Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus-adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN.
The coxsackievirus-adenovirus receptor (CAR) is the described primary receptor for adenovirus serotype 5 (Ad5), a common human pathogen that has been exploited as a viral vector for gene therapy and vaccination. This study showed that monocytes and dendritic cells (DCs), such as freshly isolated human blood myeloid DCs, plasmacytoid DCs and monocyte-derived DCs, are susceptible to recombinant Ad5 (rAd5) infection despite their lack of CAR expression. Langerhans cells and dermal DCs from skin expressed CAR, but blocking CAR only partly decreased rAd5 infection, together suggesting that other receptor pathways mediate viral entry of these cells. Lactoferrin (Lf), an abundant protein in many bodily fluids known for its antiviral and antibacterial properties, promoted rAd5 infection in all cell populations except plasmacytoid DCs using a CAR-independent process. Lf caused phenotypic differentiation of the DCs, but cell activation played only a minor role in the increase in infection frequencies. The C-type lectin receptor DC-SIGN facilitated viral entry of rAd5-Lf complexes and this was dependent on high-mannose-type N-linked glycans on Lf. These results suggest that Lf present at high levels at mucosal sites can facilitate rAd5 attachment and enhance infection of DCs. A better understanding of the tropism and receptor mechanisms of Ad5 may help explain Ad5 pathogenesis and guide the engineering of improved rAd vectors.
Adams
William C
WC
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.|The Swedish Institute for Infectious Disease Control, Stockholm, Sweden.|Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Bond
Emily
E
The Swedish Institute for Infectious Disease Control, Stockholm, Sweden.|Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Havenga
Menzo J E
MJE
TNO Biosciences, Leiden, The Netherlands.
Holterman
Lennart
L
Crucell Holland, Leiden, The Netherlands.
Goudsmit
Jaap
J
Crucell Holland, Leiden, The Netherlands.
Karlsson Hedestam
Gunilla B
GB
The Swedish Institute for Infectious Disease Control, Stockholm, Sweden.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Koup
Richard A
RA
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Loré
Karin
K
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.|Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
D000260:Adenoviruses, Human / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003713:Dendritic Cells / Q000821:virology*; D006801:Humans; D007781:Lactoferrin; D037181:Lectins, C-Type / Q000502:physiology*; D009000:Monocytes / Q000821:virology; D011956:Receptors, Cell Surface / Q000502:physiology*; D011991:Receptors, Virus / Q000502:physiology*; D053585:Virus Attachment; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007781:Lactoferrin; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011991:Receptors, Virus; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C568771:CLMP protein, human; C490098:LTF protein, human; C085301:adenovirus receptor