Overview

Parasitic nematodes are very common parasites of people and animals. Approximately 1.5 billion people are infected with parasitic nematodes. Parasitic nematodes cause 4 of the World Health Organization’s 20 Neglected Tropical Diseases.

Many parasitic nematodes share a common feature in their life-cycles, by switching between free-living transmission phases and within-host parasitic phases. As parasites, they switch on a parasitism gene expression programme that lets them infect hosts. We are trying to discover how this switch works.

We are studying one particular parasitic nematode, Strongyloides. With Strongyloides, genetically identical worms in identical environments can have parasitic or free-living developmental fates, which we hypothesize is controlled by an epigenetic switch. We are investigating the role of histone protein post-translational modifications and small non-coding RNAs in controlling this epigenetic switch.

We hope that by understanding how this switch is controlled we will learn how to turn off parasites’ parasitism programmes, thus developing a whole new approach to reduce the burden of nematode infection in people.

This work is a joint project between Mark Viney (University of Liverpool) and Peter Sarkies (University of Oxford), and funded by the Wellcome Trust.

Parasitic nematodes

Nematodes are a group of round, unsegmented worms. They are the most abundant and speciose group of living animals. They can be free-living in most terrestrial and aquatic environments, but many species are parasites of animals and of plants. In nematodes’ evolutionary history they have repeatedly evolved to be parasites, which is a good example of convergent evolution.

Parasitic nematodes that infect mammals are very common – in fact most wild mammals are infected with parasitic nematodes. In general parasitic nematode are host specific, that is that one species of parasitic nematode can only infect one species of host, or a small number of often-related species of hosts. Parasitic nematodes can live in various parts of the body of their hosts, but many are parasites of the gut.

Gut parasitic nematodes of people are collectively known as the soil-transmitted helminthiases (STHs), which the World Health Organization classify as a Neglected Tropical Disease because they affect very many people in low and middle-income countries, but they are absent from the global health agenda. The STHs include the parasites Ascaris, hookworms, Trichuris and Strongyloides. These parasites live in peoples’ guts, and the parasite eggs come out in peoples’ faeces, so that stages ready to infect new hosts are in the soil. People get infected when the eggs develop into infective larvae that then penetrate host skin (Strongyloides and hookworms) or when people accidentally eat parasite eggs (Ascaris and Trichuris). Similar types of parasites infect most other animals, including livestock.

 

Mass Drug Administration

About 1.5 billion people are infected with STHs. These infections cause harm. According to the World Health Organization these infections cause more Years Lost to Disability than do malaria, TB or HIV/AIDS, though thankfully STHs very rarely kill people, unlike these other infections.

Because STH parasites are so common, many low and middle income countries have programmes of mass drug administration, where children are treated at least annually with so-called anthelmintic drugs that kill nematodes. While these drugs are currently effective and kill the worms, there is the worry that with the continued, widespread use of these drugs that the nematodes will become resistant to them.

 

Strongyloides

Strongylodies is one of the STHs. Two species infect humans. The most common is S. stercoralis which infects some 600 million people worldwide, and occurs throughout the tropics. The species S fuelleborni also infects people, though in two different settings. One, is in the island of New Guinea where it is an endemic infection in people, particularly of very young children. The other is a zoonosis from primates in some parts of Africa and in Asia, but this isn’t very well studied.

More generally, there are some 60 species of Strongyloides that infect a wide range of terrestrial tetrapods. These species of Strongyloides infect animals worldwide. For example, S. ratti infects rats, and about 60% of UK rats are infected with it. This is the species that we are studying because we can easily maintain it in the lab.

The Strongyloides life cycle has a quirk compared with most other gut parasitic nematodes. Inside the host, the parasitic stages are only female worms. They reproduce by parthenogenesis, meaning that there is no sexual reproduction. Eggs produced by these parasitic females get into the environment in the host faeces. There, the eggs can either develop into larvae ready to infect new hosts, or they can develop into adult female worms that themselves go through a round of sexual reproduction. Critically, the parasitic female and the free-living female worms are genetically identical, because they have the same genome, but they are quite different in what they look like, and how and where they live. These differences between them must therefore be because of epigenetics.

Epigenetics

How can the same genome produce two entirely different forms, one parasitic and one free living? We think that the answer lies in epigenetics. The information contained in the genome sequence is not enough to control how cells work, because each cell needs to know which genes to use and which to shut down. This extra level of information is known as ‘epigenetic’ and, importantly, it can be inherited when cells divide just like the DNA sequence. There are lots of different molecular ways in which epigenetic information is encoded and different methods are used in different organisms. In nematodes, a key aspect of epigenetic information are histone proteins that wrap DNA. The histone proteins can have chemical modifications, and different modifications are associated with genes that are active and genes that are shut down. Additionally, small RNA molecules that target genes can control which genes are used and which are shut down. Our hypothesis is that differences in histone protein modifications and in small non-coding RNAs controls whether Strongyloides is parasitic or free-living. We are trying to find out whether this is true. If we are successful it will potentially enable us to target these epigenetic mechanisms to prevent parasitic development, thus helping to combat Strongyloides infections in people.