Award details

Quorum sensing motility metabolism and biofilm development in Yersinia

Reference	BB/D52336X/1
Principal Investigator / Supervisor	Professor Brendan Wren
Co-Investigators / Co-Supervisors
Institution	London Sch of Hygiene and Trop Medicine
Department	Infectious and Tropical Diseases
Funding type	Research
Value (£)	192,968
Status	Completed
Type	Research Grant
Start date	01/02/2006
End date	31/01/2009
Duration	36 months

Abstract

The Yersiniae include species which are pathogenic for animals (both farmed and wild), birds and fish. Yersinia pseudotuberculosis whose lifestyle alternates between the food/water environment and the mammalian gastrointestinal tract, infects deer and sheep as well as a variety of captive zoo animals and birds. It also causes gastro-intestinal infections in humans. Y. pestis, the causative agent of bubonic and pneumonic plague evolved from Y. pseudotuberculosis about 20,000 years ago and these two pathogenic bacteria are more than 98 per cent identical at the genetic level although they cause very different diseases. As unicellular micro-organisms, the Yersiniae are capable of adapting to diverse environmental stresses and have evolved sophisticated regulatory systems that facilitate survival in, and migration from, soil and water environments into different hosts (both insects and animals). Although bacteria are single-celled organisms, they exhibit complex, multi-cellular types of behaviour including the ability to co-ordinate behaviour through cell-to-cell communication via small diffusible signal molecules (quorum sensing (QS)) and by forming interactive, surface-associated communities known as biofilms which protect from extreme environments and, in the host, from the immune system and antibiotics. Consequently, biofilms play an important role in both nature and in disease. With respect to Yersinia, bubonic plague is transmitted by fleas whose feeding is blocked by a dense mass of Y. pestis in their digestive tract. Y. pestis also blocks the feeding of the nematode, Caenorhabditis elegans by forming a biofilm on the nematodes anterior cuticle. This suggests that flea blockage by Y. pestis is a biofilm-mediated process. Y pseudotuberculosis also readily forms biofilms on C. elegans and because it is not such a dangerous pathogen, offers a much safer simpler, less expensive and more ethically acceptable means of investigating biofilm development on living tissues. The C. elegans/Yersinia biofilm model is particularly appealing because both the C. elegans and Yersinia genomes have been sequenced, DNA microarrays are available for both and Yersinia mutants can be readily constructed, complemented, and fluorescently labelled. Similarly for C. elegans many mutants are available and orthologous genes are frequently studied in human health and disease. Thus the C. elegans/Yersinia model can be used to identify genetic features of both the pathogen and the host that contribute to biofilm-mediated interactions between bacteria and invertebrates which will have interesting implications for both the Yersinia/flea and animal biofilm-centred infections. We have discovered that Y. pseudotuberculosis uses a sophisticated N-acylhomoserine-lactone dependent (AHL) QS system employing the AHL synthases, Ypsl and Ytbl and the LuxR-type proteins, YpsR and YtbR which co-ordinates swimming motility (via the master flagellar regulator, fhlDC and the flagellar sigma factor, fliA) and also biofilm development on C. elegans. This project aims to gain detailed molecular insights into how Y. pseudotuberculosis orchestrates the use of multiple QS signal molecules to co-ordinate swimming motility and biofilm development on C. elegans and to investigate the links between QS, nitrogen metabolism and type III secretion. We will also seek to understand the nature of the Yersinia biofilm formed on C. elegans and the role of the C. elegans host in biofilm formation. The specific aims of this collaborative project are to: (1) define the extend and nature of the Y. pseudotuberculosis QS regulon; (2) determine which AHLs activate YpsR and YtbR respectively; (3) investigate the extent of the flhDC regulon and its relationship with the QS regulon; (4) determine whether Type III secretion is regulated by QS via FihDC; (5) elucidate the relationship between QS, nitrogen metabolism and Type III secretion; (6) determine the nature of the QS-dependent biofilm formed on C. elegans by Yersinia; (7) identify the key Y. pseudotuberculosis genes required for biofilm development on C. elegans and (8) investigate the role of the C. elegans host in biofilm formation. Our overall aim is to understand the QS-dependent regulatory network involved in the control of motility, metabolism, biofilm formation and type III secretion which may uncover novel targets for the prevention or treatment of disease in humans and other animals. This is especially important with respect to biofilms which are often the cause of chronic, infections highly refractory to conventional antimicrobial chemotherapy. Joint with BB/D523294/1.

Summary

The Yersinia are bacteria which occupy a prominent place in the history of microbiology. Yersinia pestis, the causative agent of bubonic and pneumonic plague has claimed millions of lives in period pandemics, influencing human history possibly to a greate

Committee	Closed Committee - Plant & Microbial Sciences (PMS)
Research Topics	Microbiology, The 3 Rs (Replacement, Reduction and Refinement of animals in research)
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/D523294/1 Quorum sensing motility metabolism and biofilm development in Yersinia

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