Human non-polio EVs are an emerging human health threat and result in a high burden on healthcare. EVs are among the most common infections in mankind, with 10–15 million infections and at least 30,000–50,000 hospitalisations (mostly meningitis) per year in the United States. Over the last decade, several EV outbreaks have been reported in Europe, Asia, the US, and Australia causing thousands of cases of Central Nervous System (CNS) infections with increased child mortality. EVs use the faecal-oral route for entry but questions remain on the mechanism of entry in the gut, and the way the virus spreads to the CNS. This complicated pathogenesis is difficult to mimic in animal models and there is no antiviral treatment available. Understanding disease, as well as the availability of a better testing platform, are needed to develop accurate treatment strategies.

HIV is a major global health threat with nearly 2 million new infections each year. The gut is an important portal of entry during mother-to-child transmission as well as during sexual intercourse, as it houses the largest mass of lymphoid cells in the body. HIV can enter the CNS within days after primary infection, posing a major threat to neurodevelopment and cognitive functioning. Combination antiretroviral therapy (cART) is highly effective in suppressing viral replication. However, HIV persists in long-lived cells, rapidly rebounding when cART is halted. Many efforts are ongoing to explore novel treatments to eradicate these latent HIV reservoirs prominent in gut and brain tissues and to obtain a complete cure for HIV. However, this research is hampered by the lack of human model systems in which the different anatomical reservoirs and the viral dynamics can be studied.

HuNoV is the main cause of viral gastroenteritis and causes 700 million infections each year leading to 219,000 deaths and 60 billion dollars in societal costs. HuNoV follows the faecal-oral route to infect the intestinal epithelium, replicating in both the enterocytes and immune cells, and inducing vomiting and diarrhoea. Historically, HuNoV lacked cultivation systems which have been addressed with reports of successful HuNoV replication in gut organoids. However, several questions regarding HuNoV infection cannot be studied on single organ systems. For instance, the indirect mechanism through which HuNoV interacts with the brain to induce disease and whether it encodes for an enterotoxin is not known. Furthermore, the interaction with immune cells and their role in disease needs to be elucidated. There is currently no antiviral treatment available.