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In the Hadjifrangiskou Lab (or in short, the H-Lab, or the Mighty Hadjis), we are interested in understanding regulatory mechanisms that underlie multicellular behavior, bacterial competition and virulence in bacteria that cause urinary tract infections (UTI). The bacterial uropathogen we focus on the most is uropathogenic E. coli, which accounts for the majority of community- and hospital-acquired UTIs worldwide.

Our long-term goal is to identify better disease diagnostics, as well as pathogen-specific therapeutic targets

Currently, antibiotics are the primary treatment option for UTI, however they oftentimes fail to eliminate infection, they perturb the host microbial flora and select for increased antibiotic resistance. This means that there is a pressing need for the development of alternative strategies for preventing and/or treating UTIs. Uropathogenic Escherichia coli (UPEC), have developed a remarkable mechanism to evade host immune defenses and establish infection, by forming biofilm-like intracellular bacterial communities inside bladder cells, in addition to forming extracellular biofilms on host cell surfaces and on catheter implants. Following acute infection, UPEC can persist within the host, either in underlying epithelial cell layers in the bladder, or within the host GI tract.

We are interested in identifying and dissecting the sensory/signal transduction networks that UPEC rely on to sample the host environment and guide: A) UPEC bacterial interactions in the gut and en route to the urinary tract and; B) biofilm formation on and withing bladder cells. Projects that have been developed to understand A) and B) above are:

(1) Dissection of the molecular interactions between closely related two-component systems in extra-intestinal pathogenic E. coli.

Bacterial two-component systems integrate signals, modulating gene expression changes to tailor adaptation to changing surrounding environments. In their simplest form, two-component systems consist of a sensor kinase that upon signal interception alters the phosphorylation state of a cognate response regulator, which then mediates transcription. Typically, two-component system interactions are restricted to cognate partners and non-cognate partner cross-talk while possible, is not strong. We have found that closely related two-component systems in UPEC maintain the ability to co-opt each other’s cognate partners in order to respond to specific signals. We have ongoing projects dedicated to understanding (i) HOW does “cross-interaction” become possible (i.e. what residues allow for non-partner interactions? (ii) WHY does this occur in the uropathogens? (i.e. what selective pressures drive this co-evolution in the studied systems?). (iii) WHERE in the different host niches does TCS cross-interaction become critical for pathogen fitness? (iv) WHAT are the signals that trigger cross-interactions and are there signals that are distinct for the cognate partners? (v) HOW can we exploit non-partner interactions to thwart persistence and recurrence of infection?

We currently are working towards answering questions (i) – (v) using the interacting systems QseBC-PmrAB and YehUTS-YpdABC.

(2) Determination of pathogenic biofilm stratification and identification of regulatory factors that lead to heterogeneity within the biofilm community in UPEC.

When bacteria form multicellular communities called biofilms they become less susceptible to host immune responses and antibiotic treatments. This recalcitrance stems in part from the protection afforded by a self-secreted extracellular matrix that shrouds the biofilm bacteria and retards penetration of the biomass by incoming stressors. Another factor that contributes to biofilm resilience is the presence of transient bacterial subpopulations that each provide the community with common goods and exhibit distinct characteristics. Identification of subpopulations and further characterization of their behavior will uncover potential biofilm markers, as well as targets for biofilm distortion/disassembly or inhibition. We detected areas with distinct protein profiles within preformed biofilms using Imaging Mass Spectrometry and this analysis revealed differential localization of adhesive fibers within the preformed biofilm that is driven by the presence of oxygen gradients within the biofilm. We are currently working towards: (i) identifying the sensory system(s) that detect(s)/sense(s) changes in oxygen levels; (ii) identifying the regulatory mechanisms that are responsible for altering the expression and abundance of known biofilm factors in response to the changing oxygen concentration and (iii) understanding the biological significance of oxygen-dependent regulation of biofilm in the context of the different host niches.

(3) Define how UPEC sense and respond to stresses such as blue light in the environment and in the context of treatment (In collaboration with Dr. Bridget Rogers at Biomolecular Engineering)

If you are creative and want to join our lab, email Dr. H. at: maria.hadjifrangiskou@vanderbilt.edu

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