Matthew Shepherd, PhD

Arbeitsvorhaben

The Role of Regulatory Changes in Shaping the Evolvability of Opportunistic Pathogens

Opportunistic pathogens cause the majority of global disease burden and dominate the WHO’s antimicrobial resistance (AMR) priority pathogens list. Unlike specialised obligate pathogens, opportunists that infect hosts from an environmental reservoir face a major challenge: they are poorly adapted to cause infections. Infection by an opportunist can therefore be viewed as an important example of an evolutionary niche transition—a situation where opportunists must rapidly adapt their biology to meet the challenges of a novel and hostile host environment. My research seeks to understand how opportunistic pathogens achieve the remarkable adaptability and evolvability needed to establish infection. I am especially interested in the role of gene regulatory network changes—which commonly occur in opportunistic bacteria during infection—and how these rewire to adapt gene expression responses to better suit the host environment. During my stay at the Wissenschaftskolleg, I would like to explore how regulatory mutations drive infection by these organisms, and how these changes impact their evolvability to future challenges, for example antibiotic therapy. I will do this with a focus on the model opportunist Pseudomonas aeruginosa, and will seek to outline similarities in gene regulatory network adaptation between this organism and other bacterial species, for example when infecting comparable body sites. This project will form an important foundation to direct my future experimental plans and shape my hypotheses. My goal is to understand the fundamental evolutionary systems forces shaping the niche transition of opportunistic pathogens from the environment to becoming clinical and epidemic pathogens.

Recommended Reading

Shepherd, Matthew J., Aidan P. Pierce, and Tiffany B. Taylor (2023). “Evolutionary Innovation through Transcription Factor Rewiring in Microbes Is Shaped by Levels of Transcription Factor Activity, Expression, and Existing Connectivity.” PLOS Biology 21 (10): e3002348. https://doi.org/10.1371/journal.pbio.3002348.
Shepherd, Matthew J., Mitchell Reynolds, Aidan P. Pierce, Alan M. Rice, and Tiffany B. Taylor (2023). “Transcription Factor Expression Levels and Environmental Signals Constrain Transcription Factor Innovation.” Microbiology 169 (8): 001378. https://doi.org/10.1099/mic.0.001378.
Shepherd, Matthew J., Taoran Fu, Niamh E. Harrington, et al. (2024). “Ecological and Evolutionary Mechanisms Driving Within-Patient Emergence of Antimicrobial Resistance.” Nature Reviews Microbiology 22: 650–665. https://doi.org/10.1038/s41579-024-01041-1.