Marcia Goldberg, MD

Goldberg Laboratory

Research within the Marcia B. Goldberg, MD Laboratory focuses on the molecular nature of interactions between microbial pathogens and the host and the development of rapid diagnostics for infectious diseases.

Overview

Our research focuses on two related scientific ideas:

  1. The molecular nature of interactions between microbial pathogens and the host, with an emphasis on the intracellular human pathogen Shigella, a major cause of diarrhea and dysentery
  2. The development of rapid diagnostics for infectious diseases.

Our Team

Marcia B. Goldberg, MD
Professor of Medicine, Harvard Medical School

Heather D. Eshleman, PhD, postdoctoral fellow

Kelly A. Miller, PhD, postdoctoral fellow

Brian C. Russo, PhD, postdoctoral fellow

Alexandra Wiscovitch, post-baccalaureate student

Austin Hachey, technician

Our Research

Alteration of host cell biology by bacterial pathogens

Our research focuses on the interface of bacterial pathogens with human cells. Most gram-negative bacterial pathogens use specialized secretion systems (“type III secretion systems”) to deliver virulence proteins into human cells during infection. The proteins that are delivered by this means (“effector proteins”) manipulate human signaling pathways, cytoskeletal dynamics, and innate and adaptive immune responses, in ways that promote disease. These effector proteins are absolutely necessary for disease. Using genome-wide screens, we identified human signaling pathways required for infection by the gram-negative bacterial pathogen Shigella flexneri. Shigella are important human pathogens that cause diarrhea and dysentery, predominantly in daycare centers, institutions, and developing regions of the world.

We investigate:

  1. The molecular mechanisms by which bacterial effector proteins alter cellular targets and cellular signaling pathways
  2. The mechanisms by which human signaling pathways identified in our screens contribute to infection

Images

Images Legends
Goldberg Lab Image 1
Shigella triggers its own entry into intestinal epithelial cells. Uptake of Shigella occurs upon activation of host cell actin polymerization and the formation of plasma membrane extensions that engulf the bacteria. The Shigella proteins that cause actin polymerization and membrane extensions are delivered into the cell via a specialized secretion system, the type 3 secretion system. Red, phalloidin staining of cellular actin; blue, DAPI staining of bacterial and cellular DNA; green, bacteria that have not yet entered the cell.
Goldberg Lab Image 2
Shigella is able to move within and spread between cells by assembling actin at the pole of the bacterium, a process that generates force. In this fluorescence microscopy image, the bacterium is indicated in blue (DAPI staining of DNA), the comet-like actin tail in red (phalloidin staining of actin), and N-WASP, a cellular actin nucleation promoting factor recruited and activated by Shigella, in green (GFP-N-WASP).
Goldberg Lab Image 3
During Shigella spread from one cell into an adjacent cell, the bacterium pushes out within a sleeve of plasma membrane ("protrusion") that is subsequently engulfed by the adjacent cell. Left, phase micrograph showing Shigella at the tips of two protrusions. Right, fluorescent micrograph of Shigella at the tips of two protrusions. Green, tail of polymerized actin behind each Shigella bacterium; blue, DAPI staining of bacterial and cellular DNA.
Goldberg Lab Image 4
Like many other gram-negative bacterial pathogens, Shigella delivers proteins into the cytoplasm of host cells from outside the cell. The proteins that are delivered - effector proteins – alter the function of host proteins in ways that promote bacterial infection. The apparatus by which these proteins are delivered - the type 3 secretion apparatus – consists of a long needle-like structure that extends from the bacterial surface. When the tip of the needle contacts with the plasma membrane, two bacterial proteins are secreted through the needle that form a pore (translocon pore) in the plasma membrane. The needle docks onto the pore, thereby creating a continuous channel from the bacterial cytoplasm (bottom of image) to the host cell cytoplasm (top of image), through which effector proteins are delivered. We showed that host cell intermediate filaments bind one of the pore proteins and that this binding interaction is required for docking of the needle onto the pore (Russo BC et al., Nat Microbiol, 2016).

Publications

View a full list of our publications on PubMed.

  1. Russo BC, Stamm LM, Raaben M, Kim CM, Kahoud E, Robinson LR, Bose S, Queiroz AL, Herrera BB, Baxt LA, Mor-Vaknin N, Fu Y, Molina G, Markovitz DM, Whelan SP, Goldberg MB. Intermediate filaments enable pathogen docking to trigger type 3 effector translocation. Nat Microbiol. 2016. Article No. 16025; DOI: 10.1038.
  2. Lu R, Herrera BB, Eshleman HD, Fu Y, Bloom A, Li Z, Sacks DB, Goldberg MB. Shigella effector OspB activates mTORC1 in a manner that depends on IQGAP1 and promotes cell proliferation. PLoS Pathogens. 2015; 11(10):e1005200. PMC4608727.
  3. Lee SY, Gertler FB, Goldberg MB. Vasodilator-stimulated phosphoprotein (VASP) restricts cell-to-cell spread of Shigella flexneri at the cell periphery. Microbiology. 2015; 161:2149-2160. PMC4806587.
  4. Garza-Mayers AC, Miller KA, Russo BC, Nagda DV, Goldberg MB. Shigella flexneri regulation of ARF6 activation during bacterial entry via an IpgD-mediated positive feedback loop. mBio. 2015; 6(2). pii: e02584-14. PMC4358011
  5. Yi C-R, Allen JE, Russo B, Lee SY, Heindl JE, Baxt LA, Herrera BB, Kahoud E, MacBeath G, Goldberg MB. Systematic analysis of bacterial effector-postsynaptic density 95/discs large/zonula occludens-1 (PDZ) interactions demonstrates Shigella OspE promotes PKC activation via PDLIM proteins. J Biol Chem. 2014; 289:30101-30113. PMC4208017
  6. Baxt LA, Goldberg MB. Host and bacterial proteins that repress recruitment of LC3 to Shigella early during infection. PLoS One. 2014;9(4):e94653. PMC3983221
  7. Li Z, Boyd D, Reindl M, Goldberg MB. Identification of YidC residues that define interactions with the Sec Apparatus. J Bacteriol. 2014;196(2):367-77. PMC3911256
  8. Gray AN, Li Z, Henderson-Frost J, Goldberg MB. Biogenesis of YidC cytoplasmic membrane substrates is required for positioning of autotransporter IcsA at future poles. J Bacteriol. 2014;196(3):624-32. PMC3911155
  9. Baxt LA, Garza-Mayers AC, Goldberg MB. Bacterial subversion of host innate immune pathways. 2013;340(6133):697-701.
  10. Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA, Vyas JM, Goldberg MB, Xavier RJ. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe. 2012;12(6):778-90. PMCID: PMC3785244
  11. Fixen KR, Janakiraman A, Garrity S, Slade DJ, Gray AN, Karahan N, Hochschild A, Goldberg MB. Genetic reporter system for positioning of proteins at the bacterial pole. MBio. 2012;3(2). PMC3302567
  12. Gray AN, Henderson-Frost JM, Boyd D, Shirafi S, Niki H, Goldberg MB. Unbalanced charge distribution as a determinant for dependence of a subset of E. coli membrane proteins on the membrane insertase YidC. 2011; 2(6): doi:10.1128/mBio.00238-11. PMC3911155
  13. Stamm LM, Goldberg MB. Establishing the secretion hierarchy. Science 2011 4;331(6021): 1147-1148.
  14. Jehl S, Doling A, Giddings, KS, Phalipon A, Sansonetti PJ, Goldberg MB, Starnbach MN. Antigen-specific CD8+ T cells fail to respond to Shigella flexneri. Infect Immun. 2011: 79(5); 2021-2030. PMC3088127
  15. Stamm LM, Heller DM, Goldberg MB. Caging targets for destruction. Cell Host Microbe. 2010: 8: 391-393.
  16. Baxt LA, Goldberg MB. Anaerobic environment of the intestine primes pathogenic Shigella for infection. Expert Rev Anti Infect Ther. 2010: 8(11): 1225-1229.
  17. Lu R, Goldberg MB. Bacterial Exploitation of Host Cell Signaling. Sci Transl Med 2010; 2(51): 48.
  18. Heindl JE, Saran I, Yi CR, Lesser CF, Goldberg MB. Requirement for formin-induced actin polymerization during spread of Shigella. Infect Immun. 2009 Jan; 78(1):193-203. PMC2798232
  19. Yi CR, Goldberg MB. Enterohemorrhagic Escherichia coli raises the I-BAR. Proc Natl Acad Sci USA 2009; 106(16): 6431-2.
  20. Yi CR, Goldberg MB. Putting enterohemorrhagic E. coli on a pedestal. Cell Host Microbe 2009; 5(3): 215-7.
  21. Janakiraman A, Fixen KR, Gray AN, Niki H, Goldberg MB. A genome-scale screen identifies a role for DnaK in chaperoning of polar autotransporters in Shigella. J Bacteriol. 2009; 191(20): 6300-6311. PMC2753027
  22. Wagner JK, Heindl JE, Gray AN, Jain S, Goldberg MB. Contribution of the periplasmic chaperone Skp to efficient presentation of the autotransporter IcsA on the surface of Shigella flexneri. J Bacteriol. 2009 Feb;191(3):815-821. PMC2632083

Contact

Contact Us

Marcia B. Goldberg, MD

  • Phone: 617-768-8741
  • Fax: 617-768-8738
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