As a group of infections, diarrheal diseases still rank as some of the leading causes of death worldwide. While we often things of adenoviruses (AdVs) infecting the respiratory tract and conjunctiva of the eye, many other species of AdVs can inhabit the gastrointestinal tract, causing severe diarrhea. These enteric AdVs are estimated to kill more than 50,000 children under the age of five each year, mainly in developing countries. Understanding the structure of enteric AdVs would be enormously helpful in developing therapeutics, such as vaccines, to help control infection rates.

Now, a team of investigators led by scientists at Umeå University in Sweden has determined the structure of the human AdV (HAdV)-F41, known to cause severe disease, using a cryo-electron microscopy to a resolution of 3.8 Å. Findings from the new study were published recently in Science Advances through an article titled, “The structure of enteric human adenovirus 41—A leading cause of diarrhea in children.”

“The findings provide an increased understanding of how the virus gets through the stomach and intestinal system,” noted senior study investigator Lars-Anders Carlson, PhD, a group leader at Umeå University. “Continued research can provide answers to whether this property can also be used to create vaccines that ride ‘free rides’ and thus be given in edible form instead of as syringes.”

Most adenoviruses are respiratory, that is, they cause respiratory disease, while the lesser-known enteric variants of adenovirus instead cause gastrointestinal disease. The enteric adenoviruses, therefore, need to be equipped to pass through the acidic environment of the stomach without being broken down so that they can then infect the intestines.

With the help of the advanced cryo-electron microscope available in Umeå, the researchers have now managed to take such detailed images of an enteric adenovirus that it has been possible to put a three-dimensional puzzle that shows what the virus looks like right down to the atomic level. The virus is one of the most complex biological structures studied at this level. The shell that protects the virus’s genome when it is spread between humans consists of two thousand protein molecules with a total of six million atoms.

“We presented 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 authors wrote. “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.”

The researchers were able to see that the enteric adenovirus manages to keep its structure basically unchanged at the low pH value found in the stomach. They could also see other differences compared to respiratory adenoviruses in how a particular protein is altered in the shell of the virus, as well as new clues to how the virus packs its genome inside the shell. All in all, it provides an increased understanding of how the virus manages to move on to create disease and death.

Interestingly, several of the new vaccines being tested against COVID-19 are based on genetically modified adenovirus. Today, these adenovirus-based vaccines must be injected to work in the body. If a vaccine could instead be based on enteric adenovirus, the vaccine might be given in the edible form. This would, of course, facilitate large-scale vaccination.

“The hope is that you will be able to turn the ability that this unpleasant virus has to get to something that can instead be used as a tool to fight disease, perhaps even COVID-19. This is a step in the right direction, but it is still a long way off,” concluded Carlson.

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