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In the Hadjifrangiskou Lab (or in short, the H-team, or the Mighty Hadjis), we are interested in understanding regulatory mechanisms that underlie multicellular behavior 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. We are especially interested in infection dynamics of uropathogenic E. coli in the context of specialized populations, such as catheterized individuals and diabetics.
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.
We are interested in identifying and dissecting the sensory networks that UPEC rely on to sample the host environment and modulate infection. Towards this end, we study the regulatory relationships that exist between two-component signaling networks, we investigate how these regulatory relationships stratify biofilm formation and we study how we can interfere with signaling cascades to reprogram bacteria and enhance targeting. To achieve these goals, we employ a combination of genetic, biochemical and mass spectrometry analyses with robust in vivo functional assays and three murine models of UTI.
Current Projects include:
(1) Characterization of the QseBC- PmrAB two-component system network and its role in pathogenesis
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 previously shown that in the case of QseBC, deletion of the QseC sensor in UPEC leads to gene dysregulation and virulence attenuation, due to constitutive signal-independent activation of the QseB response regulator by the PmrB sensor. We are currently exploring: A) The identification of QseC residues responsible for QseB deactivation. B) The basis of interaction between QseB and and PmrAB, and C) The role of the PmrAB-QseBC interactions in response to different and multiple sensory inputs.
(2) Define the contribution and function of metabolite sensing networks during infection in diabetic and non-diabetic mouse models
(3) Define how UPEC sense and respond to stressors such as blue light in the environment and in the context of treatment (In collaboration with Dr. Bridget Rogers at Biomolecular Engineering)
(4) Determine how pathogenic biofilms stratify, using imaging mass spectrometry (IMS) (In collaboration with Dr. Richard Caprioli)
When bacteria form multicellular communities called biofilms they become less susceptible to host immune responses and antibiotic treatments. This recalcitrances 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 are using IMS to detect areas with distinct protein profiles within preformed biofilms and we are using this information to understand how the immediate extracellular environment shapes the fate of these subpopulations within biofilms
(5) Investigate previously uncharacterized UPEC biofilm effectors, the disruption of which diminishes IBC formation and attenuates UPEC virulence
Using a transposon screen, several UPEC biofilm determinants were discovered, which also impact UPEC IBC formation and in vivo virulence. We are interested in further characterizing each category of mutants and understanding the mechanism by which they modulate IBC formation.
…AND… … if UPEC does not rock your boat:
(6) Understand the mechanism by which rationally designed small molecules act against Helicobacter pylori transport systems
Our collaborator chemists have designed small molecular weight inhibitors to block UPEC pilus assembly, thereby impeding bacterial adherence to biotic and abiotic surfaces; we have come to discover that these molecules impact UPEC gene expression, causing pleiotropic effects on virulence gene regulation and inhibiting biofilm formation. In collaboration with labs at Washington University in Saint Louis and Umea University in Sweden, we leveraged these inhibitors towards understanding assembly and function of type 4 secretion systems in diverse extra-cellular pathogens such as H. pylori and Agrobacterium tumefaciens. This project was spearheaded by a post-doctoral fellow in the lab. If you are creative and want to join our lab, email Dr. H. at: email@example.com