Using helminth secreted proteins to treat pathology in a chronic model of asthma

Abstract

Helminths are parasitic worms. Some helminths infect humans, and cause longterm and recurring infections. Infection often comes from touching soil with helminth eggs or larvae in it. They can also infect from contaminated food and water. Helminth infections are common in many tropical areas. This includes Africa, South America, and some parts of south-east Asia.

Some people have helminth infections that last for decades, or their whole lives. Most other infections are quickly cleared by the host immune system. Since this doesn't happen to helminths, we know they do something to change or hide from the immune system. Scientists have found soluble molecules that helminths secrete, which suppress the immune response. By doing this, they can survive inside the host for longer.

The kind of immune response that happens against helminths is called type 2 immunity. This is the same kind of immune response involved in allergies and allergic diseases. Some types of asthma are mediated by type 2 immunity. This is what this study focuses on.

Asthma is one of the most common non-transmittable lung diseases in the world. More than 300 million people in the world have asthma, and since the 1960s, it has become a lot more common. Rates of asthma are highest in developed countries like the USA and UK. This could be because of how urbanised and high-sanitation these countries are. People living in these countries aren't exposed to as many germs or parasites. This means they aren't exposed to the factors helminths make to suppress type 2 immunity. This might be why allergies and asthma are so much more common in these places. Studies also show that after mass deworming, rates of asthma in an area increase.

Scientists have been working to characterise specific immunomodulatory molecules made by helminths. If we figure out which molecules are important and how they work, we can use them to develop new medicines.

Studying this is hard to do in humans. Mice have related parasites and similar immune responses, so we use them as models. In this project, we used molecules secreted by a murine hookworm, Heligmosomoides polygyrus bakeri. Two of them, HpARI and HpBARI, have been studied before in this lab. They target the IL-33/ST2 pathway, which is important for initiating allergic responses. HpARI binds to IL-33, a signalling chemical released when airways are damaged.

HpBARI binds to ST2, the IL-33 receptor. They are very effective at suppressing allergic responses in short-term models. We also studied two more recentlydescribed molecules. These are HpAPY-3 and HpDNAseII, which degrade ATP and DNA respectively. ATP and DNA are normally contained inside cells, but are released when allergens damage airways. Getting rid of them might help treat or prevent allergen-driven asthma.

In asthma, there are large numbers of eosinophils in the bronchoalveolar lavage (BAL). This is because eosinophils are important cells in the type 2 immune response. They are recruited to sites of inflammation. We measured the number of eosinophils in BAL to see if our proteins affected this. We also looked at the pathophysiology of the lungs using histology. This let us see lung inflammation and cellular infiltrate under the microscope. HpARI and HpBARI did not reduce eosinophil numbers or asthma pathology in this model. This might be because IL33/ST2 signalling is less important in this model. HpAPY-3 increased the numbers of eosinophils in BAL when we gave it at the start of the model. It didn't change anything when we gave it at the end of the model. HpDNAseII decreased the number of eosinophils when we gave it at the start of the model, but not at the end of the model. Antibodies were produced against HpBARI, HpARI, and HpAPY-3, but not HpDNAseII. This could be why HpDNAseII reduced eosinophil numbers and the other molecules didn't.

Date of Award	2024
Original language	English
Awarding Institution	University of Dundee
Supervisor	Henry McSorley (Supervisor) & Ignacio Moraga Gonzalez (Supervisor)