Regulation of virulence and biofilm formation by quorum sensing and the "stress alarmone" ppGpp in gram-negative pathogenic bacteria.

About the Project

We are investigating the complex interplay between cell-cell signalling (quorum sensing), microbial lifestyle (i.e., free-living planktonic cultures vs sessile biofilm communities), growth phase and virulence in gram-negative bacteria. We work on two genetically-amenable pathogens: the opportunstic human pathogen Pseudomonas aeruginosa (the scourge of hospital clinicians and a major cause of morbidity and mortality in individuals with cystic fibrosis) and Erwinia atroseptica, an economically important plant pathogen.

In spite of their different target hosts, both pathogens use very similar mechanisms to regulate their virulence. We are combining the techniques of "classical" molecular microbiology (such as targetted construction of mutants, over-expression constructs, transposon mutageneses etc) with newer technologies including whole genome sequencing and functional genomics (metabolomics, proteomics, microarray analyses etc) to investigate how virulence and lifestyle decisions are regulated in these pathogens.

Recent data indicate that at the top of the hierarchy of regulatory factors in these organisms lies an "apex regulator", ppGpp. This "stress alarmone" is made when the cells become limited for nutrients, and appears to be an ancestral regulatory system that pre-dates the more widely studied (but sub-ordinate) regulatory mechanism known as "quorum sensing".

References

Mikkelsen H, Duck Z, Lilley, KS. & Welch, M. “The Inter-relationship between colonies, biofilms and planktonic cells of Pseudomonas aeruginosa”. J. Bacteriol. 189:2411-2416 (2007).

Hannah G. Stickland, Peter W. Davenport, Kathryn S. Lilley, Julian L. Griffin and Martin Welch. Mutation of nfxB causes global changes in the physiology and metabolism of Pseudomonas aeruginosa. In Press (2010). J. Proteome. Res.

Wang J-H, Gardiol. N., Burr, T., Salmond GPC & Welch M “RelA-dependent (p)ppGpp production controls exoenzyme synthesis in Erwinia carotovora subsp. atroseptica.” J. Bacteriol. (2007) 189: 7643-7652.

Mikkelsen H, Bond N, Skindersoe ME, Givskov M, Lilley KS & Welch M. “Biofilms and Type III secretion are not mutually exclusive in Pseudomonas aeruginosa”. 155: 687-698. Microbiology (2008).

Sanaya Patell, Muxin Gu, Peter Davenport, Michael Givskov, Richard D. Waite and Martin Welch. Comparative microarray analysis reveals that the core biofilm-associated transcriptome of Pseudomonas aeruginosa comprises very few genes. In Press (2010) Environ. Microbiol. Reports.

James Hodgkinson, Steven D. Bowden, Warren R. J. D. Galloway, David R. Spring and Martin Welch. Structure-activity analysis of the Pseudomonas quinolone signal molecule. In Press (2010). J. Bacteriol.

Welch, M., D.E. Todd, N.A. Whitehead, S.J. McGowan, B.W. Bycroft and G.P.C. Salmond. " N-acyl homoserine lactone binding to the CarR receptor determines quorum sensing specificity in Erwinia." EMBO. J.19: 631 - 641 (2000).

Whitehead, N.A., M. Welch and G.P.C. Salmond. "Silencing the majority" Nature Biotechnology. 19:735 - 736 (2001).

Byers, J.T., C. Lucas, G.P.C. Salmond and M. Welch. "Non-enzymatic turnover of an Erwinia carotovora quorum sensing signaling molecule" J. Bacteriol. 184:1163-1171 (2002).