Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA.
Infectious Diseases Institute, Viruses and Emerging Pathogens Program, The Ohio State University, Columbus, OH, USA.
Sci Adv. 2022 May 13;8(19):eabm5371. doi: 10.1126/sciadv.abm5371. Epub 2022 May 11.
Cardiac dysfunction is a common complication of severe influenza virus infection, but whether this occurs due to direct infection of cardiac tissue or indirectly through systemic lung inflammation remains unclear. To test the etiology of this aspect of influenza disease, we generated a novel recombinant heart-attenuated influenza virus via genome incorporation of target sequences for miRNAs expressed in cardiomyocytes. Compared with control virus, mice infected with miR-targeted virus had significantly reduced heart viral titers, confirming cardiac attenuation of viral replication. However, this virus was fully replicative in the lungs and induced similar systemic inflammation and weight loss compared to control virus. The miR-targeted virus induced fewer cardiac conduction irregularities and significantly less fibrosis in mice lacking interferon-induced transmembrane protein 3 (IFITM3), which serve as a model for influenza-associated cardiac pathology. We conclude that robust virus replication in the heart is required for pathology, even when lung inflammation is severe.
心脏功能障碍是严重流感病毒感染的常见并发症，但这种情况是由于心脏组织的直接感染还是通过肺部炎症的全身反应尚不清楚。为了研究流感疾病的这一方面病因，我们通过将心肌细胞中表达的 miRNA 的靶序列整合到基因组中，生成了一种新型的心脏减毒流感病毒。与对照病毒相比，感染 miRNA 靶向病毒的小鼠心脏中的病毒滴度显著降低，证实了病毒复制的心脏衰减。然而，与对照病毒相比，这种病毒在肺部仍能完全复制，并引起相似的全身炎症和体重减轻。在缺乏干扰素诱导跨膜蛋白 3 (IFITM3)的小鼠中，miRNA 靶向病毒诱导的心脏传导不规则和纤维化明显减少，IFITM3 作为流感相关心脏病理学的模型。我们得出结论，即使肺部炎症严重，心脏内的病毒复制也需要大量进行，才能导致病理学改变。
