Researchers at the Tokyo University of Science have developed a miniature biomimetic model of the human intestine that, for the first time, has enabled long-term infection with Enterovirus A71 (EV-A71) to be reproduced under laboratory conditions.

The study, published in the Journal of Virology, sheds new light on how the virus persists in the intestine while triggering only a minimal immune response. The findings could help accelerate the development of new antiviral therapies.

EV-A71 is a common pathogen that primarily affects infants and young children. It is best known for causing hand, foot, and mouth disease, which typically produces mild symptoms such as fever and skin rashes. In some cases, however, the virus can spread to the central nervous system and cause serious complications, including encephalitis and meningitis, both of which can be life-threatening.

Despite decades of research, no specific approved treatment for EV-A71 infection currently exists.

One major obstacle has been the limited understanding of how the virus behaves within the human intestine, its primary site of infection. Traditional models based on animals or cancer-derived cell lines fail to accurately replicate the structure and function of human intestinal tissue. More advanced organoid systems also have limitations because they do not fully reproduce the diversity and organization of cells found in the intestine.

To address these challenges, a team led by Kazuo Takayama, graduate researcher Hiroki Futagasako, and associate professor Sayaka Deguchi developed a microphysiological “gut-on-a-chip” system.

The model was constructed using human embryonic stem cells and incorporates multiple intestinal cell types, including enterocytes, goblet cells, and fibroblasts. As a result, it more closely mimics the architecture and biological behavior of real intestinal tissue.

After infecting the system with EV-A71, researchers monitored viral replication and tissue integrity for 14 days. Unlike conventional cell cultures, which rapidly deteriorate after infection, the miniature intestinal model maintained its structural integrity and supported long-term viral replication without significant tissue damage.

One of the most important findings was that the virus triggered only a weak interferon response. Interferons are key signaling molecules involved in the body's innate antiviral defense. Their secretion remained largely unchanged following infection, which may help explain how EV-A71 can persist in the intestine for extended periods without causing obvious symptoms.

When researchers introduced recombinant interferons, however, antiviral genes were strongly activated and levels of viral RNA dropped substantially.

These results suggest that EV-A71 may evade early immune detection by suppressing or avoiding the normal interferon response, allowing it to establish a relatively quiet infection within intestinal tissue.

Beyond revealing important aspects of the virus’s biology, the new gut-on-a-chip platform may serve as a valuable tool for testing antiviral drugs and investigating other intestinal infections. By providing a more realistic model of human gut tissue, it offers researchers a promising way to study how pathogens interact with the body and how those interactions might be disrupted therapeutically.