PDF(Pubmed)
Abstract：
Zika virus (ZIKV) is transmitted mostly via mosquito bites and no vaccine is available, so it may reemerge. We and others previously demonstrated that neonatal infection of ZIKV results in heart failure and can be fatal. Animal models implicated ZIKV involvement in viral heart diseases. It is unknown whether and how ZIKV causes heart failure in adults. Herein, we studied the effects of ZIKV infection on the heart function of adult A129 mice. First, we found that ZIKV productively infects the rat-, mouse-, or human-originated heart cell lines and caused ubiquitination-mediated degradation of and distortive effects on connexin 43 (Cx43) protein that is important for communications between cardiomyocytes. Second, ZIKV infection caused 100% death of the A129 mice with decreasing body weight, worsening health score, shrugging fur, and paralysis. The viral replication was detected in multiple organs. In searching for the viral effects on heart of the A129 mice, we found that ZIKV infection resulted in the increase of cardiac muscle enzymes, implicating a viral acute myocardial injury. ZIKV-caused heart injury was also demonstrated by electrocardiogram (ECG) showing widened and fragmented QRS waves, prolonged PR interval, and slower heart rate. The intercalated disc (ICD) between two cardiomyocytes was destroyed, as shown by the electronic microscopy, and the Cx43 distribution in the ICDs was less organized in the ZIKV-infected mice compared to that in the phosphate-buffered saline (PBS)-treated mice. Consistently, ZIKV productively infected the heart of A129 mice and decreased Cx43 protein. Therefore, we demonstrated that ZIKV infection caused heart failure, which might lead to fatal sequelae in ZIKV-infected A129 mice. IMPORTANCE Zika virus (ZIKV) is a teratogen causing devastating sequelae to the newborns who suffer a congenital ZIKV infection while it brings about only mild symptoms to the health-competent older children or adults. Mouse models have played an important role in mechanistic and pathogenic studies of ZIKV. In this study, we employed 3 to 4 week-old A129 mice for ZIKV infection. RT-qPCR assays discovered that ZIKV replicated in multiple organs, including the heart. As a result of ZIKV infection, the A129 mice experienced weight loss, health score worsening, paralysis, and deaths. We revealed that the ZIKV infection caused abnormal electrocardiogram presentations, increased cardiac muscle enzymes, downregulated Cx43, and destroyed the gap junction and the intercalated disc between the cardiomyocytes, implicating that ZIKV may cause an acute myocardial injury in A129 mice. Therefore, our data imply that ZIKV infection may jeopardize the immunocompromised population with a severe clinical consequence, such as heart defect.
摘要：
寨卡病毒（ZIKV）主要通过蚊虫叮咬传播，没有疫苗可用，所以它可能会重新出现。我们和其他人先前证明，新生儿感染ZIKV会导致心力衰竭，并且可能是致命的。动物模型暗示ZIKV参与病毒性心脏病。尚不清楚ZIKV是否以及如何导致成人心力衰竭。在这里，我们研究了ZIKV感染对成年A129小鼠心功能的影响。首先,我们发现ZIKV有效地感染了老鼠-，mouse-,或人类起源的心脏细胞系，并对连接蛋白43（Cx43）蛋白产生泛素化介导的降解和扭曲作用，该蛋白对心肌细胞之间的通讯很重要。第二,ZIKV感染导致体重下降的A129小鼠100%死亡，恶化的健康评分，耸耸肩的毛皮，和瘫痪。在多个器官中检测到病毒复制。在寻找病毒对A129小鼠心脏的影响时，我们发现ZIKV感染导致心肌酶的增加，涉及病毒性急性心肌损伤。ZIKV引起的心脏损伤也通过心电图（ECG）显示QRS波变宽和碎裂来证明。延长PR间隔，和更慢的心率。两个心肌细胞之间的插入盘（ICD）被破坏，如电子显微镜所示，与磷酸盐缓冲盐水（PBS）处理的小鼠相比，ZIKV感染的小鼠中ICD中的Cx43分布组织较少。始终如一，ZIKV有效地感染A129小鼠的心脏并降低Cx43蛋白。因此,我们证明ZIKV感染导致心力衰竭，这可能导致ZIKV感染的A129小鼠的致命后遗症。重要性寨卡病毒（ZIKV）是一种致畸剂，对患有先天性ZIKV感染的新生儿造成毁灭性后遗症，而对健康有能力的大龄儿童或成人仅带来轻微症状。小鼠模型在ZIKV的机制和致病机理研究中发挥了重要作用。在这项研究中,我们使用3至4周龄的A129小鼠进行ZIKV感染。RT-qPCR分析发现ZIKV在多个器官中复制，包括心脏。由于ZIKV感染,A129小鼠体重下降,健康评分恶化，瘫痪和死亡。我们发现ZIKV感染导致心电图异常,心肌酶增加，下调Cx43，破坏了心肌细胞之间的间隙连接和插入盘，提示ZIKV可能导致A129小鼠急性心肌损伤。因此,我们的数据暗示ZIKV感染可能会危及免疫受损人群，并带来严重的临床后果，如心脏缺陷。
