Listeria monocytogenes cytoplasmic entry induces fetal wastage by disrupting maternal Foxp3+ regulatory T cell-sustained fetal tolerance.
Listeria monocytogenes cytoplasmic entry induces fetal wastage by disrupting maternal Foxp3+ regulatory T cell-sustained fetal tolerance.
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DOI：
10.1371/journal.ppat.1002873
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Way SS
中科院分区：
文献类型：
--
作者：
Rowe JH;Ertelt JM;Xin L;Way SS
尽管细胞内细菌单核细胞增生李斯特氏菌在怀孕期间容易发生播散性感染，常常导致自然流产或死产，但导致这些灾难性并发症的特定宿主-病原体相互作用仍未完全确定。在此，我们证明妊娠期间母体全身性李斯特菌感染会破坏胎儿的耐受性并以剂量依赖性方式引发胎儿消耗。在高剂量感染后，从大多数受孕体中回收到李斯特菌，这说明了子宫内侵入的可能性。有趣的是，随着接种量的减少，胎儿损耗的发生并没有直接的胎盘或胎儿侵入，而是与母体 Foxp3+ 调节性 T 细胞抑制效力的降低同时伴随着母体胎儿特异性效应 T 细胞的相互扩增和激活。使用缺乏子宫入侵所需毒力决定因素的突变体，我们确定李斯特菌进入细胞质对于破坏胎儿耐受性至关重要，从而触发母体 T 细胞介导的胎儿吸收。因此，感染引起的母体 Foxp3+ 调节性 T 细胞抑制的减少以及随后胎儿耐受性的破坏在免疫介导的胎儿消耗的发病机制中发挥着关键作用。孕妇对单核细胞增生李斯特菌特别敏感，这种细菌优先生活在受感染的细胞内。由于怀孕期间的感染通常会引发早产、流产或死产，因此我们建议了解这些并发症如何发生是改善母亲和发育中胎儿健康的重要先决条件。在这里，我们研究了李斯特菌与母亲体内的免疫抑制细胞子集之间的特定相互作用，这些细胞会扩展为胎儿创造和维持一个适宜的环境。我们发现，虽然李斯特菌（尤其是高剂量感染的李斯特菌）可以侵入胎儿，但感染引起的母体免疫细胞变化也可能造成损害，使其明显不适合胎儿。在这种情况下，母体免疫介导的排斥反应会在没有病原体直接入侵的情况下导致胎儿损伤。我们证明，使用减少剂量的强毒力或弱化李斯特菌进行感染时会发生这种情况。通过比较妊娠结局和感染引起的母亲变化（这些变化或多或少对胎儿有利），我们进一步证明李斯特菌进入受感染细胞是免疫介导的胎儿损伤的关键因素。这些结果说明感染引起的母亲变化导致胎儿受伤，对于设计改善妊娠结局的新方法具有重要意义。
Although the intracellular bacterium Listeria monocytogenes has an established predilection for disseminated infection during pregnancy that often results in spontaneous abortion or stillbirth, the specific host-pathogen interaction that dictates these disastrous complications remain incompletely defined. Herein, we demonstrate systemic maternal Listeria infection during pregnancy fractures fetal tolerance and triggers fetal wastage in a dose-dependent fashion. Listeria was recovered from the majority of concepti after high-dose infection illustrating the potential for in utero invasion. Interestingly with reduced inocula, fetal wastage occurred without direct placental or fetal invasion, and instead paralleled reductions in maternal Foxp3+ regulatory T cell suppressive potency with reciprocal expansion and activation of maternal fetal-specific effector T cells. Using mutants lacking virulence determinants required for in utero invasion, we establish Listeria cytoplasmic entry is essential for disrupting fetal tolerance that triggers maternal T cell-mediated fetal resorption. Thus, infection-induced reductions in maternal Foxp3+ regulatory T cell suppression with ensuing disruptions in fetal tolerance play critical roles in pathogenesis of immune-mediated fetal wastage. Pregnant women are uniquely susceptible to the bacterium Listeria monocytogenes that preferentially lives inside infected cells. Since infection during pregnancy often triggers prematurity, abortion, or stillbirth, we propose that understanding how these complications occur represent important prerequisites for improving the health of mothers and the developing fetus. Here we investigate the specific interaction between Listeria and a subset of immune-suppressive cells in the mother that expand to create and maintain a hospitable environment for the fetus. We find although Listeria, especially with highdosage infection, can invade the fetus, damage can also occur by infection-induced changes in maternal immune cells that make it markedly less hospitable for the fetus. Under these circumstances, maternal immune-mediated rejection causes fetal injury without direct pathogen invasion. We show this occurs using both reduced-dosages of virulent or weakened Listeria for infection. By comparing pregnancy outcomes and infection-induced changes in the mother that make it more or less hospitable for the fetus, we further demonstrate Listeria gaining entry inside infected cells is the critical factor for immune-mediated fetal injury. These results illustrating infection-induced changes in the mother that lead to fetal injury have important implications for designing new ways to improve the outcomes of pregnancy.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
DOI：
10.4049/jimmunol.1101649
发表时间：
2011-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kastenmuller W;Gasteiger G;Subramanian N;Sparwasser T;Busch DH;Belkaid Y;Drexler I;Germain RN
通讯作者：
Germain RN
影响因子：
3.1
作者：
Bahjat, Keith S.;Liu, Weiqun;Brockstedt, Dirk G.
通讯作者：
Brockstedt, Dirk G.
影响因子：
56.9
作者：
Pasare, C;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
3.8
作者：
Orgun, Nural N.;Way, Sing Sing
通讯作者：
Way, Sing Sing