Perforin-2 Is Essential for Intracellular Defense of Parenchymal Cells And
RESEARCH ARTICLE elifesciences.org Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria Ryan M McCormack1, Lesley R de Armas1, Motoaki Shiratsuchi1, Desiree G Fiorentino1, Melissa L Olsson1, Mathias G Lichtenheld1, Alejo Morales1, Kirill Lyapichev1, Louis E Gonzalez1, Natasa Strbo1, Neelima Sukumar2, Olivera Stojadinovic3, Gregory V Plano1, George P Munson1, Marjana Tomic- Canic3, Robert S Kirsner3, David G Russell2, Eckhard R Podack1* 1Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, United States; 2Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, United States; 3Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, United States 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 A˚ 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.
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