Lower respiratory infections caused by ssRNA viruses are a major health burden globally. Translational mouse models are a valuable tool for medical research, including research on respiratory viral infections. In in vivo mouse models, synthetic dsRNA can be used as a surrogate for ssRNA virus replication. However, studies investigating how genetic background of mice impacts the murine lung inflammatory response to dsRNA is lacking. Hence, we have compared lung immunological responses of BALB/c, C57Bl/6N and C57Bl/6J mice to synthetic dsRNA. dsRNA was administered intranasally to BALB/c, C57Bl/6N and C57Bl/6J mice once/day for three consecutive days. Lactate dehydrogenase (LDH) activity, inflammatory cells, and total protein concentration were analyzed in bronchoalveolar lavage fluid (BALF). Pattern recognition receptors levels (TLR3, MDA5 and RIG-I) were measured in lung homogenates using RT-qPCR and western blot. Gene expression of IFN-β, TNF-α, IL-1β and CXCL1 was assessed in lung homogenates by RT-qPCR. ELISA was used to analyze protein concentrations of CXCL1 and IL-1β in BALF and lung homogenates. BALB/c and C57Bl/6J mice showed infiltration of neutrophils to the lung, and an increase in total protein concentration and LDH activity in response to dsRNA administration. Only modest increases in these parameters were observed for C57Bl/6N mice. Similarly, dsRNA administration evoked an upregulation of MDA5 and RIG-I gene and protein expression in BALB/c and C57Bl/6J, but not C57Bl/6N, mice. Further, dsRNA provoked an increase in gene expression of TNF-α in BALB/c and C57Bl/6J mice, IL-1β only in C57Bl/6N mice and CXCL1 exclusively in BALB/c mice. BALF levels of CXCL1 and IL-1β were increased in BALB/c and C57Bl/6J mice in response to dsRNA, whereas the response of C57Bl/6N was blunt. Overall, inter-strain comparisons of the lung reactivity to dsRNA revealed that BALB/c, followed by C57Bl/6J, had the most pronounced respiratory inflammatory responses, while the responses of C57Bl/6N mice were attenuated. We report clear differences of the lung innate inflammatory response to dsRNA between BALB/c, C57Bl/6J and C57Bl/6N mice. Of particular note, the highlighted differences in the inflammatory response of C57Bl/6J and C57Bl/6N substrains underscore the value of strain selection in mouse models of respiratory viral infections.

中文翻译：

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与 C57Bl/6J 和 BALB/c 小鼠相比，C57Bl/6N 小鼠对 dsRNA 的肺部炎症反应减弱

由 ssRNA 病毒引起的下呼吸道感染是全球主要的健康负担。转化小鼠模型是医学研究的宝贵工具，包括呼吸道病毒感染的研究。在体内小鼠模型中，合成的 dsRNA 可用作 ssRNA 病毒复制的替代物。然而，缺乏研究小鼠的遗传背景如何影响小鼠肺部对 dsRNA 的炎症反应。因此，我们比较了 BALB/c、C57Bl/6N 和 C57Bl/6J 小鼠对合成 dsRNA 的肺免疫反应。dsRNA 鼻内给药于 BALB/c、C57Bl/6N 和 C57Bl/6J 小鼠，每天一次，连续三天。在支气管肺泡灌洗液 (BALF) 中分析乳酸脱氢酶 (LDH) 活性、炎症细胞和总蛋白浓度。模式识别受体水平（TLR3，MDA5 和 RIG-I) 使用 RT-qPCR 和蛋白质印迹在肺匀浆中测量。通过 RT-qPCR 在肺匀浆中评估 IFN-β、TNF-α、IL-1β 和 CXCL1 的基因表达。ELISA 用于分析 BALF 和肺匀浆中 CXCL1 和 IL-1β 的蛋白质浓度。BALB/c 和 C57Bl/6J 小鼠显示中性粒细胞浸润到肺部，响应于 dsRNA 给药，总蛋白浓度和 LDH 活性增加。对于 C57Bl/6N 小鼠，仅观察到这些参数的适度增加。类似地，dsRNA 给药在 BALB/c 和 C57Bl/6J 小鼠中引起 MDA5 和 RIG-I 基因和蛋白质表达的上调，但在 C57Bl/6N 小鼠中没有。此外，dsRNA 在 BALB/c 和 C57Bl/6J 小鼠中引起 TNF-α 基因表达的增加，仅在 C57Bl/6N 小鼠中引起 IL-1β，在 BALB/c 小鼠中引起 CXCL1。BALB/c 和 C57Bl/6J 小鼠中 CXCL1 和 IL-1β 的 BALF 水平响应于 dsRNA 而增加，而 C57Bl/6N 的响应是钝的。总体而言，肺对 dsRNA 反应性的菌株间比较表明，BALB/c，其次是 C57Bl/6J，具有最明显的呼吸道炎症反应，而 C57Bl/6N 小鼠的反应减弱。我们报告了 BALB/c、C57Bl/6J 和 C57Bl/6N 小鼠肺部先天性炎症反应对 dsRNA 的明显差异。特别值得注意的是，C57Bl/6J 和 C57Bl/6N 亚株炎症反应的突出差异强调了呼吸道病毒感染小鼠模型中菌株选择的价值。肺对 dsRNA 反应性的菌株间比较表明，BALB/c，其次是 C57Bl/6J，具有最明显的呼吸道炎症反应，而 C57Bl/6N 小鼠的反应减弱。我们报告了 BALB/c、C57Bl/6J 和 C57Bl/6N 小鼠肺部先天性炎症反应对 dsRNA 的明显差异。特别值得注意的是，C57Bl/6J 和 C57Bl/6N 亚株炎症反应的突出差异强调了呼吸道病毒感染小鼠模型中菌株选择的价值。肺对 dsRNA 反应性的菌株间比较表明，BALB/c，其次是 C57Bl/6J，具有最明显的呼吸道炎症反应，而 C57Bl/6N 小鼠的反应减弱。我们报告了 BALB/c、C57Bl/6J 和 C57Bl/6N 小鼠肺部先天性炎症反应对 dsRNA 的明显差异。特别值得注意的是，C57Bl/6J 和 C57Bl/6N 亚株炎症反应的突出差异强调了呼吸道病毒感染小鼠模型中菌株选择的价值。