Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria

  • Elife. 2015 Sep 24;4:e06508. doi: 10.7554/eLife.06508.
Ryan M McCormack  1 ,  Lesley R de Armas  1 ,  Motoaki Shiratsuchi  1 ,  Desiree G Fiorentino  1 ,  Melissa L Olsson  1 ,  Mathias G Lichtenheld  1 ,  Alejo Morales  1 ,  Kirill Lyapichev  1 ,  Louis E Gonzalez  1 ,  Natasa Strbo  1 ,  Neelima Sukumar  2 ,  Olivera Stojadinovic  3 ,  Gregory V Plano  1 ,  George P Munson  1 ,  Marjana Tomic-Canic  3 ,  Robert S Kirsner  3 ,  David G Russell  2 ,  Eckhard R Podack  1
Affiliations
  • 1. Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States.
  • 2. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, United States.
  • 3. Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, United States.
PMID: 26402460 DOI: 10.7554/eLife.06508
Abstract

Perforin-2 (MPEG1) is a pore-forming, Antibacterial protein with broad-spectrum activity. Perforin-2 is expressed constitutively in phagocytes and inducibly in parenchymal, tissue-forming cells. In vitro, Perforin-2 prevents the intracellular replication and proliferation of Bacterial pathogens in these cells. Perforin-2 knockout mice are unable to control the systemic dissemination of methicillin-resistant Staphylococcus aureus (MRSA) or Salmonella typhimurium and perish shortly after epicutaneous or orogastric Infection respectively. In contrast, Perforin-2-sufficient littermates clear the Infection. Perforin-2 is a transmembrane protein of cytosolic vesicles -derived from multiple organelles- that translocate to and fuse with bacterium containing vesicles. Subsequently, Perforin-2 polymerizes and forms large clusters of 100 Å pores in the Bacterial surface with Perforin-2 cleavage products present in bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species and hydrolytic Enzymes. Perforin-2 constitutes a novel and apparently essential bactericidal effector molecule of the innate immune system.

Keywords
E. coli; MRSA; Mycobacterium tuberculosis; NO; ROS; S. typhimurium; human; immunology; infectious disease; microbiology; mouse; pathogenic bacteria.