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Firewalls Prevent Systemic Dissemination of Vectors Derived from Human Adenovirus Type 5 and Suppress Production of Transgene-Encoded Antigen in a Murine Model of Oral Vaccination.

Authors
  • Revaud, Julien1, 2
  • Unterfinger, Yves1
  • Rol, Nicolas3
  • Suleman, Muhammad1
  • Shaw, Julia1
  • Galea, Sandra1
  • Gavard, Françoise1
  • Lacour, Sandrine A1
  • Coulpier, Muriel1
  • Versillé, Nicolas2
  • Havenga, Menzo4
  • Klonjkowski, Bernard1
  • Zanella, Gina5
  • Biacchesi, Stéphane6
  • Cordonnier, Nathalie1
  • Corthésy, Blaise3
  • Ben Arous, Juliette2
  • Richardson, Jennifer P1
  • 1 UMR Virologie INRA, Ecole Nationale Vétérinaire d'Alfort, ANSES, Université Paris-Est, Maisons-Alfort, France. , (France)
  • 2 SEPPIC Paris La Défense, Paris, France. , (France)
  • 3 R&D Laboratory, Division of Immunology and Allergy, Centre des Laboratoires d'Epalinges, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. , (Switzerland)
  • 4 Batavia Biosciences B.V., Leiden, Netherlands. , (Netherlands)
  • 5 Anses, Epidemiology Unit, Laboratoire de Santé Animale, Université Paris-Est, Maisons-Alfort, France. , (France)
  • 6 VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France. , (France)
Type
Published Article
Journal
Frontiers in Cellular and Infection Microbiology
Publisher
Frontiers Media SA
Publication Date
Jan 01, 2018
Volume
8
Pages
6–6
Identifiers
DOI: 10.3389/fcimb.2018.00006
PMID: 29423380
Source
Medline
Keywords
License
Unknown

Abstract

To define the bottlenecks that restrict antigen expression after oral administration of viral-vectored vaccines, we tracked vectors derived from the human adenovirus type 5 at whole body, tissue, and cellular scales throughout the digestive tract in a murine model of oral delivery. After intragastric administration of vectors encoding firefly luciferase or a model antigen, detectable levels of transgene-encoded protein or mRNA were confined to the intestine, and restricted to delimited anatomical zones. Expression of luciferase in the form of multiple small bioluminescent foci in the distal ileum, cecum, and proximal colon suggested multiple crossing points. Many foci were unassociated with visible Peyer's patches, implying that transduced cells lay in proximity to villous rather than follicle-associated epithelium, as supported by detection of transgene-encoded antigen in villous epithelial cells. Transgene-encoded mRNA but not protein was readily detected in Peyer's patches, suggesting that post-transcriptional regulation of viral gene expression might limit expression of transgene-encoded antigen in this tissue. To characterize the pathways by which the vector crossed the intestinal epithelium and encountered sentinel cells, a fluorescent-labeled vector was administered to mice by the intragastric route or inoculated into ligated intestinal loops comprising a Peyer's patch. The vector adhered selectively to microfold cells in the follicle-associated epithelium, and, after translocation to the subepithelial dome region, was captured by phagocytes that expressed CD11c and lysozyme. In conclusion, although a large number of crossing events took place throughout the intestine within and without Peyer's patches, multiple firewalls prevented systemic dissemination of vector and suppressed production of transgene-encoded protein in Peyer's patches.

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