The enteric adenovirus types F40 and 41 (EAdVs) have lately been implicated in the development of acute hepatitis in children and are a major contributor to diarrhea and diarrhea-related mortality in children below the age of 5. EAdVs show a clear preference for the gastrointestinal tract, but other adenovirus types can cause disease in the eyes, lungs, liver, adenoids, and/or urinary tract. Although EAdVs are a frequent cause of disease in humans, little is known about how host factors and virus entry requirements interact. The primary cause of this is the difficulty in isolating and amplifying EAdV to large virus titers in cell culture. Much research has been done on A549 and HEK293 cells due to their meticulous nature, where EAdV entrance was sluggish, happened in a clathrin-independent way, and had ineffective endosomal escape. Earlier studies on EAdV infection in human ileal organoids were successful in amplifying the virus, but they were unsuccessful in identifying EAdV target cells. This emphasizes the necessity of investigating novel infection models in order to pinpoint the molecular factors behind the distinct EAdV tissue tropism.
Adenovirus. Credit: Dr. Victor Padilla-Sanchez, PhD
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Rapid viral internalization in HuTu80 cells
EAdV were notoriously picky and challenging to grow in tissue cultures to high infectious titers. We have seen that overall yields and infectious-to-non-infectious particle ratios for this particular adenovirus are still lower than for other adenoviruses like AdV5 and AdV-D. Although being a significant contributor to acute infant gastroenteritis, EAdV is still not well understood. Children with acute gastroenteritis have EAdVs in their stool samples, but it is unknown what cells or areas of the gastrointestinal tract these viruses initially target. Thus, research on virus entry uses readily available cell lines like HEK293 and A549 cells.
Recently, an investigation was conducted to evaluate the EAdV infection kinetics and cell entrance mechanism in duodenal HuTu80 cell lines to lung-derived A549 cell lines in order to find any potential cell type-specific benefits in cells originating from the gastrointestinal system. It was discovered that in HuTu80 cells, viral internalization was more rapid and clathrin-dependent, emphasizing the necessity of tissue-specific virus infection research. Given that the gastrointestinal tract is focused on the resorption of nutrients, it is tempting to hypothesize that the kinetic advantage is due to HuTu80 cells having a distinct total endocytic activity. Clathrin-mediated endocytosis is the primary entry channel of EAdVs into intestinal cells, according to the results of the pharmacological perturbation and RNA interference experiments. Findings imply that the clinically important but little-studied species F adenovirus possesses characteristics not shared by other adenoviruses that facilitate rapid entrance into cells of the digestive system. Various host cell requirements for absorption pathways have lately become apparent, as well as the translational implications of these requirements.
Clinical significance
The use of cell lines derived from various tissue origins will continue to be crucial for identifying and validating host variables during viral infections. In the study, duodenal cells are described as a novel research tool for the study of EAdV, and previously unrecognized features of the cell entry mechanisms of these medically significant viruses are revealed.
Conclusion
This work emphasizes the value of investigating host variables and infection pathways in suitable model systems. The significance of clathrin-mediated endocytosis was established, and it was shown that the viral host cell components necessary for virus entry are different between cell lines originating from different origins.
References
Becker, M., Conca, D. V., Dorma, N., Mistry, N., Hahlin, E., Frängsmyr, L., Bally, M., Arnberg, N., & Gerold, G. (2023). Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells. Journal of Virology, 97(10), e00770-23. https://doi.org/10.1128/jvi.00770-23
