Role of the inhibitor of serine peptidase 2 (ISP2) of Trypanosoma brucei rhodesiense in parasite virulence and modulation of the inflammatory responses of the host.
Role of the inhibitor of serine peptidase 2 (ISP2) of Trypanosoma brucei rhodesiense in parasite virulence and modulation of the inflammatory responses of the host.
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布氏罗得西亚锥虫丝氨酸肽酶2（ISP 2）抑制剂在寄生虫毒力和宿主炎症反应调节中的作用
DOI：
10.1371/journal.pntd.0009526
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发表时间：
2021-06
影响因子：
3.8
通讯作者：
Lima APCA
中科院分区：
文献类型：
--
作者：
Levy DJ;Goundry A;Laires RSS;Costa TFR;Novo CM;Grab DJ;Mottram JC;Lima APCA
布氏锥虫是人类非洲锥虫病(HAT)的病原体之一，被称为昏睡病。这种寄生虫入侵中枢神经系统，导致严重的脑炎，如果不治疗，这种脑炎是致命的。我们以前已经在锥虫寄生虫中发现了丝氨酸肽酶的Ecotin样抑制物，称为ISPs。在这里，我们研究了ISP2在罗德氏锥虫血液形态中的作用。我们获得了缺失isp2的基因缺陷突变体(Δisp2)，它在体外表现出与野生型(WT)寄生虫相似的生长特征。感染Δisp2的C57BL/6小鼠表现出较低的血液寄生虫血症，后腿病理表型延迟，存活时间较长。在寄生虫血症的两个高峰对应的两个时间点检测免疫反应。感染4天后，Δ感染组小鼠脾中NOS2+髓系细胞、干扰素-γ+-NK细胞和升高的肿瘤坏死因子-α水平均高于WT组和再次表达Δ的寄生虫组(ISP2：ISP2)。在感染Δisp2的小鼠中，随着单核细胞来源的树突状细胞、CD19+B淋巴细胞、CD8+和CD4+T淋巴细胞比例的增加，NOS2+的数量持续增加。综上所述，这些发现表明，ISP2有助于罗德希氏锥虫对小鼠的毒力，并减弱早期感染期间的炎症反应。布氏锥虫是一种原生动物寄生虫，会导致人类致命的疾病。这种寄生虫通过受感染的采采蝇的叮咬传播，可以渗透到大脑，导致严重的炎症，并伴随着运动障碍、神经障碍和死亡。重要的是要了解寄生虫因素如何以及哪些因素对感染起作用，以便改进治疗方案。在它们的基因组中，这些寄生虫的基因被称为isp，类似于细菌的基因，这种基因编码的蛋白质可以抑制胰蛋白酶家族的丝氨酸肽酶。在这里，我们通过分析寄生虫isp2基因敲除突变体在小鼠实验感染中的作用，研究了isp2在罗德氏锥虫中的作用。我们发现，ISP2有助于引起血液寄生虫血症、运动障碍的临床体征，并降低宿主的炎症反应水平，从而促进感染。
Trypanosoma brucei rhodesiense is one of the causative agents of Human African Trypanosomiasis (HAT), known as sleeping sickness. The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form T. b. rhodesiense. We generated gene-deficient mutants lacking ISP2 (Δisp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with Δisp2 displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of Δisp2-infected mice had a greater percentage of NOS2+ myeloid cells, IFN-γ+-NK cells and increased TNF-α compared to those infected with WT and parasites re-expressing ISP2 (Δisp2:ISP2). By 13 days the increased NOS2+ population was sustained in Δisp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19+ B lymphocytes, and CD8+ and CD4+ T lymphocytes. Taken together, these findings indicate that ISP2 contributes to T. b. rhodesiense virulence in mice and attenuates the inflammatory response during early infection. Trypanosoma brucei rhodesiense are protozoan parasites that cause deadly diseases in humans. The parasites are transmitted by the bite of infected tsetse flies and can penetrate the brain, causing severe inflammation, accompanied by motor disability, neurological disorders and death. It is important to understand how and which parasite factors contribute to infection in order to improve treatment alternatives. In their genome, these parasites have genes called ISPs similar to genes of bacteria, which encode proteins that inhibit serine peptidases of the trypsin family. Here, we studied the role of ISP2 in T. b. rhodesiense by analyzing parasite knock-out mutants for isp2 in experimental infections in mice. We found that ISP2 contributes to blood parasitemia, to the clinical signs of motor disability, and to reduce the levels of the inflammatory response of the host, therefore, contributing to infection.
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