By designing a new organoid ‘mini gut’ model, scientists from the Wellcome Sanger Institute, the University of Manchester and collaborators identified the early immune response to whipworms.
This research, published 1 April 2022, in Nature Communications, could help in the design of future treatments and vaccines for trichuriasis, the disease caused by the whipworm parasite Trichuris trichiura. In addition, understanding how the parasite remains burrowed into the lining of the gut for years, by modulating our immune response, could lead to new insights into the control of inflammatory diseases such as Inflammatory Bowel Disease and asthma.
Trichuriasis is a neglected tropical disease that affects as many as 500 million people worldwide1, most commonly in tropical and subtropical regions, including sub-Saharan Africa, the Americas, China, and East Asia1. However, the whipworm was once globally distributed, suggesting that it evolved alongside humans until improved sanitation systems were developed in some areas, wiping it out.
Chronic whipworm infections can cause a range of debilitating gastrointestinal issues, nutritional deficiencies, and are linked to delays in physical and cognitive development, especially in children1. There are few treatments available and they are not effective in completely eradicating the infection.
Studying early infection in humans is not possible due to the ethical implications of giving participants whipworms, and the technical challenge of dealing with its microscopic size and a lack of fluorescent markers that would be needed to find it in patients. However, mice are infected by another whipworm species, and this infection closely mirrors the one in humans, enabling researchers to use this mouse model to investigate the steps involved.
In this new study, researchers from the Wellcome Sanger Institute, the University of Manchester and their collaborators developed organoids or ‘mini guts’ that can be grown in the lab from mouse gut cells to investigate the early stages and mechanisms of infection in more detail. This is the first time that this model has been used to study multicellular parasites, and paves the way for similar research in the future using the human whipworm. It is hoped that mini-guts could be used to reduce or replace mouse models in future research.
The team used single-cell sequencing technologies on the cells from whipworm-infected mice to uncover the body’s response to the worm tunnelling into the gut lining, where it resides. They found that the response of the gut lining is different to infection with other parasites, and in this case it is more similar to what happens when a virus enters the body. Identifying the early stages in the immune response to whipworms could help develop new treatments or vaccines against this parasite by blocking its key interactions with the host.
Dr Maria Duque-Correa, first author from the Wellcome Sanger Institute, said: “This is the first time that these ‘mini guts’ have been used to study infection from a multicellular parasite, and our research has demonstrated the impact of this approach. Using organoids, infections can be studied at a level of detail than was previously impossible, opening the door to new understanding that can hopefully lead to the development of novel treatments.”
Professor Richard Grencis, co-senior author from the University of Manchester, said: “Our research identified a new early immune response that is different to the ones we’ve seen previously in parasitic infections. We found that when the whipworm entered the gut, the cells that are found in the gut lining responded by activating a response similar to that of a viral infection. Further research into how this response is triggered, could lead to new ways to prevent infection.”
Dr Matthew Berriman, co-senior author from the Wellcome Sanger Institute, said: “The whipworm, Trichuris trichiura impacts millions of lives every year, there is no available vaccine and therapies to treat the disease are not effective. Our research is the first to shed light on the early stages of infection with this parasite and, armed with this new tool of organoid-based methods, we are opening up a new discovery path for the trichuriasis drug targets of the future.”