RT Journal Article SR Electronic T1 The pro-inflammatory response to influenza A virus infection is fueled by endothelial cells JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201837 DO 10.26508/lsa.202201837 VO 6 IS 7 A1 Lisa Bauer A1 Laurine C Rijsbergen A1 Lonneke Leijten A1 Feline FW Benavides A1 Danny Noack A1 Mart M Lamers A1 Bart L Haagmans A1 Rory D de Vries A1 Rik L de Swart A1 Debby van Riel YR 2023 UL https://www.life-science-alliance.org/content/6/7/e202201837.abstract AB Morbidity and mortality from influenza are associated with high levels of systemic inflammation. Endothelial cells play a key role in systemic inflammatory responses during severe influenza A virus (IAV) infections, despite being rarely infected in humans. How endothelial cells contribute to systemic inflammatory responses is unclear. Here, we developed a transwell system in which airway organoid–derived differentiated human lung epithelial cells were co-cultured with primary human lung microvascular endothelial cells (LMECs). We compared the susceptibility of LMECs to pandemic H1N1 virus and recent seasonal H1N1 and H3N2 viruses and assessed the associated pro-inflammatory responses. Despite the detection of IAV nucleoprotein in LMEC mono-cultures, there was no evidence for productive infection. In epithelial–endothelial co-cultures, abundant IAV infection of epithelial cells resulted in the breakdown of the epithelial barrier, but infection of LMECs was rarely detected. We observed a significantly higher secretion of pro-inflammatory cytokines in LMECs when co-cultured with IAV-infected epithelial cells than LMEC mono-cultures exposed to IAV. Taken together, our data show that LMECs are abortively infected by IAV but can fuel the inflammatory response.