La Trobe

File(s) stored somewhere else

Please note: Linked content is NOT stored on La Trobe and we can't guarantee its availability, quality, security or accept any liability.

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

journal contribution
posted on 12.11.2020, 01:24 by S Liong, O Oseghale, EE To, K Brassington, JR Erlich, R Luong, F Liong, R Brooks, C Martin, S O'Toole, Antony Vinh, LAJ O'Neill, S Bozinovski, R Vlahos, PC Papagianis, JJ O'Leary, DA Brooks, S Selemidis
Copyright © 2020 the Author(s). Published by PNAS. 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.

Funding

We thank Prof. Patrick Reading (Peter Doherty Institute, The University of Melbourne) for providing the IAV stocks. This work was supported by the Australian Research Council Future Fellowship Scheme ID FT120100876 (to S.S.) and National Health and Medical Research Council of Australia Project IDs 1122506 and 1128276.

Australian Research Council | FT120100876

National Health and Medical Research Council of Australia | 1122506

National Health and Medical Research Council of Australia | 1128276

History

Publication Date

06/10/2020

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

117

Issue

40

Pagination

10p. (p. 24964-24973)

Publisher

National Academy of Sciences

ISSN

0027-8424

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.

Licence

Exports