Award details

sRNA-based therapeutics for disease caused by A. pleuropneumoniae

Reference	BB/M020576/1
Principal Investigator / Supervisor	Professor Anastasia Callaghan
Co-Investigators / Co-Supervisors
Institution	University of Portsmouth
Department	Inst of Biomedical and Biomolecular Sc
Funding type	Research
Value (£)	367,549
Status	Completed
Type	Research Grant
Start date	01/12/2015
End date	31/05/2019
Duration	42 months

Abstract

Actinobacillus pleuropneumoniae (APP) causes acute and chronic lung disease in pigs and is of substantial economic importance to the worldwide swine industry. There is an urgent need for improved vaccines and therapeutics as antibiotic resistance is an increasing problem. The focus of this proposal is bacterial small non-coding RNAs (sRNAs) which, facilitated by Hfq, play a key role controlling mRNAs responsible for virulence. Our work has shown that the hfq-mutants of APP are severely attenuated and rapidly cleared from pigs. While Hfq could be targeted directly as a therapeutic approach, the presence of homologous eukaryotic proteins suggests that targeting the associated sRNAs will be a more effective strategy. In particularly, this approach will bring about a therapeutic effect without the risk of developing bacterial resistance, since no survival pressure, from which traditional antibiotic resistance originates, is imposed. To date, our work has experimentally identified 15 Hfq-associated sRNAs in APP, and computationally a further 30 have been predicted. Our recent bioinformatic analysis confirms a number of these sRNAs target mRNAs with relevance to virulence. This proposal represents a major collaboration between Imperial College London and the University of Portsmouth, utilising the extensive experience in APP and Hfq-sRNA interactions, respectively. We plan to ascertain the identity of Hfq-associated sRNAs that are key in turning on virulence genes and determine whether inhibiting these sRNAs using peptide nucleic acids (PNAs) provides a novel therapeutic approach to treating APP disease. Using a combination of in vitro biochemical and biophysical molecular characterisation approaches, coupled with in vivo reporter and/or phenotypic assays, we will determine the viability of this therapeutic approach. Success would offer a step change in capability for combating APP, but with far reaching impact for the treatment of bacterial diseases more broadly.

Summary

The bacterium Actinobacillus pleuropneumoniae (APP) causes is a highly contagious lung disease in pigs which affects herds in the UK and worldwide. Infection results in either rapid mortality or slow growth, breathing problems and suffering. APP is responsible for substantial economic losses to the worldwide pig industry. After good husbandry practices (provision of good ventilation, all in/all out facilities, avoidance of temperature fluctuations and good hygiene) are taken into account there are two basic methods used to limit APP infection: namely vaccines and antibiotics. However, current vaccines have severe limitations and antibiotic resistance is of increasing concern, a recent survey suggesting that 70% of APP isolates in the UK are now resistant to one or more antibiotics. Consequently, there is an urgent need for effective therapeutic approaches to combat APP. Addressing such issues directly aligns to the key BBSRC strategic priorities of 'Animal Health', 'Welfare of Managed Animals' and 'Combating Antimicrobial Resistance'. Traditional antibiotics seek to simply kill bacteria, but a novel therapeutic alternative is to target functions that are essential for the bacteria's ability to infect the host. Such an approach effectively disarms the bacteria, rather than killing them, thereby avoiding the selective pressure from which traditional antibiotic resistance originates. Bacterial cells, such as APP, have important switching molecules (sRNAs) which are responsible for turning on the mechanisms that enable host infection to occur. Our proposal plans to identify these crucial sRNAs in APP and then inhibit their function using compounds called peptide nucleic acids (PNAs). Targeting the sRNAs in this manner will lead to a new therapeutic approach for treating APP disease. More broadly, this research also provides the basis for exploring sRNA inhibition as an alternative therapeutic approach to bacterial diseases caused by other major pathogens of animals and man. This work is innovative, timely and multi-disciplinary, building on recent work and employing the latest molecular tools and technological advances to deliver results. This is a joint collaborative venture which benefits from the synergy between world leading expertise in APP (Imperial College London) and an outstanding track record in sRNA research (University of Portsmouth). Within this context, the project has a substantial chance of success, standing to offer a step change in capability for treating APP, but with far reaching impact for the therapeutic treatment of bacterial diseases more broadly.

Impact Summary

Please see main proposal.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/M023052/1 sRNA-based therapeutics for disease caused by A. pleuropneumoniae

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