Influenza A virus (IAV) infection during pregnancy causes severe maternal and perinatal complications, despite a lack of vertical transmission of IAV across the placenta. Here, we demonstrate a significant alteration in the maternal vascular landscape that underpins the maternal and downstream fetal pathology to IAV infection in mice. In IAV infection of nonpregnant mice, the local lung inflammatory response was contained to the lungs and was self-resolving, whereas in pregnant mice, virus dissemination to major maternal blood vessels, including the aorta, resulted in a peripheral "vascular storm," with elevated proinflammatory and antiviral mediators and the influx of Ly6C^low and Ly6C^high monocytes, plus neutrophils and T cells. This vascular storm was associated with elevated levels of the adhesion molecules ICAM and VCAM and the pattern-recognition receptors TLR7 and TLR9 in the vascular wall, resulting in profound vascular dysfunction. The sequalae of this IAV-driven vascular storm included placental growth retardation and intrauterine growth restriction, evidence of placental and fetal brain hypoxia, and increased circulating cell free fetal DNA and soluble Flt1. In contrast, IAV infection in nonpregnant mice caused no obvious alterations in endothelial function or vascular inflammation. Therefore, IAV infection during pregnancy drives a significant systemic vascular alteration in pregnant dams, which likely suppresses critical blood flow to the placenta and fetus. This study in mice provides a fundamental mechanistic insight and a paradigm into how an immune response to a respiratory virus, such as IAV, is likely to specifically drive maternal and fetal pathologies during pregnancy.

尽管IAV在胎盘中缺乏垂直传播，但怀孕期间的A型流感病毒（IAV）感染会导致严重的母亲和围产期并发症。在这里，我们证明了母本血管景观的显着改变，为小鼠IAV感染的母体和下游胎儿病理奠定了基础。在未怀孕小鼠的IAV感染中，局部肺部炎症反应包含在肺中并且可以自行解决，而在怀孕小鼠中，病毒向主要母体血管（包括主动脉）的传播会导致周围的“血管风暴”，促炎和抗病毒介质升高，Ly6C^低和Ly6C^高流入单核细胞，以及中性粒细胞和T细胞。该血管风暴与血管壁中粘附分子ICAM和VCAM以及模式识别受体TLR7和TLR9水平升高有关，从而导致严重的血管功能障碍。IAV驱动的血管风暴的后遗症包括胎盘生长迟缓和子宫内生长受限，胎盘和胎儿脑缺氧的证据以及胎儿游离循环DNA和可溶性Flt1增加。相反，未怀孕小鼠的IAV感染未引起内皮功能或血管炎症的明显改变。因此，怀孕期间的IAV感染会在怀孕的大坝中引起明显的全身血管改变，这很可能会抑制流向胎盘和胎儿的关键血液。