TY - JOUR
T1 - Human Dendritic Cells Transmit Enterovirus A71 via Heparan Sulfates to Target Cells Independent of Viral Replication
AU - Helgers, Leanne C
AU - Bhoekhan, Michel S
AU - Pajkrt, Dasja
AU - Wolthers, Katja C
AU - Geijtenbeek, Teunis B H
AU - Sridhar, Adithya
N1 - Funding Information: This work was supported by the Netherlands Organization for Scientific Research (NWO) VIDI Grant 91718331, the European Research Council (ERC) Advanced Grant 670424, and the ZonMW Meer Kennis met Minder Dieren Grant 114021506. L.C.H., M.S.B., and A.S. designed, performed, and interpreted most experiments and prepared the manuscript; L.C.H., M.S.B., D.P., K.C.W., T.H.B.G., and A.S. participated in discussion of the data; T.B.H.G. and A.S. supervised all aspects of the project. We declare no competing interests. Publisher Copyright: Copyright © 2022 Helgers et al.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - Enterovirus A71 (EV-A71) is a causative agent of life-threatening neurological diseases in young children. EV-A71 is highly infectious but it remains unclear how the virus disseminates from primary entry sites—the mucosa of the respiratory tract or the intestine—to secondary replication sites—skin or brain. Here, we investigated the role of dendritic cells (DCs) in EV-A71 dissemination. DCs reside in the mucosa of the airway and gut, and migrate to lymphoid tissues upon activation and, therefore, could facilitate EV-A71 dissemination to secondary replication sites. Monocyte-derived DCs were not permissive to different genotypes of EV-A71 but, notably, coculture with EV-A71-susceptiblle RD99 cells led to very efficient infection of RD99 cells. Notably, EV-A71 transmission of DCs to RD99 was independent of viral replication as a replication inhibitor did not affect transmission. Soluble heparin blocked EV-A71 transmission by DCs to RD99 cells, in contrast to antibodies against known attachment receptor DC-SIGN. These results strongly suggest that DCs might be a first target for EV-A71 and involved in viral dissemination via heparan sulfates and heparin derivatives might be an effective treatment to attenuate dissemination.
AB - Enterovirus A71 (EV-A71) is a causative agent of life-threatening neurological diseases in young children. EV-A71 is highly infectious but it remains unclear how the virus disseminates from primary entry sites—the mucosa of the respiratory tract or the intestine—to secondary replication sites—skin or brain. Here, we investigated the role of dendritic cells (DCs) in EV-A71 dissemination. DCs reside in the mucosa of the airway and gut, and migrate to lymphoid tissues upon activation and, therefore, could facilitate EV-A71 dissemination to secondary replication sites. Monocyte-derived DCs were not permissive to different genotypes of EV-A71 but, notably, coculture with EV-A71-susceptiblle RD99 cells led to very efficient infection of RD99 cells. Notably, EV-A71 transmission of DCs to RD99 was independent of viral replication as a replication inhibitor did not affect transmission. Soluble heparin blocked EV-A71 transmission by DCs to RD99 cells, in contrast to antibodies against known attachment receptor DC-SIGN. These results strongly suggest that DCs might be a first target for EV-A71 and involved in viral dissemination via heparan sulfates and heparin derivatives might be an effective treatment to attenuate dissemination.
KW - dendritic cells
KW - enterovirus
KW - picornavirus
KW - receptors
UR - http://www.scopus.com/inward/record.url?scp=85144635868&partnerID=8YFLogxK
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UR - https://www.ncbi.nlm.nih.gov/pubmed/36222686
U2 - https://doi.org/10.1128/spectrum.02822-22
DO - https://doi.org/10.1128/spectrum.02822-22
M3 - Article
C2 - 36222686
SN - 2165-0497
VL - 10
SP - e0282222
JO - Microbiology spectrum
JF - Microbiology spectrum
IS - 6
ER -