Esparza Matthew, El Zahed Sara S, Karakus Umut, Niederstrasser Hanspeter, Gao Boning, Batten Kimberly, Shay Jerry W, Posner Bruce, Hirsch Fred R, Girard Luc, Huang Lily Jun-Shen, Minna John, García-Sastre Adolfo, Fontoura Beatriz M A
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Virol. 2025 Jun 17;99(6):e0046925. doi: 10.1128/jvi.00469-25. Epub 2025 May 28.
Lung cancers develop from lung epithelial cells after a series of genetic and epigenetic changes, and these cells are major sites of influenza virus infection. Thus, we explored how changes found in patient-derived lung cancer cell lines impacted influenza virus replication and identified two lines with opposite responses to influenza A viral infection. We show that the NCI-H820 lung adenocarcinoma (LUAD) is resistant to influenza A virus and VSV infection, while LUAD line NCI-H322 is highly susceptible to infection by both viruses. H322 cells have a homozygous deletion in a region of chromosome 9 encoding IFNαgenes, IFNβ1, IFNω1, and IFNε genes, leading to downregulation of immune response and high infection rates. In contrast, the resistant H820 cell line has three copies of these same interferon genes and shows increased expression of interferon-regulated genes. We found that the resistance of H820 cells to influenza infection is likely linked to impaired viral entry-due to high basal levels of interferon-induced proteins known to inhibit endocytosis (IFITM1/2/3, NCOA7, and CH25H)-and to increased expression of mRNAs that encode other antiviral factors. In contrast, H322 cells show the absence or low levels of interferon-regulated genes involved in the inhibition of viral entry. These results suggest that the opposite phenotypes on viral entry of H322 and H820 cells may be at least in part associated with impaired or enhanced interferon response, respectively. Since most lung cancer patients have genomic characterization of their tumors, individualized differences in interferon responses may have therapeutic and patient management implications.
Lung cancers develop from genetic and epigenetic changes that can dramatically influence patients' susceptibility to viral infection and replication. This study evaluates the responses to influenza virus infection of two patient-derived lung cancer cell lines. Interestingly, the cell lines investigated are of the same cancer type, lung adenocarcinomas, yet one cell line is highly susceptible, while the other cell line is highly resistant to viral infection. This is in part due to contrasting genetic alterations that lead to changes in the interferon response pathways, which differentially impact viral entry. Thus, identifying these risk factors can inform the prognosis of patients infected with influenza virus and guide their personalized treatment plans.
肺癌是在一系列基因和表观遗传变化后由肺上皮细胞发展而来的，而这些细胞是流感病毒感染的主要部位。因此，我们探究了患者来源的肺癌细胞系中发现的变化如何影响流感病毒复制，并鉴定出两个对甲型流感病毒感染有相反反应的细胞系。我们发现，NCI-H820肺腺癌（LUAD）对甲型流感病毒和水疱性口炎病毒（VSV）感染具有抗性，而LUAD细胞系NCI-H322对这两种病毒的感染高度敏感。H322细胞在9号染色体上一个编码IFNα基因、IFNβ1、IFNω1和IFNε基因的区域存在纯合缺失，导致免疫反应下调和高感染率。相比之下，具有抗性的H820细胞系有这些相同干扰素基因的三个拷贝，并显示干扰素调节基因的表达增加。我们发现，H820细胞对流感感染的抗性可能与病毒进入受损有关——这是由于已知抑制内吞作用的干扰素诱导蛋白（IFITM1/2/3、NCOA7和CH25H）的基础水平较高——以及与编码其他抗病毒因子的mRNA表达增加有关。相比之下，H322细胞显示参与抑制病毒进入的干扰素调节基因缺失或水平较低。这些结果表明，H322和H820细胞在病毒进入方面的相反表型可能至少部分分别与干扰素反应受损或增强有关。由于大多数肺癌患者对其肿瘤进行了基因组特征分析，干扰素反应的个体差异可能对治疗和患者管理有影响。
肺癌由基因和表观遗传变化发展而来，这些变化可显著影响患者对病毒感染和复制的易感性。本研究评估了两个患者来源的肺癌细胞系对流感病毒感染的反应。有趣的是，所研究的细胞系为同一癌症类型，即肺腺癌，但一个细胞系高度敏感，而另一个细胞系对病毒感染高度抗性。这部分是由于导致干扰素反应途径变化的相反基因改变，这些改变对病毒进入有不同影响。因此，识别这些风险因素可为感染流感病毒的患者的预后提供信息，并指导他们的个性化治疗方案。
