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Matthew Long


melng@u.washington.edu
Mentor: Lee-Ann Allen, Ph.D.
Lab Room: D133 MTF
Lab Phone: 319-335-4315

Investigation of Francisella tularensis virulence mechanisms in macrophages

Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Although inhalation of as few as ten organisms of F. tularensis can cause severe or fatal infection, we know relatively little about how this pathogen manipulates the immune response to evade elimination and cause disease. Both macrophages and neutrophils have phagocytic activity and are critical for regulation and function of immune responses. Previous work in the Allen laboratory has defined distinct roles for the mannose receptor and complement receptors in F. tularensis uptake by macrophages. Thereafter, Francisella-containing phagosomes do not undergo normal phagosome maturation and do not fuse with lysosomes. Instead, F. tularensis escapes the phagosome and replicates in the macrophage cytosol. The focus of my research is: 1) to define the mechanisms by which Francisella prevents phagosome-lysosome fusion; and 2) to begin to dissect the mechanism of phagosome escape and replication in the cytosol. A variety of experimental approaches including but not limited to screening a Francisella mutant library, quantitation of intracellular signaling, and confocal microscopy are being used investigate the interplay of host cell and pathogen factors involved in these aspects of virulence. Of current interest are the roles that different protein kinase C (PKC) isoforms have in signaling responses to Francisella. The ultimate goal of my thesis research is to elucidate molecular interactions that allow Francisella to evade killing by macrophages.

Publications:

Faron M, Fletcher JR, Rasmussen JA, Long ME, Allen LA, Jones BD. The Francisella tularensis migR, trmE, and cphA Genes Contribute to F. tularensis Pathogenicity Island Gene Regulation and Intracellular Growth by Modulation of the Stress Alarmone ppGpp. Infect Immun. 2013 Aug;81(8):2800-2811. Epub 2013 May 28. PubMed PMID: 23716606.

Long ME, Lindemann SR, Rasmussen JA, Jones BD, Allen LA. Disruption of Francisella tularensis Schu S4 iglI, iglJ, and pdpC genes results in attenuation for growth in human macrophages and in vivo virulence in mice, and reveals a unique phenotype for pdpC. Infect Immun. Published online ahead of print on 28 December 2012. PMID:23275090

Schwartz JT, Barker JH, Long ME, Kaufman J, McCracken J, Allen LA. Natural IgM Mediates Complement-Dependent Uptake of Francisella tularensis by Human Neutrophils via Complement Receptors 1 and 3 in Nonimmune Serum. J Immunol. 2012 Aug 10. [Epub ahead of print] PubMed PMID: 22888138.

Casbon AJ, Long ME, Dunn KW, Allen LA, Dinauer MC. Effects of IFN-γ on intracellular trafficking and activity of macrophage NADPH oxidase flavocytochrome b558. J Leukoc Biol. 2012 Jul 20. [Epub ahead of print] PubMed PMID: 22822009.

Lindemann SR, Peng K,Long ME, Hunt JR, Apicella MA, Monack DM, Allen LA, Jones BD. Francisella tularensis Schu S4 O-antigen and capsule biosynthesis gene mutants induce early cell death in human macrophages. Infect Immun. 2011 Feb;79(2):581-94. Epub 2010 Nov 15. PubMed PMID: 21078861; PubMed Central PMCID: PMC3028865.

Journal Cover: Journal of Leukocyte Biology Volume 92, Number 4, October 2012. IFN-γ mediated control of subcellular location of gp91phox and p22phox

Abstracts:

10/11/2009

Production of Reactive Oxygen Species and Phagosome-Lysosome Fusion are Uncoupled in Human Monocyte-Derived Macrophages University of Iowa, Department of Molecular and Cellular Biology Annual Retreat Amana, IA

06/06/2009

Replication of Type A and B Strains of Francisella tularensis in Interferon Gamma activated human macrophages. Gordon Research Seminar and Gordon Research Conference: Phagocytes, Waterville Valley, NH

09/26/2009

Replication of Type A and B strains of Francisella tularensis in Interferon Gamma activated human macrophages. University of Iowa, Department of Molecular and Cellular Biology Annual Retreat, Coralville, IA

02/18/2010

Replication of Type A and B strains of Francisella tularensis in Interferon Gamma activated human macrophages. University of Iowa Department of Internal Medicine Research Day Iowa City, IA

02/21/2010-02/24/2010

Replication of Type A and B strains of Francisella tularensis in Interferon Gamma activated human macrophages. 8th American Society For Microbiology Biodefense and Emerging Diseases Research Meeting, Baltimore, MD

10/07/2010-10/09/2010

Replication of Type A and B strains of Francisella tularensis in Interferon Gamma activated human macrophages. Annual Meeting of The Society for Leukocyte Biology and The International Endotoxin and Innate Immunity Society. The Three Rs of Immunity: Recognition, Response, and Resolution. The Fairmont Hotel, Vancouver, BC

02/10/2011

Characterization of Francisella tularensis Schu S4 Mutants Defective for Intracellular Growth in Human Macrophages. University of Iowa Department of Internal Medicine Research Day, Iowa City, IA

04/13/2011

Characterization of Francisella tularensis Schu S4 Mutants Defective for Intracellular Growth in Human Macrophages. University of Iowa Roy J. and Lucile A. Carver College of Medicine Research Day, Iowa City, IA

06/18/2011 - 06/19/2011

Francisella tularensis mutants with defect in LPS O-antigen and capsule biosynthesis exhibit pleiotropic virulence defects and induce rapid macrophage death. Phagocytes Gordon Research Conference, Davidson College, Davidon, NC

04/03/2012 A novel pheontype for a Francisella tularensis SchuS4 FPI mutant. University of Iowa Carver College of Medicine Health Sciences Research Week.

Honors and Awards

  • 2009 MCB Retreat Travel Award for Poster Presentation
  • 2012 Health Science Research Week - Poster Travel Award for Excellence in Research from the VA
  • 2012 University of Iowa Graduate Student Senate Travel Funds Award