Cell type-specific roles of PAR1 in Coxsackievirus B3 infection.
Cell type-specific roles of PAR1 in Coxsackievirus B3 infection.
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DOI：
10.1038/s41598-021-93759-8
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发表时间：
2021-07-12
影响因子：
4.6
通讯作者：
Mackman N
中科院分区：
文献类型：
--
作者：
Bode MF;Schmedes CM;Egnatz GJ;Bharathi V;Hisada YM;Martinez D;Kawano T;Weithauser A;Rosenfeldt L;Rauch U;Palumbo JS;Antoniak S;Mackman N
蛋白酶激活受体1 （PAR1）在人和小鼠中广泛表达，可被多种蛋白酶激活，包括凝血酶。最近，我们发现PAR1参与了对病毒感染的先天免疫反应。与对照小鼠相比，PAR1全局缺乏的小鼠表达较低水平的CXCL10，并且柯萨奇病毒B3 （CVB3）诱导的心肌炎增加。在这项研究中，我们确定了心肌细胞（CMs）和心脏成纤维细胞（CFs）中PAR1细胞类型特异性缺失对cvb3诱导的心肌炎的影响。与野生型对照相比，在CMs或CFs中缺乏PAR1的小鼠表现出CVB3基因组、炎症浸润、巨噬细胞和心脏炎症介质的增加，以及CVB3诱导的心肌炎的增加。有趣的是，PAR1增强了大鼠CFs中CXCL10的poly I:C诱导，但在大鼠新生CMs中没有。重要的是，PAR1的激活减少了小鼠胚胎成纤维细胞和小鼠胚胎心肌细胞中的CVB3复制。此外，我们发现PAR1减少了小鼠胚胎成纤维细胞和大鼠H9c2细胞的自噬，这可能解释了PAR1如何减少CVB3复制。这些数据表明，CFs上的PAR1通过增强抗病毒应答来保护cvb3诱导的心肌炎，而CMs和成纤维细胞上的PAR1抑制病毒复制。
Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.
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DOI：
10.1111/jth.15221
发表时间：
2021-04
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Antoniak S;Tatsumi K;Schmedes CM;Egnatz GJ;Auriemma AC;Bharathi V;Stokol T;Beck MA;Griffin JH;Palumbo JS;Mackman N
通讯作者：
Mackman N
影响因子：
1.9
作者：
Antoniak S;Cardenas JC;Buczek LJ;Church FC;Mackman N;Pawlinski R
通讯作者：
Pawlinski R
钙蛋白酶通过促进感染时自噬流调节 CVB3 诱导的病毒性心肌炎
影响因子：
5.8
作者：
Meng, Yawen;Sun, Tianle;Xiong, Sidong
通讯作者：
Xiong, Sidong
影响因子：
1.5
作者：
Acharya, Asha;Baek, Seung Tae;Banfi, Serena;Eskiocak, Banu;Tallquist, Michelle D.
通讯作者：
Tallquist, Michelle D.
影响因子：
64.8
作者：
Coughlin, SR
通讯作者：
Coughlin, SR