Virtual Presentation SRB Virtual Awards 2020

Influenza A virus provokes foetal growth restriction via maternal vascular inflammation and dysfunction (#4)

Osezua Oseghale 1 , Stella Liong 1 , Eunice E To 1 , Felicia Liong 1 , Anthony Vinh 2 , John J O'Leary 3 , Doug A Brooks 4 , Stavros Selemidis 1
  1. RMIT University, Bundoora, VIC, Australia
  2. Department of Physiology, Anatomy and Microbiology, LaTrobe University, Bundoora, Victoria, Australia
  3. Department of Histopathology , Trinity College, Dublin, Ireland
  4. School of pharmacy and medical science, University of South Australia, Adelaide, South Australia, Australia

Influenza A virus (IAV) infection during pregnancy, drives severe maternal illness and perinatal complications, such as foetal growth restriction (FGR), via enigmatic mechanisms despite a lack of vertical transmission. Although studies have identified foetal hypoxia to play significant roles in FGR and increased risk of cardiovascular disease, it remains unclear whether maternal IAV infection induces foetal hypoxia to drive FGR and through what mechanism. To address this shortfall, we aimed to examine the role of IAV activation of maternal systemic innate and adaptive immune system on vascular function and foetal health. We intranasally infected time-mated pregnant (E12 gestation) mice with mouse-adapted IAV or with PBS and assessed specific parameters at 3 and 6 days post-infection. Aorta viral burden, maternal vascular immune profile, and thoracic aorta vascular function were used to assess maternal vascular integrity. Placenta and foetal brain were assessed for hypoxia, and FGR determined by measuring placental and foetal weights. IAV infection during pregnancy resulted in an exacerbated systemic inflammation and viral dissemination into the aorta resulting in a peripheral ‘Vascular Storm’ that consist of elevated pro-inflammatory and anti-viral mediators and the influx of Ly6Clow and Ly6Chigh monocytes, and neutrophils. Moreover, the vascular storm was associated with elevated T cells infiltration and activation, that resulted in a significant and dynamic alteration in maternal vascular landscape. In the offspring, the vascular storm resulted in placental and foetal brain hypoxia, besides FGR. These results indicate that IAV during pregnancy drives a significant vascular event, which likely suppresses critical blood flow to the placenta and foetus resulting in hypoxia and concomitant foetal growth restriction. This study, provides a fundamental mechanistic insight and a new paradigm into how the immune system drives maternal and foetal pathologies during pregnancy to respiratory viruses such as influenza A virus, despite the lack of transplacental infection.