Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Life Sci Alliance. 2023 Apr 18;6(7). doi: 10.26508/lsa.202201837. Print 2023 Jul.
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.
流感的发病率和死亡率与全身性炎症反应密切相关。尽管人类内皮细胞很少受到流感病毒感染，但在严重的甲型流感病毒（IAV）感染中，内皮细胞在全身性炎症反应中发挥着关键作用。内皮细胞如何参与全身性炎症反应尚不清楚。在这里，我们开发了一种 Transwell 系统，在该系统中，气道类器官衍生的分化人肺上皮细胞与原代人肺微血管内皮细胞（LMEC）共培养。我们比较了 LMEC 对大流行性 H1N1 病毒和最近的季节性 H1N1 和 H3N2 病毒的易感性，并评估了相关的促炎反应。尽管在 LMEC 单核培养物中检测到了 IAV 核蛋白，但没有证据表明存在有复制能力的感染。在上皮细胞-内皮细胞共培养物中，大量的 IAV 感染上皮细胞导致上皮屏障的破坏，但很少检测到 LMEC 的感染。与单独暴露于 IAV 的 LMEC 单核培养物相比，当与感染了 IAV 的上皮细胞共培养时，LMEC 中促炎细胞因子的分泌显著增加。总之，我们的数据表明，LMEC 被 IAV 中止感染，但可以引发炎症反应。
