Mukhopadhyay Sudurika S, Swan Kenneth F, Pridjian Gabriella, Kolls Jay K, Zhuang Yan, Yin Qinyan, Lasky Joseph A, Flemington Erik, Morris Cindy A, Lin Zhen, Morris Gilbert F
Departments of Microbiology & Immunology and Pathology & Laboratory Medicine, School of Medicine, Tulane University, New Orleans, LA 70118, USA.
Department of Obstetrics & Gynecology, School of Medicine, Tulane University, New Orleans, LA 70118, USA.
Pathogens. 2024 Aug 31;13(9):747. doi: 10.3390/pathogens13090747.
Lung tumor-promoting environmental exposures and γherpesvirus infections are associated with Type 17 inflammation. To test the effect of γherpesvirus infection in promoting lung tumorigenesis, we infected mutant K-Ras-expressing (K-Ras) mice with the murine γherpesvirus MHV68 via oropharyngeal aspiration. After 7 weeks, the infected mice displayed a more than 2-fold increase in lung tumors relative to their K-Ras uninfected littermates. Assessment of cytokines in the lung revealed that expression of Type 17 cytokines (, , ) peaked at day 7 post-infection. These observations correlated with the post-infection appearance of known immune mediators of tumor promotion via IL-17A in the lungs of tumor-bearing mice. Surprisingly, , an immune cell marker mRNA, did not increase in MHV68-infected wild-type mice lacking lung tumors. Csf3 and Cxcl1 protein levels increased more in the lungs of infected K-Ras mice relative to infected wild-type littermates. Flow cytometric and transcriptomic analyses indicated that the infected K-Ras mice had increased Ly6G/Ly6C immune cells in the lung relative to levels seen in uninfected control K-Ras mice. Selective methylation of adenosines (mA modification) in immune-cell-enriched mRNAs appeared to correlate with inflammatory infiltrates in the lung. These observations implicate γherpesvirus infection in lung tumor promotion and selective accumulation of immune cells in the lung that appears to be associated with mA modification of mRNAs in those cells.
促进肺部肿瘤发生的环境暴露因素和γ疱疹病毒感染与17型炎症相关。为了测试γ疱疹病毒感染在促进肺部肿瘤发生中的作用，我们通过口咽吸入法用鼠γ疱疹病毒MHV68感染表达突变型K-Ras（K-Ras）的小鼠。7周后，与未感染K-Ras的同窝小鼠相比，感染的小鼠肺部肿瘤增加了两倍多。对肺部细胞因子的评估显示，17型细胞因子（、、）的表达在感染后第7天达到峰值。这些观察结果与荷瘤小鼠肺部通过IL-17A促进肿瘤发生的已知免疫介质在感染后的出现相关。令人惊讶的是，在没有肺部肿瘤的MHV68感染的野生型小鼠中，一种免疫细胞标记物mRNA没有增加。与感染的野生型同窝小鼠相比，感染的K-Ras小鼠肺部的Csf3和Cxcl1蛋白水平增加得更多。流式细胞术和转录组分析表明，与未感染的对照K-Ras小鼠相比，感染的K-Ras小鼠肺部Ly6G/Ly6C免疫细胞增加。免疫细胞富集的mRNA中腺苷的选择性甲基化（mA修饰）似乎与肺部的炎症浸润相关。这些观察结果表明γ疱疹病毒感染在促进肺部肿瘤发生以及肺部免疫细胞的选择性积累中起作用，而这种积累似乎与这些细胞中mRNA的mA修饰有关。
