Influenza A virus causes maternal and fetal pathology via innate and adaptive vascular inflammation in mice

Abstract

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 Ly6Clow and Ly6Chigh 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.

Moderately pathogenic maternal influenza A virus infection disrupts placental integrity but spares the fetal brain

“…The clinically relevant moderate dose of X31 we selected is approximately 10 times lower than comparable studies [44], yet our IAV infection model still blunted maternal weight gain without impacting litter size. Others have shown that maternal IAV infection can slow placental and fetal growth, but does not increase fetal resorption 32,45,51 , in agreement with what we report here. While we did not record placental and fetal weights, it is likely that a similar growth retardation is present in our model considering the substantial body weight reduction in pregnant dams after correcting for litter size.…”

“…Although viral transmission to placental tissue during murine IAV infection is rare 3,4,45,51 , we observed mild-to-moderate placental pathology within all IAV litters, similar to a previous report 4 . Infiltration of neutrophils, but not mononuclear cells, was especially apparent and is common to both bacterial-induced intrauterine inflammation 53,54 and preeclampsia 55 .…”

“…Infiltration of neutrophils, but not mononuclear cells, was especially apparent and is common to both bacterial-induced intrauterine inflammation 53,54 and preeclampsia 55 . Recent evidence suggests that maternal IAV infection can result in a vascular signature that mimics preeclampsia, albeit this study used a much higher dose of X31 45 . In our model, changes in placental transcription of matrix metalloproteinases 2 and 9, implicated in preeclampsia 56 , did not reach significance, although augmented secretion of metalloproteinase inhibitor TIMP-1 57 was detectable in placental lysates.…”

“…3.2 Inflammation and antimicrobial responses extend to the placenta during maternal IAV infection. Given prior reports that placental disruptions can be induced by MIA 4,45 , we next examined whether maternal respiratory IAV X31 infection had downstream effects on the placenta. We scored H&E-stained placental sections for inflammatory lesions, and found increased incidence of necrosis, multifocal neutrophil infiltration, and mild-to-moderate mineralization in placentas from IAV-infected dams that was evident in both maternal and fetal layers (Fig.…”

Future Horizons for Neurodevelopmental Disorders: Placental Mechanisms

“…Animal models show that influenza infection during pregnancy alters the placenta in multiple ways. After maternal influenza, overall placental growth is reduced ( 21 ), as well as reduced labyrinth zone thickness, suggesting that disrupted vascular development of the placenta occurs and then likely reduces nutrient and oxygen exchange ( 22 ). Maternal influenza also alters the expression of a significant number of placental genes, mainly implicating inflammatory, immune, and hypoxia pathways but also overlapping with risk genes for neuropsychiatric disorders ( 23 ).…”