Transduction of skin-migrating dendritic cells by human adenovirus 5 occurs via an actin-dependent phagocytic pathway

Abstract

Dendritic cells (DC) are central to the initiation of immune responses, and various approaches have been used to target vaccines to DC in order to improve immunogenicity. Cannulation of lymphatic vessels allows for the collection of DC that migrate from the skin. These migrating DC are involved in antigen uptake and presentation following vaccination. Human replication-deficient adenovirus (AdV) 5 is a promising vaccine vector for delivery of recombinant antigens. Although the mechanism of AdV attachment and penetration has been extensively studied in permissive cell lines, few studies have addressed the interaction of AdV with DC. In this study, we investigated the interaction of bovine skin-migrating DC and replication-deficient AdV-based vaccine vectors. We found that, despite lack of expression of Coxsackie B–Adenovirus Receptor and other known adenovirus receptors, AdV readily enters skin-draining DC via an actin-dependent endocytosis. Virus exit from endosomes was pH independent, and neutralizing antibodies did not prevent virus entry but did prevent virus translocation to the nucleus. We also show that combining adenovirus with adjuvant increases the absolute number of intracellular virus particles per DC but not the number of DC containing intracellular virus. This results in increased trans-gene expression and antigen presentation. We propose that, in the absence of Coxsackie B–Adenovirus Receptor and other known receptors, AdV5-based vectors enter skin-migrating DC using actin-dependent endocytosis which occurs in skin-migrating DC, and its relevance to vaccination strategies and vaccine vector targeting is discussed.

Recombinant Human Adenovirus Type 5 Co-expressing RABV G and SFTSV Gn Induces Protective Immunity Against Rabies Virus and Severe Fever With Thrombocytopenia Syndrome Virus in Mice

“…DCs are the core of the initiation of immune response, assist to induce antigen-specific immune responses, and development of vaccines targeting DCs can increase the immunogenicity of vaccines (Hsu et al, 1996;Guzman et al, 2016). In the current study, more DCs were activated in Ad5-G-Gn immunized mice than that in Ad5-GFP or mock immunized mice.…”

A comparative review of viral entry and attachment during large and giant dsDNA virus infections

“…Other cellular receptors targeted by adenoviruses include CD46, CD80, CD86, desmoglein-2, heparan sulphate, sialic acid, major histocompatibility complex-1-α2, and vascular cell adhesion molecule-1. Ad-2, Ad-5 and egg drop syndrome virus enter host cells via clathrin-mediated endocytosis [ 36 – 38 ], whereas Ad-3, Ad-5 and Ad-35 enter via macropinocytosis [ 37 , 39 ]. Longer lists of cellular receptors and entry pathways exploited by adenoviruses are given in Tables 2 and 3 .…”

“…The cell types used in entry assay are mentioned whenever possible; otherwise, multiple cells might be used. “∞” means “interacts with” Virus Cells Entry method and/or attachment receptors Adenoviruses Ad-2/5 – Clathrin, myeloid, and αvβ3- and αvβ5-integrins-mediated endocytosis [ 36 , 90 ] Ad-2 – Macropinocytosis [ 90 ] Ad-5 Afferent lymph DCs Actin-dependent macropinocytosis [ 39 ] Ad-3/35 EpC and haematopoietic PI3K, Rho GTPases and dynamin-dependent macropinocytosis [ 37 , 91 ] Egg drop syndrome virus Duck embryonic FbCs Low pH, clathrin-mediated endocytosis [ 38 ] Herpesviruses HSV-1 HeLa, CHO and keratinocytes, but not neuroblastoma Low-pH endocytosis [ 92 – 94 ] Vero cells Fusion [ 92 ] CHO Viral gB and gD, and cellular Nectin-1, HVEM and PILR-α are required for infection; gD ∞ Nectin-1 and gB ∞ PILR-α [ 95 ]; gD ∞ Nectin-1 and gB ∞ PILR-α [ 96 – 99 ] EpC, neuron and keratinocytes gH/gL (RGD motif) ∞ αvβ6- and αvβ8-integrins [ 100 ]; gH/gL binds to αvβ3-integrin activating IFN-I and NF-κB [ 101 ] CHO, HeLa, Vero gD ∞ HVEM [ 102 , 103 ] HeLa Syn...…”