Research

Current research interests and projects

Our research

Bacterial pathogens have evolved a diverse range of strategies to infect, survive, and replicate within a host. Dissecting the interactions between bacteria and their hosts can help us understand how pathogens cause disease and facilitate the developments of novel diagnostics and therapeutics to treat human disease. The overarching goal of our research is to study bacterial host-pathogen interactions by characterizing the mechanisms through which the virulence factors of bacterial respiratory pathogens interact with host cells. Our research addresses the global challenges posed by Burkholderia pseudomallei, Mycobacterium tuberculosis, and Pseudomonas aeruginosa on human health with specific focus on: 

The pathogenesis of Burkholderia pseudomallei, the causative agent of melioidosis.

Melioidosis a neglected tropical disease that is endemic to Southeast Asia and Northern Australia. It is also listed as a Tier 1 select agent and potential bioterrorism threat, meaning that development of a protective vaccine is a research imperative. We have identified a panel of B. pseudomallei virulence factors, including many predicted to be important for systemic dissemination, using a large-scale genetic screening method known as TraDIS. Characterizing these genes will help us to better understand this emerging threat and identify potential targets for the development of new vaccines and therapeutics. 

Image showing Burkholderia formin actin tails within cells

The role of the Tex family of bacterial RNA-binding proteins in virulence and intracellular survival.

Tex 3D structure

We originally identified the predicted transcriptional accessory factor Tex as essential for the in vivo virulence of B. pseudomallei, and subsequently showed that it both directly binds RNA and regulates intracellular survival within both mammalian macrophages and human lung epithelial cells. tex is extraordinarily conserved across an extensive range of bacterial pathogens, and has been implicated in the fitness and virulence in multiple species. Current projects within the lab include investigating the role of Tex in regulating intramacrophage survival in collaboration with Dr. Tovah Shaw, exploring the conservation of tex in other bacteria in collaboration with Professor Ross Fitzgerald, and identifying the RNA targets of Tex proteins in collaboration with Professor Sander Granneman

The dissemination and extrapulmonary spread of Mycobacterium tuberculosis, one of the leading causes of death by infectious disease worldwide.

While tuberculosis is primarily a respiratory disease, up to 15% of M. tuberculosis cases are extrapulmonary infections that are particularly difficult to diagnose and treat. The mechanisms of M. tuberculosis dissemination are unknown, but it is thought that M. tuberculosis is able to breach the barrier of the alveolar epithelium either by directly infecting epithelial cells or by transiting across the epithelia within macrophages or dendritic cells. We have identified a panel of potential M. tuberculosis dissemination factors, we are characterizing using air-liquid interface (ALI) culture models of the human lung epithelium. Current research projects include investigating the role of neutrophils in TB dissemination and the impact of co-infections with malaria in collaboration with Dr. Jason Mooney.  

Illustration of possible TB dissemination routes

Elucidating the intracellular life of the extracellular pathogen Pseudomonas aeruginosa

Microscopy image of macrophages infected with Pseudomonas aeruginosa

P. aeruginosa is a leading causes of nosocomial infections throughout the world due to the emergence of antibiotic resistance strains, and while it has historically been defined as an extracellular pathogen, it is now known that P. aeruginosa can also survive within host cells. This may represent an important mechanism through which the bacterial can persist within a host and contribute to the extensive antimicrobial resistance (AMR) of this pathogen. Current projects within the lab include exploring the impact of transitory intracellular stages on AMR in collaboration with Dr. Helen Alexander and investigating the ability of novel antimicrobials to target intracellular populations in collaboration with Maxwell Biosciences

Atypical cell wall-deficient (CWDB) forms of bacteria

Although the role of CWDB in disease remains controversial, a consistent pattern has emerged in which CWDBs have repeatedly been identified in association with latent or chronic infections. This persistence within a host may be facilitated by the loss of the highly immunogenic peptidoglycan cell wall, which helps CWDBs avoid activation of some host immune responses and establish long-term, immunologically silent colonization. Our recently awarded Human Frontiers Science Program (HFSP) research grant in collaboration with Meriem El Karoui, Karl Morton and Matthew Scott will investigate the intracellular survival of CWDBs and explore the potential of these unique forms of bacteria to establish a state of endosymbiosis reminiscent of host cell mitochondria.

Montage image of L-form bacteria through time