Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions
Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions
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DOI：
10.1038/s41564-019-0474-x
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发表时间：
2019-09-01
影响因子：
28.3
通讯作者：
Cunnington, Aubrey J.
中科院分区：
文献类型：
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作者：
Georgiadou, Athina;Lee, Hyun Jae;Cunnington, Aubrey J.
在感染期间，不断增加的病原体负荷刺激了宿主反应的保护性和危害性。这种相互作用的动态很难在人类身上量化，但这样做可以提高对疾病和保护机制的理解。我们试图仅使用临床表现时获得的数据，对感染恶性疟原虫的个体受试者的寄生虫增殖率和宿主反应对观察到的寄生虫载量的影响进行建模，然后确定它们的机制相关性。我们预测，在严重疟疾病例中，寄生虫增殖率更高，宿主反应性更低，严重贫血比脑型疟疾更隐蔽。我们预测，寄生虫生长抑制与血小板消耗、CXCL10和1型干扰素相关基因的低表达、组织蛋白酶G和基质金属肽酶9的表达增加有关。我们发现组织蛋白酶G和基质金属肽酶9直接抑制寄生虫对红细胞的侵袭。寄生虫的增殖率与宿主铁的可利用性和较高的补体因子H水平有关，配子体相关基因的表达较低，而翻译相关基因的表达较高。我们的发现表明，使用病原体负载动态的显式建模来加深对宿主-病原体相互作用的理解并识别保护机制的相关性是有潜力的。
During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of the mechanisms of disease and protection. We sought to model the contributions of the parasite multiplication rate and host response to observed parasite load in individual subjects infected with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in cases of severe malaria, with severe anaemia being more insidious than cerebral malaria. We predicted that parasite-growth inhibition was associated with platelet consumption, lower expression of CXCL10 and type 1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. The parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.