Reference
Abraham, J., Corbett, K. D., Farzan, M., Choe, H., & Harrison, S. C.
(2010). Structural basis for receptor recognition by New World
hemorrhagic fever arenaviruses. Nat Struct Mol Biol, 17 (4),
438-444. doi:10.1038/nsmb.1772
Aleksandrowicz, P., Marzi, A., Biedenkopf, N., Beimforde, N., Becker,
S., Hoenen, T., . . . Schnittler, H. J. (2011). Ebola virus enters host
cells by macropinocytosis and clathrin-mediated endocytosis. J
Infect Dis, 204 Suppl 3 , S957-967. doi:10.1093/infdis/jir326
Bailey, R. S., Casey, K. P., Pawar, S. S., & Garcia, G. J. (2017).
Correlation of Nasal Mucosal Temperature With Subjective Nasal Patency
in Healthy Individuals. JAMA Facial Plast Surg, 19 (1), 46-52.
doi:10.1001/jamafacial.2016.1445
Baum, J., Ward, R. H., & Conway, D. J. (2002). Natural selection on the
erythrocyte surface. Mol Biol Evol, 19 (3), 223-229.
doi:10.1093/oxfordjournals.molbev.a004075
Beck, Z., Brown, B. K., Wieczorek, L., Peachman, K. K., Matyas, G. R.,
Polonis, V. R., . . . Alving, C. R. (2009). Human erythrocytes
selectively bind and enrich infectious HIV-1 virions. PLoS One,
4 (12), e8297. doi:10.1371/journal.pone.0008297
Boddey, J. A., & Cowman, A. F. (2013). Plasmodium nesting: remaking the
erythrocyte from the inside out. Annu Rev Microbiol, 67 , 243-269.
doi:10.1146/annurev-micro-092412-155730
Carreau, A., El Hafny-Rahbi, B., Matejuk, A., Grillon, C., & Kieda, C.
(2011). Why is the partial oxygen pressure of human tissues a crucial
parameter? Small molecules and hypoxia. J Cell Mol Med, 15 (6),
1239-1253. doi:10.1111/j.1582-4934.2011.01258.x
Chen, Q., Gauger, P. C., Stafne, M. R., Thomas, J. T., Madson, D. M.,
Huang, H., . . . Zhang, J. (2016). Pathogenesis comparison between the
United States porcine epidemic diarrhoea virus prototype and
S-INDEL-variant strains in conventional neonatal piglets. J Gen
Virol, 97 (5), 1107-1121. doi:10.1099/jgv.0.000419
Choudhury, B., Dastjerdi, A., Doyle, N., Frossard, J. P., & Steinbach,
F. (2016). From the field to the lab - An European view on the global
spread of PEDV. Virus Res, 226 , 40-49.
doi:10.1016/j.virusres.2016.09.003
Cowman, A. F., Berry, D., & Baum, J. (2012). The cellular and molecular
basis for malaria parasite invasion of the human red blood cell. J
Cell Biol, 198 (6), 961-971. doi:10.1083/jcb.201206112
Darbonne, W. C., Rice, G. C., Mohler, M. A., Apple, T., Hebert, C. A.,
Valente, A. J., & Baker, J. B. (1991). Red blood cells are a sink for
interleukin 8, a leukocyte chemotaxin. J Clin Invest, 88 (4),
1362-1369. doi:10.1172/jci115442
David, S., & Abraham, A. M. (2016). Epidemiological and clinical
aspects on West Nile virus, a globally emerging pathogen. Infect
Dis (Lond), 48 (8), 571-586. doi:10.3109/23744235.2016.1164890
de Back, D. Z., Kostova, E. B., van Kraaij, M., van den Berg, T. K., &
van Bruggen, R. (2014). Of macrophages and red blood cells; a complex
love story. Front Physiol, 5 , 9. doi:10.3389/fphys.2014.00009
Delyea, C., Bozorgmehr, N., Koleva, P., Dunsmore, G., Shahbaz, S.,
Huang, V., & Elahi, S. (2018). CD71(+) Erythroid Suppressor Cells
Promote Fetomaternal Tolerance through Arginase-2 and PDL-1. J
Immunol, 200 (12), 4044-4058. doi:10.4049/jimmunol.1800113
Dunsmore, G., Bozorgmehr, N., Delyea, C., Koleva, P., Namdar, A., &
Elahi, S. (2017). Erythroid Suppressor Cells Compromise Neonatal Immune
Response against Bordetella pertussis. J Immunol, 199 (6),
2081-2095. doi:10.4049/jimmunol.1700742
Ebbesen, P., & Zachar, V. (1998). Oxygen tension and virus replication.Acta Virol, 42 (6), 417-421.
Elad, D., Wolf, M., & Keck, T. (2008). Air-conditioning in the human
nasal cavity. Respir Physiol Neurobiol, 163 (1-3), 121-127.
doi:10.1016/j.resp.2008.05.002
Elahi, S. (2014). New insight into an old concept: role of immature
erythroid cells in immune pathogenesis of neonatal infection.Front Immunol, 5 , 376. doi:10.3389/fimmu.2014.00376
Elahi, S. (2019). Neglected Cells: Immunomodulatory Roles of CD71(+)
Erythroid Cells. Trends Immunol, 40 (3), 181-185.
doi:10.1016/j.it.2019.01.003
Elahi, S., Ertelt, J. M., Kinder, J. M., Jiang, T. T., Zhang, X., Xin,
L., . . . Way, S. S. (2013). Immunosuppressive CD71+ erythroid cells
compromise neonatal host defence against infection. Nature,
504 (7478), 158-162. doi:10.1038/nature12675
Farrow, R. E., Green, J., Katsimitsoulia, Z., Taylor, W. R., Holder, A.
A., & Molloy, J. E. (2011). The mechanism of erythrocyte invasion by
the malarial parasite, Plasmodium falciparum. Semin Cell Dev Biol,
22 (9), 953-960. doi:10.1016/j.semcdb.2011.09.022
Forero, A., Fenstermacher, K., Wohlgemuth, N., Nishida, A., Carter, V.,
Smith, E. A., . . . Pekosz, A. (2017). Evaluation of the innate immune
responses to influenza and live-attenuated influenza vaccine infection
in primary differentiated human nasal epithelial cells. Vaccine,
35 (45), 6112-6121. doi:10.1016/j.vaccine.2017.09.058
Fukuma, N., Akimitsu, N., Hamamoto, H., Kusuhara, H., Sugiyama, Y., &
Sekimizu, K. (2003). A role of the Duffy antigen for the maintenance of
plasma chemokine concentrations. Biochemical and Biophysical
Research Communications, 303 (1), 137-139.
doi:10.1016/s0006-291x(03)00293-6
Gammella, E., Buratti, P., Cairo, G., & Recalcati, S. (2017). The
transferrin receptor: the cellular iron gate. Metallomics, 9 (10),
1367-1375. doi:10.1039/c7mt00143f
Glynn, S. A., Busch, M. P., Dodd, R. Y., Katz, L. M., Stramer, S. L.,
Klein, H. G., . . . November, N. E. I. D. T. F. c. (2013). Emerging
infectious agents and the nation’s blood supply: responding to potential
threats in the 21st century. Transfusion, 53 (2), 438-454.
doi:10.1111/j.1537-2995.2012.03742.x
Gruszczyk, J., Huang, R. K., Chan, L. J., Menant, S., Hong, C., Murphy,
J. M., . . . Tham, W. H. (2018). Cryo-EM structure of an essential
Plasmodium vivax invasion complex. Nature, 559 (7712), 135-139.
doi:10.1038/s41586-018-0249-1
Gruszczyk, J., Kanjee, U., Chan, L. J., Menant, S., Malleret, B., Lim,
N. T. Y., . . . Tham, W. H. (2018). Transferrin receptor 1 is a
reticulocyte-specific receptor for Plasmodium vivax. Science,
359 (6371), 48-55. doi:10.1126/science.aan1078
Harman, A. N., Kim, M., Nasr, N., Sandgren, K. J., & Cameron, P. U.
(2013). Tissue dendritic cells as portals for HIV entry. Rev Med
Virol, 23 (5), 319-333. doi:10.1002/rmv.1753
He, W., Neil, S., Kulkarni, H., Wright, E., Agan, B. K., Marconi, V. C.,
. . . Ahuja, S. K. (2008). Duffy antigen receptor for chemokines
mediates trans-infection of HIV-1 from red blood cells to target cells
and affects HIV-AIDS susceptibility. Cell Host Microbe, 4 (1),
52-62. doi:10.1016/j.chom.2008.06.002
Hess, C., Klimkait, T., Schlapbach, L., Del Zenero, V., Sadallah, S.,
Horakova, E., . . . Schifferli, J. A. (2002). Association of a pool of
HIV-1 with erythrocytes in vivo: a cohort study. Lancet,
359 (9325), 2230-2234. doi:10.1016/s0140-6736(02)09291-7
Horuk, R., Chitnis, C. E., Darbonne, W. C., Colby, T. J., Rybicki, A.,
Hadley, T. J., & Miller, L. H. (1993). A receptor for the malarial
parasite Plasmodium vivax: the erythrocyte chemokine receptor.Science, 261 (5125), 1182-1184. doi:10.1126/science.7689250
Hotz, M. J., Qing, D., Shashaty, M. G. S., Zhang, P., Faust, H.,
Sondheimer, N., . . . Mangalmurti, N. S. (2018). Red Blood Cells
Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain
Quiescence and to Prevent Lung Injury. Am J Respir Crit Care Med,
197 (4), 470-480. doi:10.1164/rccm.201706-1161OC
Izopet, J. (2018). [HEV and transfusion-recipient risk]. Ann
Pharm Fr, 76 (2), 89-96. doi:10.1016/j.pharma.2017.12.007
Jung, K., & Saif, L. J. (2015). Porcine epidemic diarrhea virus
infection: Etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet J, 204 (2), 134-143. doi:10.1016/j.tvjl.2015.02.017
Jung, K., Wang, Q., Scheuer, K. A., Lu, Z., Zhang, Y., & Saif, L. J.
(2014). Pathology of US porcine epidemic diarrhea virus strain PC21A in
gnotobiotic pigs. Emerg Infect Dis, 20 (4), 662-665.
doi:10.3201/eid2004.131685
Lee, C. (2015). Porcine epidemic diarrhea virus: An emerging and
re-emerging epizootic swine virus. Virol J, 12 , 193.
doi:10.1186/s12985-015-0421-2
Lee, C. (2016). Erratum to: Porcine epidemic diarrhea virus: An emerging
and re-emerging epizootic swine virus. Virol J, 13 , 19.
doi:10.1186/s12985-016-0465-y
Lee, D. (2006). Perception of blood transfusion risk. Transfus Med
Rev, 20 (2), 141-148. doi:10.1016/j.tmrv.2005.11.006
Li, Y., Wu, Q., Huang, L., Yuan, C., Wang, J., & Yang, Q. (2018). An
alternative pathway of enteric PEDV dissemination from nasal cavity to
intestinal mucosa in swine. Nature Communications, 9 (1).
doi:10.1038/s41467-018-06056-w
Manches, O., Frleta, D., & Bhardwaj, N. (2014). Dendritic cells in
progression and pathology of HIV infection. Trends Immunol,
35 (3), 114-122. doi:10.1016/j.it.2013.10.003
Martin, D. N., & Uprichard, S. L. (2013). Identification of transferrin
receptor 1 as a hepatitis C virus entry factor. Proc Natl Acad Sci
U S A, 110 (26), 10777-10782. doi:10.1073/pnas.1301764110
Martinez, M. G., Cordo, S. M., & Candurra, N. A. (2007).
Characterization of Junin arenavirus cell entry. J Gen Virol,
88 (Pt 6), 1776-1784. doi:10.1099/vir.0.82808-0
Mazzon, M., Peters, N. E., Loenarz, C., Krysztofinska, E. M., Ember, S.
W., Ferguson, B. J., & Smith, G. L. (2013). A mechanism for induction
of a hypoxic response by vaccinia virus. Proc Natl Acad Sci U S A,
110 (30), 12444-12449. doi:10.1073/pnas.1302140110
Mercer, J., & Helenius, A. (2009). Virus entry by macropinocytosis.Nat Cell Biol, 11 (5), 510-520. doi:10.1038/ncb0509-510
Minasyan, H. (2016). Mechanisms and pathways for the clearance of
bacteria from blood circulation in health and disease.Pathophysiology, 23 (2), 61-66.
doi:10.1016/j.pathophys.2016.03.001
Morinet, F., Parent, M., Bergeron, C., Pillet, S., & Capron, C. (2015).
Oxygen and viruses: a breathing story. J Gen Virol, 96 (8),
1979-1982. doi:10.1099/vir.0.000172
Olesen, A. S., Lohse, L., Dalgaard, M. D., Wozniakowski, G., Belsham, G.
J., Botner, A., & Rasmussen, T. B. (2018). Complete genome sequence of
an African swine fever virus (ASFV POL/2015/Podlaskie) determined
directly from pig erythrocyte-associated nucleic acid. J Virol
Methods, 261 , 14-16. doi:10.1016/j.jviromet.2018.07.015
Pozzetto, B., Memmi, M., & Garraud, O. (2015). Is
transfusion-transmitted dengue fever a potential public health threat?World J Virol, 4 (2), 113-123. doi:10.5501/wjv.v4.i2.113
Radoshitzky, S. R., Longobardi, L. E., Kuhn, J. H., Retterer, C., Dong,
L., Clester, J. C., . . . Bavari, S. (2011). Machupo virus glycoprotein
determinants for human transferrin receptor 1 binding and cell entry.PLoS One, 6 (7), e21398. doi:10.1371/journal.pone.0021398
Rastelli, E., Corinaldesi, C., Petani, B., Dell’Anno, A., Ciglenecki,
I., & Danovaro, R. (2016). Enhanced viral activity and dark CO2
fixation rates under oxygen depletion: the case study of the marine Lake
Rogoznica. Environ Microbiol, 18 (12), 4511-4522.
doi:10.1111/1462-2920.13484
Rios, M., Daniel, S., Chancey, C., Hewlett, I. K., & Stramer, S. L.
(2007). West Nile virus adheres to human red blood cells in whole blood.Clin Infect Dis, 45 (2), 181-186. doi:10.1086/518850
Schuch, A., Thimme, R., & Hofmann, M. (2015). Priming persistence of
HCV. Oncotarget, 6 (31), 30427-30428. doi:10.18632/oncotarget.5445
Sutherland, M. R., Simon, A. Y., Serrano, K., Schubert, P., Acker, J.
P., & Pryzdial, E. L. G. (2016). Dengue virus persists and replicates
during storage of platelet and red blood cell units. Transfusion,
56 (5), 1129-1137. doi:10.1111/trf.13454
Wang, L., Hayes, J., Byrum, B., & Zhang, Y. (2016). US variant porcine
epidemic diarrhea virus: histological lesions and genetic
characterization. Virus Genes, 52 (4), 578-581.
doi:10.1007/s11262-016-1334-x
Watanabe, K., Saito, Y., Watanabe, I., & Mizuhira, V. (1980).
Characteristics of capillary permeability in nasal mucosa. Ann
Otol Rhinol Laryngol, 89 (4 Pt 1), 377-382.
doi:10.1177/000348948008900415
Zhang, S., Hu, W., Yuan, L., & Yang, Q. (2018). Transferrin receptor 1
is a supplementary receptor that assists transmissible gastroenteritis
virus entry into porcine intestinal epithelium. Cell Commun
Signal, 16 (1), 69. doi:10.1186/s12964-018-0283-5
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.