Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections

Acute gastroenteritis caused by virus has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The main culprits are rotaviruses, noroviruses, sapoviruses, astroviruses, and enteric adenoviruses. Currently, there are no antiviral drugs available for the prevention or treatment of viral gastroenteritis. Here, we describe the antivirals that were identified as having in vitro and/or in vivo activity against these viruses, originating from in silico design or library screening, natural sources or being repurposed drugs. We also highlight recent advances in model systems available for this (hard to cultivate) group of viruses, such as organoid technologies, and that will facilitate antiviral studies as well as fill some of current knowledge gaps that hamper the development of highly efficient therapies against gastroenteric viruses.

Detection and molecular characterization of enteric adenovirus in treated wastewater in the Brazilian Federal District

Human enteric viruses, such as enteric adenoviruses (HAdV), are known to be involved with gastrointestinal disorders, especially acute gastroenteritis. Several studies have used HAdV as an indicator of water quality, since they are considered highly stable and widely distributed viruses in water matrices. The aim of this study was to detect and genotype HAdVs in water matrices impacted by discharges of treated effluents from wastewater treatment plants (WWTPs). Wastewater treatment plants from the sanitary system of the Brazilian Federal District were assessed in 2018 and 2019. Samples were collected upstream and downstream from discharge points for each WWTP. Viral concentration based on adsorption-elution and conventional PCR was used for molecular detection, and positive samples were sequenced for phylogenetic analysis. Pluviosity data for the period in which the samples were collected were obtained. Our results demonstrated the presence of HAdVs in 27.2% (61/224) of the samples. The positivity was significantly higher in downstream samples compared to upstream. Moreover, the HAdV positivity was higher in downstream samples collected from receiving water bodies impacted by secondary-level WWTPs in comparison with those impacted by tertiary-level WWTPs. Phylogenetic analysis demonstrated the presence of genotypes 40 and 41, with prevalence of HAdV genotype 41. Despite the predominance of HAdV-41, an increasing frequency of the HAdV-40 was associated with higher pluviosity. In conclusion, this study is the first documentation in the Brazilian Federal District dealing with the prevalence and diversity of HAdVs in several WWTP, along with their correlation with rainfall index.

Cryo-EM structure of enteric adenovirus HAdV-F41 highlights structural variations among human adenoviruses

Enteric adenoviruses, one of the main causes of viral gastroenteritis in the world, must withstand the harsh conditions found in the gut. This requirement suggests that capsid stability must be different from that of other adenoviruses. We report the 4-Å-resolution structure of a human enteric adenovirus, HAdV-F41, and compare it with that of other adenoviruses with respiratory (HAdV-C5) and ocular (HAdV-D26) tropisms. While the overall structures of hexon, penton base, and internal minor coat proteins IIIa and VIII are conserved, we observe partially ordered elements reinforcing the vertex region, which suggests their role in enhancing the physicochemical capsid stability of HAdV-F41. Unexpectedly, we find an organization of the external minor coat protein IX different from all previously characterized human and nonhuman mastadenoviruses. Knowledge of the structure of enteric adenoviruses provides a starting point for the design of vectors suitable for oral delivery or intestinal targeting.

Cryo-EM structure of enteric adenovirus HAdV-F41 highlights structural divergence among human adenoviruses

Enteric adenoviruses are one of the main causes of viral gastroenteritis in the world. To carry out a successful infection, the virions must withstand the harsh conditions found in the gut. This requirement suggests that capsid stability must be different from that of other adenoviruses. We have determined the structure of a human enteric adenovirus, HAdV-F41, at 4.0 Å resolution by single particle averaging cryo-electron microscopy, and compared it with that of other adenoviruses with respiratory (HAdV-C5) and ocular (HAdV-D26) tropisms. While the overall structures of hexon, penton base and internal minor coat proteins IIIa and VIII are conserved, we observe partially ordered elements reinforcing the vertex region, which suggests their role in enhancing the physicochemical capsid stability of HAdV-F41. Unexpectedly, we find an organization of the external minor coat protein IX different from all previously characterized human and non-human mastadenoviruses. Knowledge of the structure of enteric adenoviruses can provide a starting point for the design of vectors suitable for oral delivery or intestinal targeting.

Virus infections causing diarrhoea and vomiting

Acute gastroenteritis is frequently caused by rotaviruses, human caliciviruses (noroviruses, sapoviruses), astroviruses, and enteric adenoviruses (group F): these cause much disease worldwide and considerable mortality, mainly in developing countries. Other viruses found in the human gastrointestinal tract are not regularly associated with diarrhoeal disease, except in patients who are immunosuppressed and in whom herpes simplex virus, cytomegalovirus, and picobirnaviruses can cause diarrhoea, as can HIV itself. Following an incubation period of 1–2 days, there is sudden onset of watery diarrhoea lasting between 4 and 7 days, vomiting, and varying degrees of dehydration. Other features include abdominal cramps, headache, myalgia, and fever. Treatment is supportive, mainly with oral rehydration solutions or—in more severe cases—intravenous rehydration. Continued feeding is recommended, with zinc supplementation in areas where micronutrient deficiency may be present.

Adenovirus Infection of Human Enteroids Reveals Interferon Sensitivity and Preferential Infection of Goblet Cells

ABSTRACTHuman adenoviruses (HAdV) are significant human pathogens. Although only a subset of HAdV serotypes commonly cause gastroenteritis in humans, most HAdV species replicate in the gastrointestinal tract. Knowledge of the complex interaction between HAdVs and the human intestinal epithelium has been limited by the lack of a suitable cell culture system containing relevant cell types. Recently, this need has been met by the stable and prolonged cultivation of primary intestinal epithelial cells as enteroids. Human enteroids have been used to reveal novel and interesting aspects of rotavirus, norovirus, and enterovirus replication, prompting us to explore their suitability for HAdV culture. We found that both prototype strains and clinical isolates of enteric and nonenteric HAdVs productively replicate in human enteroids. HAdV-5p, a respiratory pathogen, and HAdV-41p, an enteric pathogen, are both sensitive to type I and III interferons in human enteroid monolayers but not A549 cells. Interestingly, HAdV-5p, but not HAdV-41p, preferentially infected goblet cells. And, HAdV-5p but not HAdV-41p was potently neutralized by the enteric human alpha-defensin HD5. These studies highlight new facets of HAdV biology that are uniquely revealed by primary intestinal epithelial cell culture.IMPORTANCEEnteric adenoviruses are a significant cause of childhood gastroenteritis worldwide, yet our understanding of their unique biology is limited. Here we report robust replication of both prototype and clinical isolates of enteric and respiratory human adenoviruses in enteroids, a primary intestinal cell culture system. Recent studies have shown that other fastidious enteric viruses replicate in human enteroids. Therefore, human enteroids may provide a unified platform for culturing enteric viruses, potentially enabling isolation of a greater diversity of viruses from patients. Moreover, both the ability of interferon to restrict respiratory and enteric adenoviruses and a surprising preference of a respiratory serotype for goblet cells demonstrate the power of this culture system to uncover aspects of adenovirus biology that were previously unattainable with standard cell lines.