Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector.
Toxoplasma gondii Matrix Antigen 1 Is a Secreted Immunomodulatory Effector.
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DOI：
10.1128/mbio.00603-21
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发表时间：
2021-05-18
期刊：
影响因子：
6.4
通讯作者：
Weiss LM
中科院分区：
文献类型：
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作者：
Tomita T;Mukhopadhyay D;Han B;Yakubu R;Tu V;Mayoral J;Sugi T;Ma Y;Saeij JPJ;Weiss LM
我们对新型囊壁蛋白的研究偶然地使我们发现，在世纪前首次鉴定的囊壁和空泡基质蛋白MAG 1作为分泌的免疫调节效应物发挥功能。MAG 1是一种致密的颗粒状蛋白，存在于速殖子空泡的寄生空泡基质和缓殖子空泡的囊壁和基质中。在目前的研究中，我们证明，MAG 1分泌到寄主细胞质中的速殖子和缓殖子的寄生泡之外。分泌的MAG 1逐渐减少的寄生虫空泡成熟，但突出的MAG 1斑点内存在的宿主细胞，甚至在4和6天后感染。在急性小鼠感染期间，Δ mag 1寄生虫显示出显著降低的毒力和传播。在感染的慢性阶段，Δ mag 1寄生虫几乎不产生脑囊肿。为了确定Δ mag 1寄生虫减弱病理学背后的机制，使用骨髓源性巨噬细胞（BMDM）在体外筛选了各种免疫反应。BMDM感染Δ mag 1寄生虫可诱导白细胞介素1β（IL-1β）分泌显著增加，这是炎性小体激活的标志。BMDM细胞中MAG 1的异源互补阻止了这种Δ mag 1寄生虫诱导的IL-1β释放，表明宿主胞质溶胶中分泌的MAG 1抑制了炎性小体激活。此外，敲除Δ mag 1寄生虫中的GRA 15（IL-1β释放的诱导剂）完全抑制了感染后宿主细胞的所有IL-1β释放。这些数据表明，MAG 1具有作为免疫调节分子的作用，并且通过抑制炎性小体活化，它将有利于寄生虫的存活和潜伏感染的建立。
Our studies on novel cyst wall proteins serendipitously led us to the discovery that cyst wall and vacuolar matrix protein MAG1, first identified a quarter of a century ago, functions as a secreted immunomodulatory effector. MAG1 is a dense granular protein that is found in the parasitophorous vacuolar matrix in tachyzoite vacuoles and the cyst wall and matrix in bradyzoite vacuoles. In the current study, we demonstrated that MAG1 is secreted beyond the parasitophorous vacuole into the host cytosol in both tachyzoites and bradyzoites. Secretion of MAG1 gradually decreases as the parasitophorous vacuole matures, but prominent MAG1 puncta are present inside host cells even at 4 and 6 days following infection. During acute murine infection, Δmag1 parasites displayed significantly reduced virulence and dissemination. In the chronic stage of infection, Δmag1 parasites generated almost no brain cysts. To identify the mechanism behind the attenuated pathology seen with Δmag1 parasites, various immune responses were screened in vitro using bone marrow-derived macrophages (BMDM). Infection of BMDM with Δmag1 parasites induced a significant increase in interleukin 1β (IL-1β) secretion, which is a hallmark of inflammasome activation. Heterologous complementation of MAG1 in BMDM cells prevented this Δmag1 parasite-induced IL-1β release, indicating that secreted MAG1 in host cytosol dampens inflammasome activation. Furthermore, knocking out GRA15 (an inducer of IL-1β release) in Δmag1 parasites completely inhibited all IL-1β release by host cells following infection. These data suggest that MAG1 has a role as an immunomodulatory molecule and that by suppressing inflammasome activation, it would favor survival of the parasite and the establishment of latent infection.