Abstract
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.
Highlights
The newborn piglets are at risk of iron deficiency; they are born with low iron reserves, the concentration of iron in sows’ milk is low, and the lack on contact with soil in modern confinement rearing systems combine to create conditions insufficient to meet the requirements for rapid growth and increase in blood volume during this time [1,2]
We show that the high expression of transferrin receptor 1 (TfR1) in the apical tissue of intestinal villi in newborn piglets with iron deficiency is a reason for their susceptibility to Porcine epidemic diarrhea virus (PEDV)
This study reveals that iron plays an important role in the susceptibility of newborn piglets to PEDV and provides insights into therapies for the prevention and treatment of PEDV infections
Summary
The newborn piglets are at risk of iron deficiency; they are born with low iron reserves, the concentration of iron in sows’ milk is low, and the lack on contact with soil in modern confinement rearing systems combine to create conditions insufficient to meet the requirements for rapid growth and increase in blood volume during this time [1,2]. Iron deficiency in the newborn pig population is often comorbid with a viral infection. Many HIV-positive individuals suffer from iron deficiency [5] which hinders their ability to limit infection, especially when the virus attacks immune cells [6,7]. Iron-loaded transferrin binds with transferrin receptor 1 (TfR1) on the surface of cells, which delivers the iron into the cell [8]. A variety of viruses can utilize TfR1 for binding and entry into host cells, including New World hemorrhagic fever arenaviruses, mouse mammary tumor virus, Machupo virus, canine and feline parvoviruses [14,15,16,17]
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