the two species, which invade different subclasses of red blood cells. Our results challenge some standard assumptions. For example, we show that tight synchronization of the asexual reproduction of malaria parasites may actually benefit the host by reducing parasitemia. We also demonstrate that properties of host immunity or erythropoiesis that contribute to high parasitemia and severe anemia in P. falciparum malaria would do so in P. vivax infection as well, in line with recent reports indicating that P. vivax can indeed cause “malignant” illness in some patients. This suggests that P. falciparum is more effective overall at immune evasion or suppression than P. vivax.
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DOI：
10.4269/ajtmh.1995.53.547
发表时间：
1995-11-01
影响因子：
3.3
作者：
BURCHARD, GD;RADLOFF, P;KREMSNER, PG
通讯作者：
KREMSNER, PG
DOI：
10.1073/pnas.0709715105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Casals-Pascual, Climent;Idro, Richard;Newton, Charles R. J. C.
通讯作者：
Newton, Charles R. J. C.
低钙环境中的钙信号传导：细胞内疟疾寄生虫如何解决该问题。
DOI：
10.1083/jcb.200212130
发表时间：
2003-04-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gazarini ML;Thomas AP;Pozzan T;Garcia CR
通讯作者：
Garcia CR
DOI：
10.1073/pnas.89.8.3200
发表时间：
1992-04-15
影响因子：
11.1
作者：
KARUNAWEERA, ND;GRAU, GE;MENDIS, KN
通讯作者：
MENDIS, KN
影响因子：
4.4
作者：
Artavanis-Tsakonas, K;Eleme, K;Riley, EM
通讯作者：
Riley, EM