Mass Spectrometry Identification of Biomarkers in Extracellular Vesicles From Plasmodium vivax Liver Hypnozoite Infections.
Mass Spectrometry Identification of Biomarkers in Extracellular Vesicles From Plasmodium vivax Liver Hypnozoite Infections.
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DOI：
10.1016/j.mcpro.2022.100406
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发表时间：
2022-10
影响因子：
7
通讯作者：
del Portillo, Hernando A.
中科院分区：
文献类型：
--
作者：
Gualdron-Lopez, Melisa;Diaz-Varela, Miriam;Zanghi, Gigliola;Aparici-Herraiz, Iris;Steel, Ryan W. J.;Schafer, Carola;Cusco, Pol;Chuenchob, Vorada;Kangwangransan, Niwat;Billman, Zachary P.;Olsen, Tayla M.;Gonzalez, Juan R.;Roobsoong, Wanlapa;Sattabongkot, Jetsumon;Murphy, Sean C.;Mikolajczak, Sebastian A.;Borras, Eva;Sabido, Eduard;Fernandez-Becerra, Carmen;Flannery, Erika L.;Kappe, Stefan H., I;del Portillo, Hernando A.
潜伏的肝脏阶段称为催眠虫引起复发性间日疟原虫疟疾感染，是消灭疟疾目标的主要障碍。催眠虫在临床上是无法检测到的，目前，在人类肝脏中没有这种持久性寄生虫储库的生物标志物。在这里，我们已经确定了寄生虫和人类的蛋白质与细胞外囊泡（EV）分泌的体内感染只含有催眠虫。我们使用用杀疟原虫实验药物MMV 048处理的间日疟原虫感染的人肝嵌合体（huHEP）FRG KO小鼠作为催眠虫感染模型。间日疟原虫肝脏形式的基于免疫荧光的定量显示MMV048从嵌合小鼠肝脏中去除了寄生虫。源自FRG huHEP小鼠的EV的蛋白质组学分析显示，来自感染的FRG huHEP小鼠的人EV货物含有与活跃的间日疟原虫复制相关的炎症标志物，并鉴定了66种间日疟原虫蛋白。为了鉴定与EV相关的催眠特异性蛋白质，我们从MMV 048处理的小鼠中挖掘蛋白质组数据，并进行了一项分析，包括在所有实验条件下进行组内和组间比较，然后进行肽相容性分析，预测光谱，以保证可靠的鉴定。只有一种蛋白质满足这种严格的自上而下的选择，一个假定的细丝蛋白结构域的蛋白质。这项研究为揭示人类肝脏感染的生物学特征和确定与EV相关的催眠虫感染的生物标志物奠定了基础。使用体内间日疟原虫模型研究潜伏性肝脏感染。MMV048药物选择性杀死复制的肝脏寄生虫的用途。复杂生物流体中存在的人类肝细胞特异性EV的蛋白质组。来自该模型的EV含有寄生虫蛋白，一种专门与催眠虫相关的蛋白。由间日疟原虫引起的人类疟疾是实现消灭疟疾目标的主要障碍，因为该物种进化出一种休眠的肝脏形式，称为催眠虫，可以在最初感染后保持潜伏状态。目前的诊断工具无法检测到无症状的患者窝藏催眠虫。我们已经使用MS蛋白质组学方法在间日疟原虫肝催眠虫感染的体内模型中发现与循环细胞外囊泡相关的潜伏性肝感染的生物标志物。
Latent liver stages termed hypnozoites cause relapsing Plasmodium vivax malaria infection and represent a major obstacle in the goal of malaria elimination. Hypnozoites are clinically undetectable, and presently, there are no biomarkers of this persistent parasite reservoir in the human liver. Here, we have identified parasite and human proteins associated with extracellular vesicles (EVs) secreted from in vivo infections exclusively containing hypnozoites. We used P. vivax-infected human liver-chimeric (huHEP) FRG KO mice treated with the schizonticidal experimental drug MMV048 as hypnozoite infection model. Immunofluorescence-based quantification of P. vivax liver forms showed that MMV048 removed schizonts from chimeric mice livers. Proteomic analysis of EVs derived from FRG huHEP mice showed that human EV cargo from infected FRG huHEP mice contain inflammation markers associated with active schizont replication and identified 66 P. vivax proteins. To identify hypnozoite-specific proteins associated with EVs, we mined the proteome data from MMV048-treated mice and performed an analysis involving intragroup and intergroup comparisons across all experimental conditions followed by a peptide compatibility analysis with predicted spectra to warrant robust identification. Only one protein fulfilled this stringent top-down selection, a putative filamin domain-containing protein. This study sets the stage to unveil biological features of human liver infections and identify biomarkers of hypnozoite infection associated with EVs. Use of in vivo Plasmodium vivax model to study latent liver infections. Use of the MMV048 drug to selectively kill replicating liver parasites. Proteome of human hepatocyte-specific EVs present in a complex biofluid. EVs from this model contain parasite proteins, one exclusively associated with hypnozoites. Human malaria caused by Plasmodium vivax represents a major barrier to achieve the goal of malaria elimination as this species evolved a dormant liver form called a hypnozoite that can remain latent after the initial infection. Current diagnostic tools are unable to detect asymptomatic patients harboring hypnozoites. We have used a MS proteomics approach to discover biomarkers of latent liver infections associated with circulating extracellular vesicles in an in vivo model of P. vivax liver hypnozoite infections.
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影响因子：
30.3
作者：
Gural N;Mancio-Silva L;Miller AB;Galstian A;Butty VL;Levine SS;Patrapuvich R;Desai SP;Mikolajczak SA;Kappe SHI;Fleming HE;March S;Sattabongkot J;Bhatia SN
通讯作者：
Bhatia SN
激光捕获显微解剖可以实现疟原虫复发物种的分裂和静止肝阶段的转录组分析。
影响因子：
3.4
作者：
Cubi R;Vembar SS;Biton A;Franetich JF;Bordessoulles M;Sossau D;Zanghi G;Bosson-Vanga H;Benard M;Moreno A;Dereuddre-Bosquet N;Le Grand R;Scherf A;Mazier D
通讯作者：
Mazier D
影响因子：
5.8
作者：
Degroeve, Sven;Martens, Lennart
通讯作者：
Martens, Lennart
影响因子：
16
作者：
Marcilla A;Martin-Jaular L;Trelis M;de Menezes-Neto A;Osuna A;Bernal D;Fernandez-Becerra C;Almeida IC;Del Portillo HA
通讯作者：
Del Portillo HA
影响因子：
16.6
作者：
Mantel PY;Hjelmqvist D;Walch M;Kharoubi-Hess S;Nilsson S;Ravel D;Ribeiro M;Grüring C;Ma S;Padmanabhan P;Trachtenberg A;Ankarklev J;Brancucci NM;Huttenhower C;Duraisingh MT;Ghiran I;Kuo WP;Filgueira L;Martinelli R;Marti M
通讯作者：
Marti M