Honecker Barbara, Bärreiter Valentin A, Höhn Katharina, Horváth Balázs, Harant Karel, Metwally Nahla Galal, Marggraff Claudia, Anders Juliett, Leyk Stephanie, Martínez-Tauler Maria Del Pilar, Bea Annika, Hansen Charlotte, Fehling Helena, Lütkemeyer Melanie, Lorenzen Stephan, Franzenburg Sören, Lotter Hanna, Bruchhaus Iris
RG Molecular Infection Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
RG Host-Parasite Interaction, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
PLoS Negl Trop Dis. 2025 Apr 10;19(4):e0012997. doi: 10.1371/journal.pntd.0012997. eCollection 2025 Apr.
The parasitic protozoan Entamoeba histolytica secretes extracellular vesicles (EVs), but so far little is known about their function in the interaction with the host immune system. Infection with E. histolytica trophozoites can lead to formation of amebic liver abscesses (ALAs), in which pro-inflammatory immune responses of Ly6Chi monocytes contribute to liver damage. Men exhibit a more severe pathology as the result of higher monocyte recruitment and a stronger immune response. To investigate the role of EVs and pathogenicity in the host immune response, we studied the effect of EVs secreted by low pathogenic EhA1 and highly pathogenic EhB2 amebae on monocytes. Size and quantity of isolated EVs from both clones were similar. However, they differed in their proteome and miRNA cargo, providing insight into factors potentially involved in amebic pathogenicity. In addition, EVs were enriched in proteins with signaling peptides compared with the total protein content of trophozoites. Exposure to EVs from both clones induced monocyte activation and a pro-inflammatory immune response as evidenced by increased surface presentation of the activation marker CD38 and upregulated gene expression of key signaling pathways (including NF-κB, IL-17 and TNF signaling). The release of pro-inflammatory cytokines was increased in EV-stimulated monocytes and more so in male- than in female-derived cells. While EhA1 EV stimulation caused elevated myeloperoxidase (MPO) release by both monocytes and neutrophils, EhB2 EV stimulation did not, indicating the protective role of MPO during amebiasis. Collectively, our results suggest that parasite-released EVs contribute to the male-biased immunopathology mediated by pro-inflammatory monocytes during ALA formation.
寄生原生动物溶组织内阿米巴会分泌细胞外囊泡（EVs），但目前对其在与宿主免疫系统相互作用中的功能知之甚少。溶组织内阿米巴滋养体感染可导致阿米巴肝脓肿（ALA）的形成，其中Ly6Chi单核细胞的促炎免疫反应会导致肝损伤。男性由于单核细胞募集增加和免疫反应更强，病理表现更为严重。为了研究EVs在宿主免疫反应中的作用和致病性，我们研究了低致病性EhA1和高致病性EhB2阿米巴分泌的EVs对单核细胞的影响。从这两个克隆中分离出的EVs的大小和数量相似。然而，它们的蛋白质组和miRNA含量不同，这为了解可能参与阿米巴致病性的因素提供了线索。此外，与滋养体的总蛋白质含量相比，EVs富含带有信号肽的蛋白质。暴露于来自两个克隆的EVs均诱导单核细胞活化和促炎免疫反应，活化标志物CD38的表面表达增加以及关键信号通路（包括NF-κB、IL-17和TNF信号通路）的基因表达上调证明了这一点。EVs刺激的单核细胞中促炎细胞因子的释放增加，男性来源的细胞比女性来源的细胞增加得更多。虽然EhA1 EV刺激导致单核细胞和中性粒细胞的髓过氧化物酶（MPO）释放增加，但EhB2 EV刺激则没有，这表明MPO在阿米巴病期间具有保护作用。总的来说，我们的结果表明，寄生虫释放的EVs在ALA形成过程中促成了由促炎单核细胞介导的男性偏向性免疫病理。
