Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (T_H17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced T_H17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal T_H17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1⁺ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

流行病学研究将怀孕期间接触病毒感染（包括甲型流感病毒（IAV）感染）与后代神经发育障碍（NDD）发病率增加联系起来。使用病毒模拟物的母体免疫激活 (MIA) 模型表明，产生效应细胞因子白细胞介素 (IL)-17 的母体肠道 T 辅助 17 ( _TH 17) 细胞的激活会导致胎儿大脑发育异常，例如新皮质畸形。胎儿小胶质细胞和边界相关巨噬细胞 (BAM) 也可作为 MIA 诱导的皮质异常的潜在细胞介质。然而，在妊娠期活病毒感染模型中，炎症诱导的 T _H 17 细胞途径和胎儿脑内巨噬细胞均未得到彻底检查。在这里，我们给怀孕的小鼠接种了两种感染剂量的 IAV，并评估了母鼠和胎儿的先天性和适应性免疫反应峰值。虽然呼吸道 IAV 感染导致剂量依赖性母体结肠缩短和微生物失调，但肠道 T _H 17 细胞和 IL-17 没有升高。全身性地，IAV 导致 IL-6 和 IFN-γ 持续呈剂量和时间依赖性增加。在高剂量 IAV 组中可以观察到胎儿皮质异常和胎儿脑转录本的整体变化，但在中等剂量 IAV 组中则观察不到。胎儿小胶质细胞和 BAM 的分析揭示了脑膜而非脉络丛 BAM 数量的剂量和时间依赖性差异，而小胶质细胞数量和 Iba1 ⁺细胞的增殖能力保持恒定。胎儿大脑中的巨噬细胞增加了吞噬细胞 CD68 的表达，而且还具有剂量和时间依赖性。 总而言之，我们的研究结果表明，MIA 的某些特征在模拟病毒模型和活病毒模型之间是保守的，而其他特征则不然。总体而言，我们提供了下游母体炎症和胎儿皮质异常的感染严重程度阈值的一致证据，这概括了流行病学数据的一个关键特征，并进一步强调了在 NDD 模型中使用活病原体以更好地评估完整免疫反应和改善临床翻译。