Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion.
Trypanosoma cruzi utilizes the host low density lipoprotein receptor in invasion.
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DOI：
10.1371/journal.pntd.0000953
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发表时间：
2011-02-01
影响因子：
3.8
通讯作者：
Tanowitz HB
中科院分区：
文献类型：
--
作者：
Nagajyothi F;Weiss LM;Silver DL;Desruisseaux MS;Scherer PE;Herz J;Tanowitz HB
克氏锥虫是一种感染人类和其他哺乳动物宿主的细胞内原生动物寄生虫，是恰加斯病的病原体。这种寄生虫可以侵入多种哺乳动物细胞。T. cruzi侵入其宿主细胞的机制还不完全清楚。许多信号受体在入侵过程中的激活已被报道，然而，寄生虫穿过宿主细胞膜屏障并触发寄生虫空泡与溶酶体融合的确切机制尚不清楚。为了探讨低密度脂蛋白受体（LDLr）在T。为了评估LDLr寄生虫与cruzi侵袭之间的相互作用，我们使用免疫印迹和免疫荧光（IFA）技术评估了LDLr寄生虫之间的相互作用。这些实验表明T. cruzi感染增加了受感染宿主细胞中的LDLr水平，抑制或破坏LDLr降低了受感染细胞中的寄生虫负荷，T. cruzi直接结合重组LDLr，LDLr依赖性T. cruzi入侵需要PIP 2/3。qPCR分析表明，在T. Cruzi感染小鼠，最早在感染后15天观察到。IFA显示LDL和LDLr与感染心脏中的寄生虫共定位。这些数据首次突出表明，LDLr参与了这种寄生虫对宿主细胞的入侵以及随后寄生虫空泡与宿主细胞溶酶体室的融合。本研究所提出的模型统一了以前的模型宿主细胞入侵这种致病性原虫。总体而言，这些数据表明T. cruzi在入侵期间针对LDLr及其家族成员。与LDL结合可能促进寄生虫进入宿主细胞。本报告中的观察表明，基于T。cruzi和LDLr途径应该作为可能的靶点来改变感染后疾病的发病机制。 克氏锥虫是一种引起人类恰加斯病并导致心肌病发展的细胞内原生动物寄生虫，是流行地区的主要健康问题。这种寄生虫可以侵入多种哺乳动物细胞。这些寄生虫侵入宿主细胞的机制尚未完全了解。我们的研究强调，第一次，低密度脂蛋白受体（LDLr）是重要的入侵和随后的融合寄生虫空泡与宿主溶酶体。我们证明了T. cruzi直接与LDLr结合，抑制或破坏LDLr可显著降低寄生虫进入。此外，我们已经确定，这种交联触发了LDLr和磷脂酰肌醇磷酸在包被小凹中的积累，这启动了信号级联反应，导致溶酶体的募集，可能通过LDLr细胞质尾区的分选基序，到达粘附/侵袭部位。对感染的CD 1小鼠的研究表明，LDL在感染的心脏中蓄积，并且LDLr与内化的寄生虫共定位。总之，本研究表明，主要参与脂蛋白转运的LDLr及其家族成员也参与了T。Cruzi进入宿主细胞，这种相互作用可能有助于慢性心肌病的进展。
Trypanosoma cruzi, an intracellular protozoan parasite that infects humans and other mammalian hosts, is the etiologic agent in Chagas disease. This parasite can invade a wide variety of mammalian cells. The mechanism(s) by which T. cruzi invades its host cell is not completely understood. The activation of many signaling receptors during invasion has been reported; however, the exact mechanism by which parasites cross the host cell membrane barrier and trigger fusion of the parasitophorous vacuole with lysosomes is not understood. In order to explore the role of the Low Density Lipoprotein receptor (LDLr) in T. cruzi invasion, we evaluated LDLr parasite interactions using immunoblot and immunofluorescence (IFA) techniques. These experiments demonstrated that T. cruzi infection increases LDLr levels in infected host cells, inhibition or disruption of LDLr reduces parasite load in infected cells, T. cruzi directly binds recombinant LDLr, and LDLr-dependent T. cruzi invasion requires PIP2/3. qPCR analysis demonstrated a massive increase in LDLr mRNA (8000 fold) in the heart of T. cruzi infected mice, which is observed as early as 15 days after infection. IFA shows a co-localization of both LDL and LDLr with parasites in infected heart. These data highlight, for the first time, that LDLr is involved in host cell invasion by this parasite and the subsequent fusion of the parasitophorous vacuole with the host cell lysosomal compartment. The model suggested by this study unifies previous models of host cell invasion for this pathogenic protozoon. Overall, these data indicate that T. cruzi targets LDLr and its family members during invasion. Binding to LDL likely facilitates parasite entry into host cells. The observations in this report suggest that therapeutic strategies based on the interaction of T. cruzi and the LDLr pathway should be pursued as possible targets to modify the pathogenesis of disease following infection. Trypanosoma cruzi, an intracellular protozoan parasite that causes Chagas disease in humans and results in the development of cardiomyopathy, is a major health problem in endemic areas. This parasite can invade a wide variety of mammalian cells. The mechanisms by which these parasites invade their host cells are not completely understood. Our study highlights, for the first time, that the Low Density Lipoprotein receptor (LDLr) is important in the invasion and the subsequent fusion of the parasitophorous vacuole with host lysosomes. We demonstrate that T. cruzi directly binds to LDLr, and inhibition or disruption of LDLr significantly decreases parasite entry. Additionally, we have determined that this cross-linking triggers the accumulation of LDLr and phosphotidylinositol phosphates in coated pits, which initiates a signaling cascade that results in the recruitment of lysosomes, possibly via the sorting motif in the cytoplasmic tail of LDLr, to the site of adhesion/invasion. Studies of infected CD1 mice demonstrate that LDLs accumulate in infected heart and that LDLr co-localize with internalized parasites. Overall, this study demonstrates that LDLr and its family members, engaged mainly in lipoprotein transportation, are also involved in T. cruzi entry into host cells and this interaction likely contributes to the progression of chronic cardiomyopathy.
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