Human innate immunity to Toxoplasma gondii is mediated by host caspase-1 and ASC and parasite GRA15.
Human innate immunity to Toxoplasma gondii is mediated by host caspase-1 and ASC and parasite GRA15.
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DOI：
10.1128/mbio.00255-13
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发表时间：
2013-07-09
期刊：
影响因子：
6.4
通讯作者：
Lodoen MB
中科院分区：
文献类型：
--
作者：
Gov L;Karimzadeh A;Ueno N;Lodoen MB
白细胞介素-1 β（IL-1β）作为炎症和先天免疫的关键调节剂发挥作用。原生动物寄生虫弓形虫主动感染人类血液单核细胞并诱导IL-1β的产生;然而，对弓形虫感染期间介导IL-1β产生的宿主和寄生虫因素知之甚少。我们报道了弓形虫诱导感染的原代人单核细胞和THP-1细胞的IL-1β转录、加工/切割和释放。用半胱天冬酶-1抑制剂Ac-YVAD-CMK处理单核细胞减少了IL-1β的释放，表明炎性体在刚地弓形虫诱导的IL-1β产生中的作用。这通过进行胱天蛋白酶-1和炎性体衔接蛋白ASC的短发夹RNA（shRNA）敲低来证实。IL-1β的诱导需要单核细胞的主动寄生虫侵入，因为热杀死的或真菌毒素B处理的寄生虫不诱导IL-1β。在I、II和III型弓形虫菌株中，II型菌株诱导的IL-1β mRNA和蛋白释放显著高于I型和III型菌株。由于已知IL-1β转录物在NF-κB信号传导的下游被诱导，我们研究了GRA 15蛋白的作用，其以寄生虫株特异性方式诱导持续的NF-κB信号传导。通过用GRA 15敲除的II型菌株和稳定表达II型GRA 15的I型菌株感染人单核细胞，我们确定GRA 15负责刚地弓形虫感染人单核细胞期间的IL-1β诱导。本研究通过描述经典炎性体组分caspase-1和ASC以及寄生虫GRA 15蛋白在刚地弓形虫诱导的IL-1β产生中的作用，定义了驱动人类先天免疫的途径。单核细胞是免疫细胞，通过增加体内炎症和抗菌活性来防止感染。感染寄生虫病原体弓形虫后，人类单核细胞释放白细胞介素-1 β（IL-1β），这是炎症的“主调节因子”，可放大免疫反应。虽然炎症反应对于宿主防御感染至关重要，但过度炎症可导致组织损伤和病理学。这种微妙的平衡强调了理解感染期间调节IL-1β的机制的重要性。我们研究了弓形虫诱导人单核细胞合成和释放IL-1β的分子途径。我们发现寄生虫和宿主细胞中的特异性蛋白协同诱导IL-1β的产生。这项研究意义重大，因为它有助于更好地了解人类对感染和IL-1β调节的先天免疫，从而增强我们调节体内炎症的潜力。
Interleukin-1β (IL-1β) functions as a key regulator of inflammation and innate immunity. The protozoan parasite Toxoplasma gondii actively infects human blood monocytes and induces the production of IL-1β; however, the host and parasite factors that mediate IL-1β production during T. gondii infection are poorly understood. We report that T. gondii induces IL-1β transcript, processing/cleavage, and release from infected primary human monocytes and THP-1 cells. Treating monocytes with the caspase-1 inhibitor Ac-YVAD-CMK reduced IL-1β release, suggesting a role for the inflammasome in T. gondii-induced IL-1β production. This was confirmed by performing short hairpin RNA (shRNA) knockdown of caspase-1 and of the inflammasome adaptor protein ASC. IL-1β induction required active parasite invasion of monocytes, since heat-killed or mycalolide B-treated parasites did not induce IL-1β. Among the type I, II, and III strains of T. gondii, the type II strain induced substantially more IL-1β mRNA and protein release than did the type I and III strains. Since IL-1β transcript is known to be induced downstream of NF-κB signaling, we investigated a role for the GRA15 protein, which induces sustained NF-κB signaling in a parasite strain-specific manner. By infecting human monocytes with a GRA15-knockout type II strain and a type I strain stably expressing type II GRA15, we determined that GRA15 is responsible for IL-1β induction during T. gondii infection of human monocytes. This research defines a pathway driving human innate immunity by describing a role for the classical inflammasome components caspase-1 and ASC and the parasite GRA15 protein in T. gondii-induced IL-1β production. Monocytes are immune cells that protect against infection by increasing inflammation and antimicrobial activities in the body. Upon infection with the parasitic pathogen Toxoplasma gondii, human monocytes release interleukin-1β (IL-1β), a “master regulator” of inflammation, which amplifies immune responses. Although inflammatory responses are critical for host defense against infection, excessive inflammation can result in tissue damage and pathology. This delicate balance underscores the importance of understanding the mechanisms that regulate IL-1β during infection. We have investigated the molecular pathway by which T. gondii induces the synthesis and release of IL-1β in human monocytes. We found that specific proteins in the parasite and the host cell coordinate to induce IL-1β production. This research is significant because it contributes to a greater understanding of human innate immunity to infection and IL-1β regulation, thereby enhancing our potential to modulate inflammation in the body.