ProfessorHuwWilliams

We are focused on understanding the physiology of bacterial pathogens in relation to chronic infection. We study the mechanisms by which bacteria sense starvation stress, shut down metabolism and maintain cell integrity to enter into a persistent state within the context of chronic infections. 

We employ an eclectic mix of approaches including molecular genetics, mutational studies, transcriptomic and metabolomics approaches, targeted proteomics and flow cytometry as well as in vitro characterisation of proteins.

Our research is in two main disease areas:

Tuberculosis

Over a third of the world’s population is thought to be latently or persistently infected with Mycobacterium tuberculosis, which represents a huge potential reservoir of infection.  There is an urgent need to fully understand the host/pathogen interaction, in particular during this latent state, in order to develop improved vaccine, diagnostic and treatment strategies with which to curtail this disease. In addition, persistent bacilli may be responsible for the need for the long antibiotic treatment regimes required to treat TB effectively. Understanding the ability of the tubercle bacillus to persist during latent infection has been the object of much research in attempts to define both the initiating factor(s) and the bacterial genes required for non-replicating persistence. As there is evidence that Mtb will experience hypoxic conditions in the granulomas that form during chronic infection, we are investigating the adaptation of mycobacteria to hypoxic stress. Our current focus is on determining the role of Universal Stress Proteins in mycobacterial survival and how mycobacteria maintain macromolecular stability during persistence and in particular ribosomal stability.

Infections of the Cystic Fibrosis Lung

We are interested in how bacteria infect and then adapt and evolve within the Cystic Fibrosis lung.  Cystic fibrosis is caused by a defect in the CF transmembrane regulator (CFTR) that leads to depletion and dehydration of the airway surface liquid of the lung epithelium, providing an environment that can be infected by bacteria. While a range of bacteria are able to infect the CF lung Pseudomonas aeruginosa is the most important respiratory pathogen, chronically infecting more than 80% of CF patients, its presence leading to higher morbidity and mortality. P. aeruginosa is one of a limited number of bacteria that can synthesise hydrogen cyanide and we have demonstrated that cyanide is present in sputum from CF patients when P. aeruginosa is the infecting bacterium and that the presence of cyanide is associated with a severe worsening of lung function.  These findings support the clinical significance of cyanogenesis to lung infection. Our current research is focussed on:

1.      Understanding the role of bacterial cyanide production in the lung function decline in cystic fibrosis.  P. aeruginosa This involves molecular microbiology approaches to identify genetic and metabolic factors affecting cyanogenesis.  Furthermore, Through clinical collaborations with colleagues ant the Royal Brompton Hospital, we are investigating  the  relationship between cyanide-production and lung function in Cystic Fibrosis  patients and the effects of chronic cyanide exposure on lung cell function.  

2.      Understanding the adaptation and evolution of cystic fibrosis pathogens in the lung during chronic infection and the molecular details of the regulatory processes involved.