Welch Laboratory
Uncovering the microbiology of the lung
Our research
Methodologies used in the laboratory
Molecular genetics; protein chemistry; structural biology; ‘omics (advanced proteomics, transcriptomics, and genomics);
enzymology; microbiology; computational biology.
Nutrients, metabolism, and virulence
Research in the Welch Laboratory focuses on understanding the link(s) between nutrient availability, metabolism, and virulence in Pseudomonas aeruginosa.
That these factors should be linked is beyond doubt: the organism is not inherently “malevolent” and only produces virulence factors as a [high risk!] strategy for securing additional nutrients when food is in short supply. Nutritional availability is titrated through a number of mechanisms; some involving the “stress alarmone”, (p)ppGpp, and others involving certain metabolic “nodes”, particularly those at the intersection of key metabolic pathways. An understanding of the latter and of how flux through these pathways impacts on virulence factor production, makes for some truly fascinating biology – especially given that it is becoming increasingly obvious that P. aeruginosa is “wired up” differently compared with many well-characterized organisms. Intriguingly, many of the pathways that we are investigating also impact on biofilm formation and AMR, indicating that along with virulence, these “macro-phenotypes” all share common regulatory features. ​
P. aeruginosa within polymicrobial communities
In parallel with our work on nutrient sensing, we are also interested in understanding how the microbial co-habitants that live alongside P. aeruginosa in many chronic infection scenarios influence the biology of the pathogen. Key findings have been that these co-habitants exert a strong selection pressure on the AMR profile of P. aeruginosa, and current efforts are aimed at understanding better how different species affect one another’s transcriptome and virulome. A related area of interest lies in understanding how the appearance of P. aeruginosa variants (such as mutants in the quorum sensing master regulator, lasR, which are commonly found in the airways of people with cystic fibrosis) impact on population trajectories and dynamics.
"Change of function" mutants
Another area of interest lies in the under-appreciated role of “change of function” (CoF) mutants in P. aeruginosa. In many cases, researchers adopt a somewhat black-and-white view of point mutations in microbial genomes, in that they either abolish or impair gene function (or more rarely, “improve” it), or are neutral. However, in our hands, and following detailed analyses of mutated gene products, we find that certain clinically-relevant mutations also fall into the CoF category, leading to new functionality in the gene.
Quorum sensing
Finally, we continue to find new vistas for study in a well established area: quorum sensing (QS). Recent work in the laboratory has shown that QS signaling molecules not only bind to their “cognate receptors” (e.g., OdDHL binding to LasR, and so on) but also to other proteins in the cell. An open question is whether this binding to alternative targets has any biological impact, and how to quantitate this binding on a global level. We are also investigating how the effect of mutations in the known QS receptors (lasR, rhlR, and pqsR) can be “bypassed” by mutations in other genes, thereby restoring virulence.