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Fig. 1 PEDV bind neonatal RBCs . A. The viral titer in neonatal RBCs was determined by plaque assay after PEDV infection (MOI=0.1). B. The levels of PEDV-N protein were detected at different time after PEDV infection with neonatal RBCs by Western blot.C. Transmission electron microscopy (TEM) observation of PEDV infection with neonatal RBCs. The fine ultrastructure of the virus particles (white arrowheads) was observed in neonatal RBCs. Bars = 200 nm. The data shown were the mean results ± SD from three independent experiments.
Fig. 2 CD71 and clathrin-mediated endocytosis promoted PEDV internalize into­ neonatal RBCs. A. For FACs analyses, RBCs from different age pigs were infected with PEDV (MOI=0.1) and detected through an antibody against PEDV-N protein staining. B. CD71 expression was detected in different age pig’s RBCs by Western blot.C. CD71 expression in neonatal RBCs was determined at different time after PEDV infection by Western blot. D and E.Neonatal RBCs were pre-treated with a blocking antibody against CD71, and then infected with PEDV. After blocking CD71 expression, the viral titer (D ) and the level of PEDV-N protein (E ) was determined by plaque assays and Western blot. F and G.Neonatal RBCs were pre-treated with the respective doses of chlorpromazine (CPZ) for 2 h and then infected with PEDV in RPMI 1640 medium containing CPZ. After infection, the viral titer (F ) and the level of PEDV-N protein (G ) were determined by plaque assays and Western blot. The data shown are the mean results ± SD from three independent experiments. The comparisons were performed with t-tests (two groups) or analysis of variance (ANOVA) (multiple groups). *p < 0.05, **p < 0.01.
Fig. 3 Transfusion with PEDV-loaded RBCs caused typical PED symptoms. A. Schematic representation of experimental design. RBCs were isolated from newborn piglets, and then infected with PEDV in vitro. After infection, RBCs were labeled with Dil and transfused via ear vein. B. The viral titer of transfused RBCs was determined by a plaque assays. Cand D. After 1 h or 48 h of transfusion, the percent of Dil+ RBCs (C ) and PEDV+RBCs (D ) were detected from the blood by FACS analysis.E. Quantification of the FACS results as shown in (Cand D ). F. Acute watery diarrhea and gross lesions of the small intestine in piglets after transfusion with PEDV+ RBC at 48 hpt. G. IHC results showed the distribution of PEDV (white arrowheads), and severe destruction of intestinal villous enterocytes and villous atrophy in jejunum. Bars = 100 μm. H. Sections of jejunum from different group were stained with DAPI (blue) and an antibody against PEDV-N protein (red), and were visualized by confocal microscopy. Bars = 100 μm. I.Viral RNA expression in different tissues after 1 h and 48 h of transfusion with RBCs was determined by qRT-PCR. K. The levels of PEDV-N protein in different tissues after 1h and 48 h of transfusion with RBCs was detected by Western blot. The data shown are the mean results ± SD from three independent experiments. The comparisons were performed with t-tests (two groups) or analysis of variance (ANOVA) (multiple groups). *p < 0.05, **p < 0.01.
Fig. 4 CD3+ T cells acquired PEDV from RBCs by forming conjugation. A. Schematic representation of experimental design. After infection with PEDV, RBCs were co-cultured with PBMCs. After co-culture, the co-cultured cells were collected and remove RBCs by ACK Lysis Buffer. B. The percent of PEDV+PBMCs were determined by FACS analysis. C. The levels of PEDV-N protein were detected in PBMCs after co-culture. D. Schematic representation of experimental design. After infection with PEDV and labeling with Dil, RBCs were co-cultured with PBMCs. The co-cultured cells were stained with CD3+ antibody and PEDV-N-FITC antibody to detected PEDV transmission. E. The PEDV transmission was quantified by analyzing the CD3+PEDV+ population. F. The conjugate formation between CD3+ T cells and RBCs was determined by analyzing the CD3+ Dil+ population.G. Quantification of the FACS results as shown in (Eand F ). H . TEM observation showed CD3+ T cells form conjugation with RBCs (white arrowheads). The fine ultrastructure of the virus particles (white arrowheads) was observed in the T cells adjacent to the conjugate structure (white arrowheads). The data shown are the mean results ± SD from three independent experiments. The comparisons were performed with t-tests (two groups) or analysis of variance (ANOVA) (multiple groups). *p < 0.05, **p < 0.01.
Fig. 5 Nasal capillary might be the entry of PEDV binding RBCs.A. Capillaries were immediately adjacent to nasal epithelium cells (NECs) in nasal cavity of newborn piglets by Hematoxylin and eosin (H&E) staining. B. PEDV-loaded RBCs (white arrowheads) were found in the capillary adjacent (white ellipse) to NECs after 12 h of intranasal incubation with PEDV by IHC observation. C. No PEDV-loaded RBCs was found in in the capillary (white ellipse) of PEDV-infected intestine by IHC observation. D. RBCs were cultured and infected with PEDV in normoxic condition (20 % oxygen partial pressure, pO2) or hypoxic condition (3 % pO2), and then the levels of PEDV-N protein were determined by Western blot. E.RBCs were cultured and infected with PEDV in 37 °C or 33 °C condition, and then the levels of PEDV-N protein were determined by Western blot.F. For FACS analyses, RBCs were cultured and infected with PEDV in normal, hypoxic condition or 33 °C condition, and then detected by PEDV-N protein staining. G . Quantification of the FACS results as shown in (F ). The data shown are the mean results ± SD from three independent experiments. The comparisons were performed with t-tests (two groups) or analysis of variance (ANOVA) (multiple groups). *p < 0.05, **p < 0.01.
Fig 6. Schematic of the proposed mechanism for PEDV transportation in newborn piglets.PEDV could bind and internalize into neonatal RBCs through CD71 and clathrin-mediated endocytosis. Moreover, the relatively high oxygen concentration in nasal cavity promoted PEDV bind to RBCs. CD3+ T cells could recognize and acquire the virus from PEDV-loaded RBCs. PEDV-loaded CD3+ T cells could transfer the virus to intestinal epithelial cells (IECs), causing typical PED symptoms.