Why study ?

Emerging infectious diseases (EID) pose a global health concern with significant human and economic losses. This is apparent from the recent COVID-19 pandemic that has brought the world to a standstill. As The Program for Monitoring Emerging Diseases highlights, EID outbreaks are a constant in the evolutionary race against disease-causing pathogens. In addition to the current pandemic, the 2009 swine flu pandemic, Ebola virus epidemic, and Zika virus epidemic serve as reminders of this burden.

 

Within this project, GUTVIBRATIONS will investigate Enterovirus (EV), Human immunodeficiency virus (HIV) and Human Norovirus (HuNoV).

Enterovirus (EV)

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 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.

Human immunodeficiency virus (HIV)

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.

Human norovirus (HuNoV)

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.

Our approach

A part of the preparedness against EID is having ready-to-use models that are better predictors of disease outcome, immune response, and potential therapeutics. Such models are critical for combatting viruses as they are obligate parasites that require a host and utilise specific host adaptation strategies that cannot always be replicated in an animal model. To this end, GUTVIBRATIONS will develop a multi-organ gut-brain axis organ-on-chip to study the complex viral-host interaction in the human body and to move therapeutic development against viruses forward.