Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence.
Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence.
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DOI：
10.1161/circresaha.120.318511
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发表时间：
2021-03-05
影响因子：
20.1
通讯作者：
Gonzalez-Juarbe N
中科院分区：
文献类型：
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作者：
Lin YH;Platt MP;Gilley RP;Brown D;Dube PH;Yu Y;Gonzalez-Juarbe N
有或没有心血管疾病的患者已被证明有流感介导的心脏并发症的危险。最近的临床报告支持实验室确认的流感病毒感染与不良心脏事件之间存在直接联系的概念。明确流感病毒在肺部感染消退后引起心脏发病的分子机制以及坏死下垂在这一过程中的作用。野生型和坏死缺失型（MLKL-KO）小鼠的心脏在首次感染甲型流感病毒（IAV） 12天后被解剖，当时肺部无法检测到病毒滴度。免疫荧光显微镜和斑块分析显示，心肌中存在活的IAV颗粒，但没有产生干扰素反应。利用高分辨率、准确的质谱LC-MS/MS和无标记定量技术对iav感染小鼠心脏的整体蛋白质组和磷酸化蛋白质组进行分析，结果表明，iav感染小鼠心脏的整体蛋白质组和磷酸化蛋白质组谱发生了显著改变，且与菌株无关。IAV感染后，坏死性下垂缺陷小鼠的存活率提高，体重减轻，抗氧化和线粒体功能增强，表明对IAV感染有部分保护作用。这些发现在体外通过用抗氧化剂或坏死性下垂抑制剂预处理人和大鼠肌细胞得到证实，这些抗氧化剂或坏死性下垂抑制剂可以减弱IAV感染后的氧化应激和线粒体损伤。这项研究提供了第一个证据，证明心脏蛋白质组和磷蛋白质组在肺部流感感染后显着改变。此外，在肺清除后，病毒颗粒可以在心脏中持续存在，改变线粒体功能并促进细胞死亡，而没有主动复制和干扰素反应。最后，我们的研究结果表明，抑制坏死下垂或预防线粒体损伤可能是减少流感感染期间心脏损伤的治疗干预措施。
Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events. Define the molecular mechanisms underlying influenza virus-induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process. Hearts from wild-type and necroptosis deficient (MLKL-KO) mice were dissected twelve days after initial Influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high resolution accurate mass based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain independent manner. Necroptosis deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pre-treatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection. This study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections.