Bacterial chemotaxis systems of World Health Organization 'priority pathogens'
TO INFECT AND CAUSE DISEASE, bacterial pathogens must localize to specific regions of the body where they possess the metabolic and defensive acumen for survival. Motile flagellated pathogens exercise control over their localization through chemotaxis to direct motility based on the landscape of exogenous nutrients, toxins, and molecular cues sensed within the host. Most of the pathogen genre designated by the World Health Organization as ‘priority pathogens‘ possess chemotaxis systems.
Priority pathogens that possess chemotaxis systems account for a significant number of deaths per year from infections or complications with underlying diseases such as cystic fibrosis (CF), environmental enteric dysfunction (EED), Guillain-Barré Syndrome (GBS), and chronic inflammation leading to the development of cancers. The latter include gastric cancer, bladder cancer, and colonic cancer, which are associated with infections by Helicobacter, Escherichia, and Salmonella/Escherichia/Campylobacter, respectively.
For more information, see: “Bacterial chemotaxis in human disease” by Zhou et al. Trends in Microbiology (2023). DOI: doi.org/10.1016/j.tim.2022.10.007
In the Baylink lab, we ask: How do pathogens use chemotaxis to navigate the complex landscape of the host and locate optimal colonization sites?
By understanding the network of chemotactic stimuli, and corresponding bacterial responses, we can learn how pathogens make decisions on colonization that influence clinical outcomes.
Using CIRA live imaging to study pathogen chemotactic responses
In the Baylink lab we study bacterial chemotaxis through use of a custom chemotaxis injection rig assay (CIRA).
CIRA models the biological gradients of chemoeffectors bacteria encounter through injecting solutions at 230 femtoliters per minute – a flow low enough to not perturb swimming bacteria.
Using CIRA we can directly measure the dynamics of chemotactic responses by bacterial populations.
Salmonella enterica Typhimurium exhibits chemoattraction to the amino acid serine. Serine is an important nutrient the bacteria can convert into pyruvate. In less than a minute the population of motile bacteria is able to localize to a serine source.
Salmonella enterica Typhimurium exhibits chemopulsion away from indole, a metabolite produced by the human microbiota. The bacteria rapidly reorganize to avoid the indole microgradient. This may help Salmonella avoid regions of the gut already colonized by competitors.
Chemoreceptors sense ligands to control chemotaxis
Our lab uses protein crystallography and modeling with Alphafold2 to understand the molecular function of bacterial sensory proteins like chemoreceptors. These structures are then used as tools to guide structure-based drug design to develop new antimicrobials.
Chemotaxis at the host-pathogen interface
Bacteria that colonize humans and other animals eavesdrop on the host to find suitable niches for colonizing and persisting. In the Baylink lab we identify what effectors host-associated bacteria perceive and study how bacterial populations organize in response to sources of nutrients, toxins, and cues in the host environment. We are interested in how pathogens navigate the host landscape to pirate nutrients from damaged host tissue.
How do bacteria colonize and persist in inflamed tissue?
Bacterial pathogens and pathobionts exhibit preferences for where they colonize within hosts. This bacterial “biogeography” has ramifications for disease outcomes. The same bacterial species colonizing one region may not cause disease, whereas colonizing elsewhere can instigate chronic inflammation (Ulcerative Colitis, Crohn’s Disease) and even develop into cancers.
The Baylink lab is investigating how bacterial pathogens sense effectors present in inflamed host tissue to control chemotaxis and biofilm pathways. How do redox defenses, CZB sensory proteins, and chemotaxis combine to allow pathogens to thrive in inflamed host environments? We aim to will use this knowledge to assist in the development of novel antimicrobial strategies.