The Adenovirus Dodecahedron: Beyond the Platonic Story

Abstract

Many geometric forms are found in nature, some of them adhering to mathematical laws or amazing aesthetic rules. One of the best-known examples in microbiology is the icosahedral shape of certain viruses with 20 triangular facets and 12 edges. What is less known, however, is that a complementary object displaying 12 faces and 20 edges called a 'dodecahedron' can be produced in huge amounts during certain adenovirus replication cycles. The decahedron was first described more than 50 years ago in the human adenovirus (HAdV3) viral cycle. Later on, the expression of this recombinant scaffold, combined with improvements in cryo-electron microscopy, made it possible to decipher the structural determinants underlying their architecture. Recently, this particle, which mimics viral entry, was used to fish the long elusive adenovirus receptor, desmoglein-2, which serves as a cellular docking for some adenovirus serotypes. This breakthrough enabled the understanding of the physiological role played by the dodecahedral particles, showing that icosahedral and dodecahedral particles live more than a simple platonic story. All these points are developed in this review, and the potential use of the dodecahedron in therapeutic development is discussed.

Keywords: Adenovirus; Dodecahedron; Platonic solids; Receptors; Structure; Vaccines; Viral spreading.; Virus Like Particles.

Figure 1

Schematic view of adenovirus. The icosahedral capsid is formed by the hexon. The penton base is located at the 12 vertices and forms a non-covalent complex with the trimeric fiber. The fiber’s knob domain is responsible for the interaction with the receptors.

Figure 2

Adenovirus dodecahedron formation and internalization. (a) Z-series of Hela cells infected for 16 h by wt-HAdV3. Nuclei are stained in red and the penton base is detected in green. The penton base is synthesized in the cytoplasm and transported to the nucleus (yellow results from superposition of the red and green signals) where dodecahedron assembly takes place. (b) Electron microscopy images of the purified adenovirus and (Pt-Dd) ‘penton dodecahedrons’ (bars: 90 and 30 nm, respectively). (c) Hela cells incubated with recombinant Pt-Dd for 1 h. Cell shapes were observed by DIC, nuclei are stained in blue, and Pt-Dd are detected in green.

Figure 3

Recombinant HAdV3 dodecahedrons pseudotyped with different fibers. (a) Base Dodecahedron (Bs-Dd) coexpressed with its corresponding HAdV3 fibers, (b) the enteric HAdV41 short fiber, or (c) co-incubated with the HAdV2 fiber are observed by negative staining at the same scale (Bars: 30 nm).

Figure 4

Contact between adjacent pentamers of a dodecahedron. (a) Bottom view of a single pentamer with D100 highlighted in magenta and R425 in light blue. (b) Zoomed-in slab view of a dodecahedron (grey mesh) showing contacts made by D100 and R425 from adjacent pentamers (PDB 6HCR.).

Figure 5

Biological function of the dodecahedron ‘pseudovirus’. Pt-Dd facilitates virus spreading by both interacting with DSG2 and acting as a decoy. (a) Pt-Dd binds to the virus receptor desmoglein 2 located in desmosomes and induces an epithelial to mesenchymal transition (EMT) through MAP kinase signaling and activation of the ADAM17 matrix-metalloproteinase. Moreover, competition between Pt-Dd and virions for DSG2 forces virions to spread in the tissue. (b) At the same time, Pt-Dd traps Human Defensin (HD)5, which is known to block adenovirus infection by stabilizing the capsid, thus preventing pVI release and subsequent endosomolysis. By acting as a decoy, Pt-Dd protects neo-virions from defensin attack. Figure created with BioRender.com.

Figure 6

Biotechnological applications of the dodecahedron ‘pseudovirus’. (a) The dodecahedron ‘pseudovirus’ can be used to deliver DNA due to a bispecific peptide or proteins of interest fused to the WW domains. (b) The dodecahedron ‘pseudovirus’ can be used as a therapeutic adjuvant by triggering cell remodeling by making hidden targets accessible to therapeutic monoclonal antibodies (MAbs) or by enabling better access to chemotherapeutic compounds. (c) For vaccine purposes, cancer antigens fused to WW domains can be grafted to Bs-Dd. Alternatively, a single particle can be produced to display epitopes from pathogens, such as emergent viruses. Figure created with BioRender.com.