The structure of enteric human adenovirus 41—A leading cause of diarrhea in children

Abstract

Human adenovirus (HAdV) types F40 and F41 are a prominent cause of diarrhea and diarrhea-associated mortality in young children worldwide. These enteric HAdVs differ notably in tissue tropism and pathogenicity from respiratory and ocular adenoviruses, but the structural basis for this divergence has been unknown. Here, we present the first structure of an enteric HAdV—HAdV-F41—determined by cryo–electron microscopy to a resolution of 3.8 Å. The structure reveals extensive alterations to the virion exterior as compared to nonenteric HAdVs, including a unique arrangement of capsid protein IX. The structure also provides new insights into conserved aspects of HAdV architecture such as a proposed location of core protein V, which links the viral DNA to the capsid, and assembly-induced conformational changes in the penton base protein. Our findings provide the structural basis for adaptation of enteric HAdVs to a fundamentally different tissue tropism.

Adenovirus Structure: What Is New?

“…The penton base protein folds into two domains: a single jellyroll and an upper insertion facing the solvent-exposed exterior ( Figure 2 b) [ 44 , 51 ]. This upper domain contains the hypervariable loop, which due to its flexibility, has not been traced in any of the available HAdV structures [ 7 , 27 , 29 , 30 , 51 ]. In most human adenoviruses, the hypervariable loop bears the RGD sequence, an α v integrin-binding motif.…”

“…This disordered part is absent in Atadenoviruses, which have a shorter penton base protein and also lack the mobile, variable loops on the outer surface, as observed for the hexon HVRs [ 31 ]. Comparison of a high-resolution structure of recombinant HAdV-F41 penton base with the same protein in the context of the virion has shown that regions of the protein involved in interactions with the peripentonal hexons, fiber, and protein IIIa are disordered in solution, but become ordered upon capsid assembly [ 27 ]. Virus-like particles can be formed by penton base pentamers of certain HAdV species assembling in dodecahedra, with uses in receptor identification, gene delivery, and vaccine development [ 55 ].…”

“…The two larger products of protein VIII maturation have been modeled in all available high-resolution structures of adenovirus virions [ 7 , 27 , 28 , 29 , 30 , 31 ]. The excised central peptides have lower sequence conservation, vary in size among different adenoviruses, and do not seem to follow the icosahedral symmetry.…”

“…Surprisingly, in the enteric HAdV-F41 capsid there is no density corresponding to the C-terminal 4-helix bundle at the icosahedron edges as in HAdV-C5 and HAdV-D26 [ 27 , 30 ]. Blurry density on top of the triskelions at the L3 axis suggests a conformation similar to the non-human Mastadenoviruses, but there is not any density, even weak, which could account for a helix bundle on top of the I3 triskelion.…”

Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

“…Unlike most other HAdVs, which can infect cells of multiple organs, enteric HAdVs exclusively infect the intestinal tract and do not cause any infections at other sites. We recently showed that this restricted tropism can be attributed to differences in the external structure of the virion as compared to respiratory and ocular HAdVs [28]. The restricted tropism has also been suggested to depend on the ability of the SF of HAdV-F40 and HAdV-F41 to protect the virus against acidic gastric conditions [29,30].…”