Professor
Department of Genetics
6202 Marsico Hall
Research
Molecular genetic analysis of virulence of Klebsiella pneumoniae
My laboratory has used several Gram negative bacterial pathogens, Yersinia, Salmonella and Klebsiella as model systems to study bacterial pathogenesis. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level to learn how this interaction affects the pathogenesis of infections, and to understand how these pathogens co-ordinate the expression of virulence determinants during an infection. To do this we use genetic, molecular and immunological approaches, in conjunction with the mouse model of infection.
Currently research in the Miller lab focusses on Klebsiella pneumoniae. Klebsiella pneumoniae (Kpn), is a bacterial pathogen that has a remarkable ability to cause a wide range of human diseases including pneumonia often accompanied with systemic spread to other organs. Kpn strains are broadly divided into two classes: Classical strains that are a notable problem in healthcare settings due to multidrug resistance, and hypervirulent strains that are drug sensitive, but able to establish disease in immunocompetent hosts. Alarmingly, there has been an increased frequency of clinical isolates that have both drug resistance and hv-associated genes. One such hv-associated locus is rmpADC that is required for maximal capsule gene (cps) expression and confers hypermucoviscosity (HMV). The capsule is required by all Kpn strains to cause disease and HMV has been tightly associated with hypervirulence. The lab recently found that RmpA autoregulates the expression of the promoter driving expression of the other two genes in the operon, rmpD and rmpC. The lab showed that RmpC is a transcriptional regulator that is required for maximal cps expression and RmpD is a small protein that is required for the HMV phenotype. Importantly, these analyses indicated that HMV and capsule are separable phenotypes and that HMV and capsule likely make distinct contributions to virulence in a mouse model of pneumonia. RmpC appears to regulate expression of ~200 genes in addition to regulating expression of capsule genes. We are currently employing a variety of approaches to investigate how RmpD and RmpC contribute to HMV, capsule and virulence.
Publications
Ovchinnikova, OG, LP Treat, T Teelucksingh, BR Clarke, TA Miner, C Whitfield, KA Walker and VL Miller. 2023. Hypermucoviscosity regulator RmpD interacts with Wzc and controls capsular polysaccharide chain length. mBio DOI: 10.1128/mbio.00800-23 [PMID: 37140436]
Quinn, JD, EH Weening and VL Miller. 2021. PsaF is a membrane-localized pH sensor that regulates psaA expression in Yersinia pestis. J Bacteriol e0016521. [PMID: 34060904]
Walker, KA, LP Treat, VE Sepúlveda, and VL Miller. 2020. The small protein RmpD drives hypermucoviscosity in Klebsiella pneumoniae. mBio 11(5):e01750-20. [PMID: 32963003]
Walker, KA and VL Miller. 2020. The intersection of capsule gene expression, hypermucoviscosity and hypervirulence in Klebsiella pneumoniae. Curr Opin Microbiol 48:95-102. [PMID: 32062153]
Quinn, JD, EH Weening, TA Miner and VL Miller. 2019. Temperature control of psaA expression by PsaE and PsaF in Y. pestis. J Bacteriol 201: e00217-19 [PMID: 31138630]
Walker, KA, TA Miner, M Palacios, D Trzilova, DR Frederick, CA Broberg, VE Sepúlveda, JD Quinn, and VL Miller. 2019. A Klebsiella pneumoniae regulatory mutant that has reduced capsule expression but retains hypermucoviscosity. mBio 10:e00089-19 [PMID: 30914502]
Will, W, P Brzovic, I Le Trong, R Stenkamp, M Lawrenz, J Karlinsey, W Navarre, K Main-Hester, V Miller, S Libby, and F Fang. 2019. The evolution of SlyA/RovA transcription factors from repressors to counter-silencers in Enterobacteriaceae. mBio:e00009-19. [PMID: 30837332]
Palacios, M, TA Miner, DR Frederick, VE Sepulveda, JD Quinn, KA Walker, and VL Miller. 2018. Identification of two regulators of virulence that are conserved in Klebsiella pneumoniae classical and hypervirulent strains. mBio 9e01443-18. [PMID: 30087173]
Palacios, M, CA Broberg, KA Walker, and VL Miller. 2017. A serendipitous mutation reveals the severe virulence defect of a Klebsiella pneumoniae fepB mutant. mSphere 2:e00341-17. [PMID: 28861522]
Gonzalez, RJ and VL Miller. 2016. A deadly path: Bacterial spread during bubonic plague. Trends Microbiol 24:239-241. [PMID:26875618]
Gonzalez, RJ, EH Weening, MC Lane, and VL Miller. 2015. Comparison of models for bubonic plague reveals unique pathogen adaptations to the dermis. Infect Immun 83:2855-2861. (Recommended for F1000) [PMID: 25939507]
Gonzalez, R. J., M. C. Lane, N. Wagner, E. H. Weening and V. L. Miller. 2015. Dissemination of a highly virulent pathogen: tracking the early events that define infection. PLoS Pathog. 11:e1004587. [PMID: 25611317]
