Matthew A. Mulvey
Professor of Microbiology and Immunology
Bacterial Pathogenesis, Innate Immunity, Antibiotics, Antibiotic Resistance, Urinary Tract Infection, Sepsis, Virulence Factors, Genetics, Cell Biology, Zebrafish, Infection
The Mulvey lab is focused on understanding the survival and virulence strategies employed by a group of important bacterial pathogens collectively known as Extraintestinal Pathogenic Escherichia coli, or ExPEC. These bacteria have a broad host range and display a remarkable ability to adapt to widely varying environmental conditions, often facing nutrient limitations, antibiotics, and aggressive host defense mechanisms. In humans, ExPEC can efficiently colonize the gastrointestinal tract, like commensal strains, but have the added capacity to disseminate and cause disease in other host niches, including the bloodstream, central nervous system, and the urinary tract. Infections caused by ExPEC are among the most common and costly on the planet. Making matters worse is the recent global dissemination and expansion of multidrug-resistant ExPEC strains that cannot be treated with frontline antibiotics.
We are working to delineate both bacterial and host factors that control the ability of ExPEC to colonize and persist within diverse host environments, with a major goal being the development of improved anti-bacterial therapeutics. This research utilizes genetics, microscopy, biochemistry, global gene expression analysis, bioinformatics, and molecular biology techniques coupled with clinical data analyses and cell culture, mouse, and zebrafish infection model systems. Specific goals of this research include:
- Defining the mechanisms by which ExPEC invades, traffics, multiplies, and persists within host cells and tissues.
- Identify and functionally define bacterial fitness and virulence factors, including small regulatory RNAs, tRNA modifying enzymes, and other regulators that enable ExPEC isolates to resist the multitude of environmental stresses encountered during the course of an infection.
- Determining how ExPEC-associated toxins and other virulence factors modulate and hijack host signaling events, including host cell death, survival, and inflammatory pathways.
- Delineating how flagellin variants and flagellin receptors impact the onset, progression, and outcomes of sepsis in children.
- Developing improved therapeutics, including antibiotics and vaccines, that can be used for the prevention and treatment of ExPEC-associated infections.
Figure: Image shows phagocytes (red) localized with ExPEC (green) that has disseminated into the eye of an infected zebrafish embryo. The Mulvey lab is using zebrafish as surrogate hosts for rapid, high-throughput genetic and drug screens.
References (Selected Publications)
- Forde BM, Roberts LW, Phan M-D, Peters KM, Fleming BA, Russell CW, Lenherr SM, Myers JB, Barker AP, Fisher MA, Chong T-M, Yin WF, Chang KG, Schembri MA*, Mulvey MA*, Beatson SA (2019). Population Dynamics of an Escherichia coliST131 Lineage during Recurrent Urinary Tract Infection. Nature Comm., 10(1): doi: 10.1038/s41467-019-11571-5. PMCID: PMC6692316. *Co-corresponding authors.
- Brannon JR, Mulvey MA (2019). Jekyll and Hyde: Bugs with Double Personalities that Muddle the Distinction between Commensal and Pathogen. J Mol Biol., 431(16):2911-2913.
- Russell CW, Fleming BA, Jost CA,Tran A, Stenquist AT, Wambaugh MA, Bronner MP, Mulvey MA (2018). Context-dependent Requirements for FimH and Other Canonical Virulence Factors in Gut Colonization by Extraintestinal Pathogenic Escherichia coli. Infect Immun. 86(3): pii: e00746-17. PMCID:PMC5820936.
- Russell CW, Richards AC, Chang AS, Mulvey MA (2017). The Rhomboid Protease Glpg Promotes the Persistence of Extracellular Pathogenic Escherichia coli within the Gut. Infect Immun. 85(6):e00866-16. PMCID: PMC5442614.
- Wambaugh MA, Shakya VPS, Lewis AJ, Mulvey MA, Brown JCS (2017). High-Throughput Identification and Rational Design of Synergistic Small Molecule Pairs for Combating and Bypassing Antibiotic Resistance. PLoS Biol. 15(6): e2001644. https://doi.org/10.1371/journal.pbio.2001644. PMCID: PMC5478098.
- Barber AE, Fleming BA, Mulvey MA (2016). Similarly Lethal Strains of Extraintestinal Pathogenic Escherichia coli Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis. mSphere 1(2): pii: e00062-16. DOI:1128/mSphere.00062-16. Discussed on This Week in Microbiology (TWiM) podcast, episode #126: http://www.microbe.tv/twim/twim-126/
- Barber AE*, Norton JP*, Wiles TJ, Mulvey MA (2016). Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies. Microbiol Mol Biol Rev 80(2): 351-367. *Equal contributors. PMID: 26935136.
- Lewis AJ, Dhakal BK, Liu T, Mulvey MA (2016). Histone Deacetylase 6 Regulates Bladder Architecture and Host Susceptibility to Uropathogenic Escherichia coli. Pathogens. 5(1). 20; doi:10.3390/pathogens5010020.
- Russell CW and Mulvey MA (2015). The Extraintestinal Pathogenic Escherichia coli Factor Rqli Constrains the Genotoxic Effects of the RecQ-like Helicase RqlH. PLoS Pathogens. 11(12):e1005317.
- Blango MG, Ott EM, Erman A, Veranic P, Mulvey MA (2014). Forced Resurgence and Targeting of Intracellular Uropathogenic Escherichia coli PLOS One. 9(3): e93327.
- Barber AE, Norton JP, Spivak AM, Mulvey MA (2013). Urinary Tract Infections: Current and Emerging Management Strategies. Infect. Dis. 57:719-724.
- Wiles TJ, Norton JP, Russell CW, Dalley BK, Fischer KF, Mulvey MA (2013). Combining Quantitative Genetic Footprinting and Trait Enrichment Analysis to Identify Fitness Determinants of a Bacterial Pathogen. PLOS Genetics.
- Debnath I, Barber AE, Dhakal BK, Kulesus RR, Norton JP, Mulvey MA (2012). The Cpx Stress Response System Potentiates the Fitness and Virulence of Uropathogenic Escherichia coli. Infect Immun. 81:1450-1459.
- Wiles TJ, Norton JP, Smith SN, Lewis AJ, Mobley HLT, Casjens SR, Mulvey MA (2013). A Phyletically Rare Gene Promotes the Niche-specific Fitness of an coli Pathogen during Bacteremia. PLoS Path. 9(2):e1003175.
- Wiles TJ, Mulvey MA (2013). The RTX Pore-forming Toxin a-Hemolysin of Uropathogenic Escherichia coli: Progress and Perspectives. Future Microbiol. 8(1):73-84.
- Donovan GT, Norton JP, Bower JM, Mulvey MA (2013). Adenylate Cyclase and the cAMP Receptor Protein (CRP) Modulate the Resistance and Virulence Capacity of Uropathogenic Escherichia coli. Infect Immun. 81(1):249-258.
- Jordan JP, Mulvey MA (2012). Toxin-Antitoxin Systems are Important for Niche-Specific Colonization and Stress Resistance of Uropathogenic Escherichia coli. PLoS Path 8(10):e1002954.
- Dhakal BK, Mulvey MA (2012). The UPEC Pore Forming Toxin a-Hemolysin Triggers Proteolysis of Host Proteins to Disrupt Cell Adhesion, Inflammatory and Survival Pathways. Cell Host Microbe 11:58-69.
- Blango MG, Mulvey MA (2010). Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Agents Chemother. 54(5):1855-63.
- Wiles TJ, Bower JM, Redd MJ, Mulvey MA (2009). Use of Zebrafish to Probe the Divergent Virulence Potentials and Toxin Requirements of Extraintestinal Pathogenic Escherichia coli. PLoS Pathogens, 5(12):e1000697.
- Bower JM, Gordon-Ragaas, HB, Mulvey MA (2009). Conditioning of Uropathogenic Escherichia coli for Enhanced Colonization of the Host. Immun. 77(5): 2104-2112.
- Dhakal BK, Mulvey MA (2009). Uropathogenic Escherichia coli Invade Host Cells via an HDAC6-modulated Microtubule-dependent Pathway. Biol. Chem. 284(1): 446-454.
- Eto ES, Gordon HB, Dhakal DK, Jones TA, Mulvey MA (2008). Clathrin, AP-2, and the NPXY-binding Subset of Alternate Endocytic Adaptors Facilitate FimH-mediated Bacterial Invasion of Host Cells. Microbiol. 10(12): 2553-2567.
- Kulesus RR, Diaz-Perez K, Slechta ES, Eto DS, Mulvey MA (2008). Impact of the RNA Chaperone Hfq on the Fitness and Virulence Potential of Uropathogenic Escherichia coli. Immun. 76(7):3019-3026.
- Wiles TJ, Dhakal BK, Eto DS, Mulvey MA (2008). Inactivation of Host Akt/protein Kinase B Signaling by Bacterial Pore-forming Toxins. Biol. Cell, 19(4):1427-1438.
- Eto DS, Jones TA, Sunbdsbak JL, Mulvey MA (2007). Integrin-mediated Invasion of Host Cells by Type 1-piliated Uropathogenic Escherichia coli. PLoS Pathogens, 3(7):e100.
- Eto DS, Sundsbak JL, Mulvey MA (2006). Actin-gated Intracellular Growth and Resurgence of Uropathogenic Escherichia coli. Microbiol. 8:704-717.