The structure and function of nematode pathogenicity islands
Lead Research Organisation:
University of Liverpool
Department Name: Evolution, Ecology and Behaviour
Abstract
Parasitic nematode worms are some of the most abundant parasites on the planet - it is normal for animals and plants to be infected with them. Nematode worms infect about a quarter of people on the planet, mainly the young and poor in the developing world. They are also important parasites of livestock, and continued production of meat, milk, wool etc. requires controlling these parasites.
Despite the ubiquity and importance of these parasites, we don't understand how they harm their hosts. Specifically, we don't understand what genes they use to live inside their hosts and to feed on them, but it is this which ultimately harms hosts. If we understand more about these genes we could better predict how these might evolve and we could think about new ways to better control these parasites, which we need to do to protect human and animal health, and to secure food production.
We have discovered 12 concentrated sets of genes that we think control infection by a parasitic nematode. Looking at our pilot data we see that these sets of genes differ a lot among different individual worms and we think this is a tell-tale sign that the worms are using these sets of genes to compete with one another inside the host, and that this competition is driving the harm that these parasites cause to their hosts.
We are now proposing to investigate these sets of genes is more detail, to very precisely understand how they differ among individual worms, and to see whether or not different genetic types naturally occur together inside a host. By looking at the gene sequences we'll also predict which worms should be most different from each other in how they infect hosts, and then we'll test this in experiments with laboratory animals. In this way our work will move from just comparing gene sequences to also testing how nematode worms actually infect hosts. We will study this in a nematode parasite called Strongyloides that naturally infects rats in the UK, but which we can also study in the lab.
By testing our ides we will establish whether or not we have discovered the sets of genes that parasitic nematodes use to infect hosts. If so, this opens up a whole new understanding of how nematode worms infect and cause harm to their hosts, which can then be used to better understand, predict and treat these infections in the future.
Despite the ubiquity and importance of these parasites, we don't understand how they harm their hosts. Specifically, we don't understand what genes they use to live inside their hosts and to feed on them, but it is this which ultimately harms hosts. If we understand more about these genes we could better predict how these might evolve and we could think about new ways to better control these parasites, which we need to do to protect human and animal health, and to secure food production.
We have discovered 12 concentrated sets of genes that we think control infection by a parasitic nematode. Looking at our pilot data we see that these sets of genes differ a lot among different individual worms and we think this is a tell-tale sign that the worms are using these sets of genes to compete with one another inside the host, and that this competition is driving the harm that these parasites cause to their hosts.
We are now proposing to investigate these sets of genes is more detail, to very precisely understand how they differ among individual worms, and to see whether or not different genetic types naturally occur together inside a host. By looking at the gene sequences we'll also predict which worms should be most different from each other in how they infect hosts, and then we'll test this in experiments with laboratory animals. In this way our work will move from just comparing gene sequences to also testing how nematode worms actually infect hosts. We will study this in a nematode parasite called Strongyloides that naturally infects rats in the UK, but which we can also study in the lab.
By testing our ides we will establish whether or not we have discovered the sets of genes that parasitic nematodes use to infect hosts. If so, this opens up a whole new understanding of how nematode worms infect and cause harm to their hosts, which can then be used to better understand, predict and treat these infections in the future.
Technical Summary
Parasitic nematodes are very common and important parasites in natural ecosystems, in livestock, and in human populations, but we do not understand how they compete to exploit their hosts, nor how they are pathogenic to hosts, nor how their pathogenicity evolves. In microparasites, these phenomena are well understood and often effected by pathogenicity islands.
We have discovered genomic clusters of highly-diverse, transposon-enriched parasitism genes in the parasitic nematode Strongyloides that we think are "pathogenicity islands". We call these pathogenicity islands by analogy with bacterial pathogenicity islands because: (i) they are large genomic features and (ii) we hypothesise, that they are central to nematode infection and pathogenicity; they differ from bacterial pathogenicity islands because they are not inherited by horizontal gene transfer.
We have evidence of similar gene clusters in other parasitic nematodes that have evolved parasitism independently of Strongyloides, suggesting that such islands may be widespread genomic features of parasitic nematodes. If so, the discovery of parasitic nematode pathogenicity islands could be transformative in understanding nematode parasitism and pathogenicity, its molecular and genomic basis, and its evolution. We hypothesise that these islands underlie different infection phenotypes with which parasites compete to exploit hosts, to further their own fitness.
We now propose to investigate this hypothesis in Strongyloides. We will do this by precisely resolving the islands' detailed structure and patterns of diversity in wild Strongyloides, and discover the patterns of co-infection among different pathogenicity island genotypes in naturally infected wild rat populations. We will then predict the functional consequences of genetic diversity in pathogenicity islands and test these predictions in vivo.
We have discovered genomic clusters of highly-diverse, transposon-enriched parasitism genes in the parasitic nematode Strongyloides that we think are "pathogenicity islands". We call these pathogenicity islands by analogy with bacterial pathogenicity islands because: (i) they are large genomic features and (ii) we hypothesise, that they are central to nematode infection and pathogenicity; they differ from bacterial pathogenicity islands because they are not inherited by horizontal gene transfer.
We have evidence of similar gene clusters in other parasitic nematodes that have evolved parasitism independently of Strongyloides, suggesting that such islands may be widespread genomic features of parasitic nematodes. If so, the discovery of parasitic nematode pathogenicity islands could be transformative in understanding nematode parasitism and pathogenicity, its molecular and genomic basis, and its evolution. We hypothesise that these islands underlie different infection phenotypes with which parasites compete to exploit hosts, to further their own fitness.
We now propose to investigate this hypothesis in Strongyloides. We will do this by precisely resolving the islands' detailed structure and patterns of diversity in wild Strongyloides, and discover the patterns of co-infection among different pathogenicity island genotypes in naturally infected wild rat populations. We will then predict the functional consequences of genetic diversity in pathogenicity islands and test these predictions in vivo.
