Current Projects
Ecology and evolution of urogenital bacteria
Most of the millions of urinary tract infections (UTIs) that occur every year are caused by Escherichia coli. To establish an infection, this bacterium must migrate to and survive within the bladder. This means that E. coli must contend with competition and antagonism from the commensal microbes inhabiting the bladder and any niche (gut, vagina, etc.) it passes through. A limited but growing body of evidence suggests that Lactobacilli, prevalent commensals of the female urogenital tract, may protect women from UTIs through direct antagonism against E. coli and/or improving the host immune response. However, some women with active UTIs are colonized with Lactobacilli, indicating that E. coli might be able to evolve resistance.
Through in vitro experiments, I have demonstrated that E. coli can evolve increased resistance to urinary Lactobacilli. Currently, I am working to identify the genetic loci that underlie this adaptation and to characterize clinically relevant trade-offs that might come with increased resistance to Lactobacilli. I am also leveraging VUMC’s pathogen biorepository with the help of Dr. Maria Hadjifrangiskou to expand the clinical applicability of my findings.
Mutation rates and spectra of anaerobic bacteria
Mutation is the ultimate source of all genetic variation. Mutagenesis is commonly associated with oxygen, the source of DNA damaging reactive oxygen species. However, life on Earth emerged in an anaerobic environment and evolved in one for over 1 billion years, and many important organisms today remain strict or facultative anaerobes. Understanding mutation in anaerobic environments is essential for understanding our history on this planet and managing the evolution of the microbes that cause infections, ferment our food, and carry out important geochemical processes.
I performed mutation accumulation experiments with anaerobically cultured Lactobacillus acidophilus, Lactobacillus crispatus, and Lactococcus lactis subsp. lactis, three anaerobic bacteria used in food fermentation and found in the human microbiome. I found that these organisms have extremely high mutation rates that are consistent with their domesticated and host-associated lifestyles. In L. acidophilus, I observed the highest mutation rate ever recorded in a natural bacterium and identified intrachromosomal variation in the rate G:C > A:T transitions, which occur ~3 times as frequently in the ~100 kb around the origin of replication as they do in the rest of the chromosome.
Collaborations
Within-host evolution of bladder bacteria
I work with the Hadjifrangiskou and Schmitz labs, as well as Dr. Douglass Clayton’s urology team at the Vanderbilt Children’s Hospital, to understand the evolution of urinary pathogens, especially in patients with spina bifida.
Commensal aerotolerance
I work with the Zhu lab to understand how anaerobic commensals in the gut handle the exposure to oxygen that comes with inflammation. We are also applying evolutionary methods to increase the aerotolerance of probiotic strains, which we hope will make them easier to produce and more efficacious.
Past Projects
Mycobacterial heme homeostasis
Mycobacterium tuberculosis is the second deadliest pathogen and the deadliest bacterium. While progress has been made in fighting tuberculosis, antimicrobial resistance in this pathogen is growing rapidly. The need for new therapies requires us to understand new potential targets. Heme is an essential cofactor required by M. tuberculosis for respiration, gas sensing, neutralizing reactive oxygen species, and other processes necessary for pathogenesis. However, the reactivity that makes it so useful as a cofactor also makes it toxic. Free heme can dangerously alter proteins, lipids, and nucleic acids resulting in cell death. Using the model mycobacterium, Mycobacterium smegmatis, I identified physiologically relevant conditions that altered heme synthesis and bioavailability. My work on this topic contributed to a larger project driven by Dr. Rebecca Donegan that described idiosyncratic patterns in mycobacterial heme homeostasis and showed that heme synthesis may be a promising drug target.
Agricultural microbiomes
Indigo Agriculture produces staple crop seeds treated with microbes which increase yield and can protect plants from stresses like drought or fungal infection. I screened pairs of microbes for antagonism using in vitro and in planta assays to determine if they were compatible for coinnoculation. I also contributed to a metabolite function knowledge base to enhance genome motivated microbe nominations.
Electrophysiology of alcohol addiction
Alcohol addiction is a leading cause of morbidity and mortality and it is believed that binge drinking may play a causal role in its pathogenesis. Working in Dr. Gilles Martin’s lab at UMass Medical School, I performed mouse husbandry and set up whole-cell patch clamping experiments aimed at determining how binge drinking may lead to alcohol addiction. I also completed a small project aimed at addressing a major issue common in animal research: the exclusion of female research subjects. Addressing this problem is a priority of the NIH. My goal was to understand if there is a difference in alcohol consumption between male and female mice so that the lab could confidently move forward with including female mice in future experiments.