Transferrin receptor 1 levels at the cell surface influence the susceptibility of newborn piglets to PEDV infection
Transferrin receptor 1 levels at the cell surface influence the susceptibility of newborn piglets to PEDV infection
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细胞表面转铁蛋白受体1水平影响新生仔猪对PEDV感染的易感性
DOI：
10.1371/journal.ppat.1008682
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发表时间：
2020-07-01
期刊：
影响因子：
6.7
通讯作者：
Yang, Qian
中科院分区：
文献类型：
--
作者：
Zhang, Shuai;Cao, Yanan;Yang, Qian
猪流行性腹泻病毒（PEDV）主要感染新生仔猪的肠上皮细胞，引起急性、重症萎缩性肠炎。 PEDV 感染的潜在机制以及新生仔猪比老猪更易受影响的原因仍不完全清楚。缺铁在新生仔猪中很常见。我们发现新生仔猪肠绒毛顶端组织中分布着高水平的转铁蛋白受体1（TfR1），细胞内铁水平影响新生仔猪对PEDV的易感性。我们发现，去铁胺（DFO，一种铁螯合剂）诱导的铁缺乏会促进 PEDV 感染，而柠檬酸铁铵（FAC，一种铁补充剂）诱导的铁积累会在体外和体内损害 PEDV 感染。此外，通过用抗体封闭TfR1或降低TfR1表达来抑制PEDV感染。此外，PEDV 抗性 Caco-2 和 HEK 293T 细胞过表达猪 TfR1 时 PEDV 感染增加。从机制上讲，PEDV进入过程中，PEDV S1蛋白与TfR1胞外区相互作用，促进TfR1重新定位和聚集，然后激活Src激酶介导的TfR1酪氨酸磷酸化，增强TfR1的内化，从而促进PEDV进入。综上所述，这些数据表明，缺铁引起的肠绒毛顶端组织中 TfR1 的较高表达是新生仔猪对 PEDV 高度敏感的原因。
Porcine epidemic diarrhea virus (PEDV) mainly infects the intestinal epithelial cells of newborn piglets causing acute, severe atrophic enteritis. The underlying mechanisms of PEDV infection and the reasons why newborn piglets are more susceptible than older pigs remain incompletely understood. Iron deficiency is common in newborn piglets. Here we found that high levels of transferrin receptor 1 (TfR1) distributed in the apical tissue of the intestinal villi of newborns, and intracellular iron levels influence the susceptibility of newborn piglets to PEDV. We show that iron deficiency induced by deferoxamine (DFO, an iron chelating agent) promotes PEDV infection while iron accumulation induced by ferric ammonium citrate (FAC, an iron supplement) impairs PEDV infection in vitro and in vivo. Besides, PEDV infection was inhibited by occluding TfR1 with antibodies or decreasing TfR1 expression. Additionally, PEDV infection was increased in PEDV-resistant Caco-2 and HEK 293T cells over-expressed porcine TfR1. Mechanistically, the PEDV S1 protein interacts with the extracellular region of TfR1 during PEDV entry, promotes TfR1 re-localization and clustering, then activates TfR1 tyrosine phosphorylation mediated by Src kinase, and heightens the internalization of TfR1, thereby promoting PEDV entry. Taken together, these data suggest that the higher expression of TfR1 in the apical tissue of the intestinal villi caused by iron deficiency, accounts for newborn piglets being acutely susceptible to PEDV.