An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.

Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective...

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Autores principales:	Silayuv E Bongfen, Ian-Gael Rodrigue-Gervais, Joanne Berghout, Sabrina Torre, Pablo Cingolani, Sean A Wiltshire, Gabriel A Leiva-Torres, Louis Letourneau, Robert Sladek, Mathieu Blanchette, Mark Lathrop, Marcel A Behr, Samantha Gruenheid, Silvia M Vidal, Maya Saleh, Philippe Gros
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f2ebc22ce44b429ab6dc2ed68254a468
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spelling	oai:doaj.org-article:f2ebc22ce44b429ab6dc2ed68254a4682021-11-18T07:27:24ZAn N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.1932-620310.1371/journal.pone.0031012https://doaj.org/article/f2ebc22ce44b429ab6dc2ed68254a4682012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363534/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.Silayuv E BongfenIan-Gael Rodrigue-GervaisJoanne BerghoutSabrina TorrePablo CingolaniSean A WiltshireGabriel A Leiva-TorresLouis LetourneauRobert SladekMathieu BlanchetteMark LathropMarcel A BehrSamantha GruenheidSilvia M VidalMaya SalehPhilippe GrosPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 2, p e31012 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Silayuv E Bongfen Ian-Gael Rodrigue-Gervais Joanne Berghout Sabrina Torre Pablo Cingolani Sean A Wiltshire Gabriel A Leiva-Torres Louis Letourneau Robert Sladek Mathieu Blanchette Mark Lathrop Marcel A Behr Samantha Gruenheid Silvia M Vidal Maya Saleh Philippe Gros An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
description	Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.
format	article
author	Silayuv E Bongfen Ian-Gael Rodrigue-Gervais Joanne Berghout Sabrina Torre Pablo Cingolani Sean A Wiltshire Gabriel A Leiva-Torres Louis Letourneau Robert Sladek Mathieu Blanchette Mark Lathrop Marcel A Behr Samantha Gruenheid Silvia M Vidal Maya Saleh Philippe Gros
author_facet	Silayuv E Bongfen Ian-Gael Rodrigue-Gervais Joanne Berghout Sabrina Torre Pablo Cingolani Sean A Wiltshire Gabriel A Leiva-Torres Louis Letourneau Robert Sladek Mathieu Blanchette Mark Lathrop Marcel A Behr Samantha Gruenheid Silvia M Vidal Maya Saleh Philippe Gros
author_sort	Silayuv E Bongfen
title	An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
title_short	An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
title_full	An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
title_fullStr	An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
title_full_unstemmed	An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
title_sort	n-ethyl-n-nitrosourea (enu)-induced dominant negative mutation in the jak3 kinase protects against cerebral malaria.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/f2ebc22ce44b429ab6dc2ed68254a468
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An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.

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