Key Points Pregnancy results in recruitment of tolerogenic dendritic cells to the uterus. Pregnancy results in lessened IL-12 responses to Zika virus infection. Pregnant mice have fewer Ag-experienced T cells after Zika infection. Recent outbreaks of Zika virus (ZIKV) have been associated with birth defects, including microcephaly and neurologic impairment. However, the mechanisms that confer potential susceptibility to ZIKV during pregnancy remain unclear. We hypothesized that poor outcomes from ZIKV infection during pregnancy are due in part to pregnancy-induced alteration of innate immune cell frequencies and cytokine expression. To examine the impact of pregnancy on innate immune responses, we inoculated immunocompetent pregnant and nonpregnant female C57BL/6 mice with 5 × 105 focus-forming units of ZIKV intravaginally. Innate immune cell frequencies and cytokine expression were measured by flow cytometry at day 3 postinfection. Compared with nonpregnant mice, pregnant mice exhibited higher frequencies of uterine macrophages (CD68+) and CD11c+ CD103+ and CD11c+ CD11b+ dendritic cells. Additionally, ZIKV-infected pregnant mice had lower frequencies of CD45+ IL-12+ and CD11b+ IL-12+ cells in the uterus and spleen. Next, we measured the frequencies of Ag-experienced CD4 (CD4+ CD11a+ CD49d+) and CD8 (CD8lo CD11ahi) T cells at day 10 postinfection to determine the impact of pregnancy-associated changes in innate cellular IL-12 responses on the adaptive immune response. We found that pregnant mice had lower frequencies of uterine Ag-experienced CD4 T cells and ZIKV-infected pregnant mice had lower frequencies of uterine Ag-experienced CD8 T cells compared with ZIKV-infected nonpregnant mice. These data show that pregnancy results in altered innate and adaptive immune responses to ZIKV infection in the reproductive tract of mice and that pregnancy-associated immune modulation may play an important role in the severity of acute ZIKV infection.

中文翻译：

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怀孕改变生殖道对寨卡病毒感染的先天和适应性免疫反应


要点 怀孕会导致耐受性树突状细胞募集到子宫。怀孕会导致 IL-12 对寨卡病毒感染的反应减弱。感染寨卡病毒后，怀孕小鼠的 Ag 经历过的 T 细胞较少。最近爆​​发的寨卡病毒（ZIKV）与出生缺陷有关，包括小头畸形和神经系统损伤。然而，妊娠期间对 ZIKV 具有潜在易感性的机制仍不清楚。我们假设妊娠期间 ZIKV 感染造成的不良后果部分是由于妊娠引起的先天免疫细胞频率和细胞因子表达的改变。为了检查妊娠对先天免疫反应的影响，我们在免疫功能正常的妊娠和非妊娠雌性 C57BL/6 小鼠阴道内接种了 5 × 105 病灶形成单位的 ZIKV。在感染后第 3 天通过流式细胞术测量先天免疫细胞频率和细胞因子表达。与非怀孕小鼠相比，怀孕小鼠表现出更高频率的子宫巨噬细胞（CD68+）和CD11c+CD103+和CD11c+CD11b+树突状细胞。此外，感染 ZIKV 的怀孕小鼠子宫和脾脏中 CD45+ IL-12+ 和 CD11b+ IL-12+ 细胞的频率较低。接下来，我们测量了感染后第 10 天经历 Ag 的 CD4 (CD4+ CD11a+ CD49d+) 和 CD8 (CD8lo CD11ahi) T 细胞的频率，以确定与妊娠相关的先天细胞 IL-12 反应变化对适应性免疫反应的影响。我们发现，与感染 ZIKV 的非怀孕小鼠相比，怀孕小鼠子宫内 Ag 经历过的 CD4 T 细胞的频率较低，而感染 ZIKV 的怀孕小鼠子宫内 Ag 经历过的 CD8 T 细胞的频率也较低。 这些数据表明，妊娠导致小鼠生殖道对 ZIKV 感染的先天性和适应性免疫反应发生改变，并且妊娠相关的免疫调节可能在急性 ZIKV 感染的严重程度中发挥重要作用。