Patricia Champion Associate Professor

Molecular Genetics of Mycobacterial Pathogenesis
Patricia Champion

Research Interests:

One in three people globally are infected with Mycobacterium tuberculosis, the causative agent of Tuberculosis (TB). Although only 5-10% of infected people develop active disease, there are still approximately 1.4 million deaths annually (WHO). This burden of infection and disease is in part due to a lack of a viable vaccine that protects adults from pulmonary disease, the most common form of TB. To develop the vaccines and therapeutics needed to control the TB epidemic, we first need a better understanding of M. tuberculosis biology and the mechanisms it uses to cause disease.

A key mechanism that bacteria use to promote their survival is by the targeted transport of bacterial proteins, small molecules or nucleic acids directly into the host (secretion). In the host these molecules directly interact with and disrupt the function of cellular processes which are required for identifying and eliminating the bacteria. Targeted protein secretion is used by several successful bacterial pathogens, including M. tuberculosis, to transport proteins to distinct cellular locations. Through a better understanding of protein transport systems and the proteins they transport we will gain important insight into how mycobacteria interact with the host and cause disease. The long-term goal of my research program is to define the molecular mechanisms underlying mycobacterial pathogenesis. To address this goal, our current research is focused on identifying novel genes and mechanisms required for mycobacterial protein transport. We expect that this course of research will not only expand our understanding M. tuberculosis biology, but may also lead to the identification of novel targets for anti-virulence based therapeutics against TB.

In mycobacteria, targeted secretion requires that protein substrates transverse not only the cytoplasmic membrane (CM), but also the unique mycobacterial cell envelope including the peptidoglycan (CW) and the mycolate outer membrane (MOM). Although multiple protein components are required to move protein substrates across membranes, it is unknown how export occurs. The C-termini of substrates are recognized by components of the export apparatus. After recognition, the substrates are moved through the CM via an unknown mechanism to extra-cytoplasmic destinations including the CW, the MOM, the cell surface (extrinsically associated proteins), and the bacteriological media (exoproteins) in vitro. It is not clear how substrates are targeted to each destination, or which population functions to promote virulence. It is also unknown if substrates are actively exported to the surrounding environment or are extrinsically associated with the bacterial cell and passively released. We are particularly interested in substrate modification, targeting and localization.

 

Biography:

  • Associate Professor, University of Notre Dame, IN 2015-Present
  • Assistant Professor, University of Notre Dame, IN 2009-2015
  • Postdoctoral Fellow, University of California San Francisco, CA 2003-2009
  • PhD. in Molecular Biology, Princeton University, NJ 2003
  • B.S. in Biological Sciences, Carnegie Mellon University, PA 1998

 

Recent Papers:

  • Bosserman RE, Nguyen TT, Sanchez KG, Chirakos EA, Ferrell MJ, Thompson CR, Champion MM, Abramovitch RB, and Champion PA. WhiB6 regulation of ESX-1 gene expression is controlled by a negative feedback loop in Mycobacterium marinum. PNAS, 2017; doi:10.1073/pnas.1710167114
  • Williams EA, Mba Medie F, Bosserman RE, Johnson BK, Reyna C, Ferrell MJ, Champion MM, Abramovitch RB, Champion PA. A Nonsense Mutation in Mycobacterium marinum That Is Suppressible by a Novel Mechanism. Infect Immun. 2017 Jan 26;85(2).
  • Reyna C, Mba Medie F, Champion MM, Champion PA. Rational engineering of a virulence gene from Mycobacterium tuberculosis facilitates proteomic analysis of a natural protein N-terminus. Sci Rep. 2016 Sep 14;6:33265.
  • Johnson BK, Colvin CJ, Needle DB, Mba Medie F, Champion PA, Abramovitch RB. The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence.Antimicrob Agents Chemother. 2015 Aug;59(8):4436-45. 
  • Zhao Y, Riley NM, Sun L, Hebert AS, Yan X, Westphall MS, Rush MJ, Zhu G, Champion MM, Mba Medie F, Champion PA, Coon JJ, Dovichi NJ. Coupling capillary zone electrophoresis with electron transfer dissociation and activated ion electron transfer dissociation for top-down proteomics. Anal Chem. 2015;87(10):5422-9.
  • Mba Medie F, Champion MM, Williams EA, Champion PA. 2014. Homeostasis of N- -terminal acetylation of EsxA correlates with virulence in Mycobacterium marinum. Infection and Immunity. Nov;82(11):4572-86
  • Champion MM, Williams EA, Pinapati RS, Champion PA. 2014. Correlation of phenotypic profiles using targeted proteomics identifies Esx-1 substrates. J Proteome Research. Nov 7;13(11):5151-64.
  • Kennedy GM, Hooley GC, Champion MM, Mba Medie F, Champion PA. 2014. A novel Esx-1 locus reveals that surface-associates Esx-1 substrates mediate virulence in Mycobacterium marinum. J Bacteriology. May;196(10):1877-88.
  • Champion PA. 2013. Disconnecting in vitro Esx-1 secretion from mycobacterial virulence. J. Bacteriol. Dec;195(24):5418-20.
  • Champion MM, Williams EA, Kennedy GM, Champion PA. 2012. Direct detection of bacterial protein secretion using whole colony proteomics. Mol Cell Proteomics. Sep;11(9):596-604.
  • Kennedy GM, Morisaki JH, Champion PA. 2012. Conserved mechanisms of Mycobacterium marinum pathogenesis within the environmental amoeba Acanthamoeba castellanii. Appl Environ Microbiology. 2012 Mar;78(6):2049-52.