Pregnant women have long been recognized as especially vulnerable during influenza outbreaks, yet the biological reasons for their disproportionate risk have remained incompletely understood. Now, preclinical research from RMIT University offers a mechanistic explanation, identifying a specific immune sensor that, when overactivated during pregnancy, can transform a manageable respiratory infection into a life-threatening systemic event affecting both mother and fetus.
The study, published in Science Advances and led by researchers at RMIT University in collaboration with Adelaide University and Trinity College Dublin, centers on Toll-like receptor 7, or TLR7 — a molecular sensor the immune system uses to detect RNA viruses, including influenza A.
The Virus Doesn’t Have to Reach the Baby to Cause Harm
In most healthy individuals, influenza remains confined to the upper respiratory tract and resolves without systemic spread. But the RMIT-led team had previously shown that in pregnant animal models, influenza viral RNA appears in the aorta within 24 hours of infection, with levels approximately ten times higher in pregnant animals than in non-pregnant controls. The current study builds on that earlier finding by identifying TLR7 as the key driver of this dangerous spillover.
Using TLR7-knockout mouse models — animals genetically engineered to lack TLR7 — the research team compared disease progression between normal pregnant mice and those without functioning TLR7 receptors. Despite carrying similar viral loads in their lungs, TLR7-knockout pregnant mice experienced significantly reduced disease severity. Critically, their offspring were also protected: pups born to TLR7-knockout mothers showed better body weight, less placental inflammation, and reduced signs of fetal neuroinflammation compared to those born to normal infected mice.
This finding reframes the central question of fetal harm. Because influenza virus rarely crosses the placenta directly, the longstanding puzzle has been how a maternal respiratory infection could cause fetal neurological damage. The study provides a compelling answer: TLR7 overactivation triggers a “vascular storm” — a state of systemic vascular dysfunction characterized by impaired endothelial function, elevated inflammatory cytokines, and widespread immune cell infiltration of the maternal aorta. This disruption reduces blood flow and oxygen delivery to the placenta, impairing fetal development without the virus itself ever reaching the baby.
From Respiratory Infection to Systemic Crisis
The molecular pathway the researchers describe involves TLR7 driving type I interferon signaling, which in turn elevates expression of oncostatin M (Osm), a cytokine known to degrade the tight junctions that maintain vascular and epithelial barrier integrity. This barrier breakdown appears to permit viral RNA to escape the lungs and enter the cardiovascular system. The team also identified elevated expression of adhesion molecules in the aortic wall — including ICAM and VCAM — that facilitate T cell infiltration and amplify vascular injury in a self-reinforcing inflammatory loop.
Importantly, TLR7-knockout mice showed a compensatory shift toward type II interferon responses and enhanced neutrophil activity, suggesting that blocking TLR7 does not simply suppress immunity but may redirect it toward a more controlled and less destructive antiviral program. The potential dual benefit — preserving viral clearance while reducing systemic inflammation — is a key consideration for any future therapeutic development.
Historical Record of Inluenza in Pregnancy is Sobering
During the 1918 H1N1 pandemic, mortality among pregnant women reached 27%, compared to roughly 1% among age-matched non-pregnant women. Risk escalated sharply with gestational age, reaching 64% mortality in the third trimester. Contemporary data confirm that pregnant women face elevated rates of hospitalization, ICU admission, and mechanical ventilation during severe influenza seasons. The downstream risks to infants — including preterm birth, spontaneous abortion, and neurodevelopmental changes — compound the public health burden considerably.
This research positions TLR7 as a tractable therapeutic target that could complement existing prevention strategies. For public health practitioners, the immediate implication is straightforward: influenza vaccination remains the most effective tool available, and both authors explicitly reinforce the safety of vaccination at any stage of pregnancy. But the discovery also opens a longer-term pathway toward adjunctive treatments that target immune-mediated harm rather than the virus itself — an approach with potential relevance beyond influenza to other respiratory viral threats in pregnancy.
This work underscores the need to prioritize pregnant women in both vaccine distribution strategies and the development of pregnancy-safe therapeutics, particularly in planning for novel influenza strains or future pandemic scenarios.
Sources and further reading:
Trollope G, et al. TLR7 alters the maternal immune landscape during influenza A infection to increase maternal and fetal morbidity. Science Advances. 29 April 2026.
Immune system overreaction linked to deadly flu in pregnancy. EurekAlert / RMIT University.