Neuregulin-1 prevents death from a normally lethal respiratory viral infection.

Respiratory infections with RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen, Sendai virus (SeV), which is similar to RSV, mice made atopic with house dust mite survived a normally lethal SeV infection. Since we previously demonstrated a critical role for CD11c+ cells in the immune axis linking SeV to post-viral airway disease we posited that some of the protection against lethal SeV infection could be due to CD11c+ cells from atopic mice. Therefore, we performed RNA-seq analysis of CD11c+ cells isolated from atopic and non-atopic (NA) mouse lungs. While there were several dysregulated genes, one gene product whose expression was increased several-fold in atopic CD11c+ cells was neuregulin-1(NRG1) whose protein was found to be markedly elevated in the lungs and bronchoalveolar lavage fluid of atopic mice. When NRG1 was administered to naïve (non-atopic) mice it protected them from death with both SeV and mouse adapted influenza A virus (IAV). Survival was associated with reduced alveolar epithelium permeability and reduced phosphorylation of mixed lineage kinase domain-like (MLKL) protein indicating inhibition of necroptosis. In conclusion, our data demonstrate a unique function of NRG1 in respiratory viral infections by reducing alveolar leak, inhibiting epithelial necroptosis, and promoting homeostatic regulation of airway epithelium, all of which associate with markedly reduced mortality to the respiratory viral insult. Overall design: To investigate the role of CD11c positive cells in providing survival advantage in atopic mice we isolated CD11c+ cells from HDM sensitized and challenged mice vs PBS control control We then performed gene expression profiling analysis of CD11c+ cells that occur as a result of making mice atopic. FACS was performed to isolate CD11c+ cells from both atopic and NA mouse lung and RNA-seq performed. Comparative gene expresssion analysis was performed of RNA-seq data for CD11c+ cells from atopic (HDM group) vs non-atopic (PBS treated group) two days after the last HDM challenge.

呼吸道合胞病毒（respiratory syncytial virus, RSV）、流感病毒等RNA病毒引发的呼吸道感染会造成显著的发病率与死亡率。本研究选用与RSV相似的天然啮齿类病原体——仙台病毒（Sendai virus, SeV），实验发现经屋尘螨（house dust mite, HDM）致敏的特应性小鼠可耐受原本致命的仙台病毒感染。既往研究已证实CD11c+细胞在连接仙台病毒与病毒感染后气道疾病的免疫轴中发挥关键作用，据此我们推测，特应性小鼠体内的CD11c+细胞或许介导了针对致命仙台病毒感染的部分保护效应。
为此，我们对从特应性及非特应性（NA）小鼠肺部分离得到的CD11c+细胞开展了RNA测序（RNA-seq）分析。尽管存在多个表达失调的基因，但在特应性小鼠的CD11c+细胞中，有一个基因产物的表达上调数倍——神经调节蛋白-1（neuregulin-1, NRG1），且该蛋白在特应性小鼠的肺部与支气管肺泡灌洗液中显著升高。
将NRG1给予未致敏（非特应性）小鼠后，可使其免受仙台病毒与鼠适应性甲型流感病毒（IAV）感染导致的死亡。该保护作用与肺泡上皮通透性降低、混合谱系激酶结构域样（mixed lineage kinase domain-like, MLKL）蛋白磷酸化水平下降相关，提示NRG1可抑制细胞坏死性凋亡。
综上，本研究数据揭示了NRG1在呼吸道病毒感染中的独特功能：通过减少肺泡渗漏、抑制上皮细胞坏死性凋亡以及促进气道上皮稳态调节，最终显著降低呼吸道病毒感染所致的死亡率。
总体实验设计：为探究CD11c+细胞在特应性小鼠中赋予生存优势的作用机制，我们分别从屋尘螨致敏并激发的小鼠与磷酸盐缓冲液（PBS）对照小鼠体内分离CD11c+细胞，随后对特应性状态诱导后产生的CD11c+细胞进行基因表达谱分析。通过流式细胞术（FACS）从特应性与非特应性小鼠肺部分离CD11c+细胞并开展RNA-seq。在末次屋尘螨激发后第2天，对特应性组（屋尘螨处理组）与非特应性组（PBS处理组）小鼠的CD11c+细胞RNA-seq数据进行比较基因表达分析。