Please use this identifier to cite or link to this item:
https://www.arca.fiocruz.br/handle/icict/14882
Type
ArticleCopyright
Open access
Embargo date
2018-07-14
Collections
Metadata
Show full item record
KILLER LYMPHOCYTES USE GRANULYSIN, PERFORIN AND GRANZYMES TO KILL INTRACELLULAR PARASITES.
Granzymes/immunology
Killer Cells Natural/immunology Leishmaniasis
Cutaneous/immunology
Mice Transgenic
Perforin/immunology
T-Lymphocytes
Toxoplasmosis/immunology
Author
Affilliation
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/ Harvard Medical School. Department of Pediatrics. Boston, MA, USA
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/ Harvard Medical School. Department of Pediatrics. Boston, MA, USA.
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/Harvard Medical School. Department of Pediatrics. Boston, MA, USA/ Fundação Oswaldo Cruz.Centro de Pesquisas René Rachou. Belo Horizonte, MG,Brasil.
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA.
Harvard School of Public Health. Department of Immunology and Infectious Diseases. Boston, MA, USA.
Université de Fribourg. Department of Medicine. Fribourg, Switzerland.
Fundação Oswaldo Cruz.Centro de Pesquisas René Rachou. Belo Horizonte, MG,Brasil/ Harvard School of Public Health. Department of Immunology and Infectious Diseases. Boston, MA, USA/niversity of Massachusetts Medical School. Department of Medicine. Worcester, MA, USA.
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/ Harvard Medical School. Department of Pediatrics. Boston, MA, USA
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/ Harvard Medical School. Department of Pediatrics. Boston, MA, USA.
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/Harvard Medical School. Department of Pediatrics. Boston, MA, USA/ Fundação Oswaldo Cruz.Centro de Pesquisas René Rachou. Belo Horizonte, MG,Brasil.
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA.
Harvard School of Public Health. Department of Immunology and Infectious Diseases. Boston, MA, USA.
Université de Fribourg. Department of Medicine. Fribourg, Switzerland.
Fundação Oswaldo Cruz.Centro de Pesquisas René Rachou. Belo Horizonte, MG,Brasil/ Harvard School of Public Health. Department of Immunology and Infectious Diseases. Boston, MA, USA/niversity of Massachusetts Medical School. Department of Medicine. Worcester, MA, USA.
Boston Children's Hospital. Program in Cellular and Molecular Medicine. Boston, MA, USA/ Harvard Medical School. Department of Pediatrics. Boston, MA, USA
Abstract
Protozoan infections are a serious global health problem. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents--granzyme (Gzm) proteases and the pore-forming perforin (PFN)--into the infected cell. However, these cytotoxic molecules do not kill intracellular parasites. CD8(+) CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-γ. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes, and GNLY, PFN and Gzms rapidly kill intracellular bacteria. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell-mediated parasite death, which we term 'microbe-programmed cell death' or 'microptosis', is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism.
Keywords
T-Lymphocyte/immunologyGranzymes/immunology
Killer Cells Natural/immunology Leishmaniasis
Cutaneous/immunology
Mice Transgenic
Perforin/immunology
T-Lymphocytes
Toxoplasmosis/immunology
Share