Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites.

dc.creatorDotiwala, Farokh
dc.creatorMulik, Sachin
dc.creatorBarbosa, Rafael Polidoro Alves
dc.creatorAnsara, James A
dc.creatorBurleigh, Barbara A
dc.creatorWalch, Michael
dc.creatorGazzinelli, Ricardo Tostes
dc.creatorLieberman, Judy
dc.date2016-07-14T13:53:44Z
dc.date2016-07-14T13:53:44Z
dc.date2016
dc.date.accessioned2023-09-27T00:08:02Z
dc.date.available2023-09-27T00:08:02Z
dc.identifierDOTIWALA, Farokh et al. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nat Med., vol. 22, n. 2, p. 2010-216, 2016
dc.identifier1078-8956
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/14882
dc.identifier10.1038/nm.4023
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8897761
dc.descriptionProtozoan 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.
dc.description2018-07-14
dc.formatapplication/pdf
dc.languageeng
dc.publisherNature Publishing Company
dc.rightsopen access
dc.subjectT-Lymphocyte/immunology
dc.subjectGranzymes/immunology
dc.subjectKiller Cells Natural/immunology Leishmaniasis
dc.subjectCutaneous/immunology
dc.subjectMice Transgenic
dc.subjectPerforin/immunology
dc.subjectT-Lymphocytes
dc.subjectToxoplasmosis/immunology
dc.titleKiller lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites.
dc.typeArticle


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