The potential of Genetics and Genomics research to progress understanding of drug resistance in parasites
The recent special issue of Parasitology on Genetic and Genomic Approaches to Understanding Drug Resistance in Parasites is discussed here by Guest Editor Eileen Devaney.
“Drug resistance, defined as a heritable reduction in sensitivity to drug action in a population of infectious agents, remains a major challenge in the control of parasitic diseases. The lack of new drugs to treat parasitic infections, coupled with the inexorable spread of resistance, has heralded a potential catastrophe as exemplified by anthelmintic resistance in nematodes of veterinary importance. However, new commitments by pharma (i.e. the London declaration) plus the increasing availability of genetic and genomic resources will hopefully lead to a better understanding of the mechanisms of resistance, as well as providing novel therapies for controlling parasites.
In this Special Issue, we have assembled seven important reviews that describe approaches to the understanding of drug resistance in a range of protist and helminth parasites of man and animals. It is widely recognised that drug treatment failure and true drug resistance may differ leading to the requirement for molecular probes to assess the extent and distribution of resistance to drugs. To this end, the contributors to this Special Issue describe current work on the genetics and genomics of drug resistance in malaria parasites and malaria vectors, in trypanosomes and leishmania, and in selected helminths of animals and man – Haemonchus, Fasciola and Schistosoma.
Mwangi and Cartwright review the history of drug development and resistance for malaria and focus on chloroquine and artemisinin, and on combination therapies designed to slow the spread of resistance. The development of resistance to insecticides by malaria vectors parallels that of malaria parasites to drugs. Witzig et al. review the problems of resistance to pyrethroid insecticides in anopheline mosquitoes. The authors describe the use of genetic crosses between field populations of mosquitoes (rather than laboratory colonies) to map QTLs associated with resistance.
The limitations and risks associated with the current chemotherapy of African trypanosomiases and Chagas’ disease are described by Alsford et al. Their novel approach, combining high throughput RNAi with next generation sequencing has helped identify drug resistance genes in Trypanosoma brucei. Drug transporters have been implicated in the development of resistance, in addition to several novel genes.
Leishmanias, as with many protistan parasites, employ a number of drug resistance mechanisms, including sequence polymorphisms, gene amplification and changes in gene copy number. Berg et al. summarise data from metabolomics studies and suggest that the integration of such methods with genomic approaches will provide valuable new information on resistance mechanisms.
Drug resistance in helminth parasites of both farm animals and man is of major global significance. Review papers in this Special Issue by Gilleard and by Hodgkinson et al. discuss drug resistance in Haemonchus, Teladorsagia and Fasciola. Both authors reflect on the general lack of genetic and genomic resources that hamper our understanding of resistance mechanisms. The recent publication of H. contortus draft genomes and the transcriptome, together with the availability of genetic back-crosses between anthelmintic-resistant and -susceptible worms should advance studies aimed at identifying markers and mechanisms of resistance.
A similar approach to triclabendazole resistance has been adopted for the liver fluke F. hepatica. The availability of genome sequence and the generation of a back-cross between susceptible and resistant parasites are important tools in defining regions of the genome under triclabendazole selection. Praziquantel is widely used to treat the blood fluke, Schistosoma mansoni, and, although resistance has been slow to develop, suggestions of its occurrence have been published. Greenberg et al. summarise studies focused on the role of drug efflux mechanisms in resistance and summarise the genetic tool box available to study mechanisms of resistance in S. mansoni.
These papers illustrate many of the problems faced by the parasitology community in trying to better understand the problems of drug resistance and highlight the resourcefulness of the community in adopting new approaches to deal with the issues, many of which will also advance our basic understanding of the life cycle and biology of these important organisms. ”
Read the Special Issue for free until 30th April 2014