Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence

ABSTRACT The Toxoplasma gondii SRS gene superfamily is structurally related to SRS29B (formerly SAG1), a surface adhesin that binds host cells and stimulates host immunity. Comparative genomic analyses of three Toxoplasma strains identified 182 SRS genes distributed across 14 chromosomes at 57 genom...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	James D. Wasmuth, Viviana Pszenny, Simon Haile, Emily M. Jansen, Alexandra T. Gast, Alan Sher, Jon P. Boyle, Martin J. Boulanger, John Parkinson, Michael E. Grigg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2012
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/29c657891aca450c82653a06a7d1225a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:29c657891aca450c82653a06a7d1225a
record_format	dspace
spelling	oai:doaj.org-article:29c657891aca450c82653a06a7d1225a2021-11-15T15:39:11ZIntegrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence10.1128/mBio.00321-122150-7511https://doaj.org/article/29c657891aca450c82653a06a7d1225a2012-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00321-12https://doaj.org/toc/2150-7511ABSTRACT The Toxoplasma gondii SRS gene superfamily is structurally related to SRS29B (formerly SAG1), a surface adhesin that binds host cells and stimulates host immunity. Comparative genomic analyses of three Toxoplasma strains identified 182 SRS genes distributed across 14 chromosomes at 57 genomic loci. Eight distinct SRS subfamilies were resolved. A core 69 functional gene orthologs were identified, and strain-specific expansions and pseudogenization were common. Gene expression profiling demonstrated differential expression of SRS genes in a developmental-stage- and strain-specific fashion and identified nine SRS genes as priority targets for gene deletion among the tissue-encysting coccidia. A Δsag1 ∆sag2A mutant was significantly attenuated in murine acute virulence and showed upregulated SRS29C (formerly SRS2) expression. Transgenic overexpression of SRS29C in the virulent RH parent was similarly attenuated. Together, these findings reveal SRS29C to be an important regulator of acute virulence in mice and demonstrate the power of integrated genomic analysis to guide experimental investigations. IMPORTANCE Parasitic species employ large gene families to subvert host immunity to enable pathogen colonization and cause disease. Toxoplasma gondii contains a large surface coat gene superfamily that encodes adhesins and virulence factors that facilitate infection in susceptible hosts. We generated an integrated bioinformatic resource to predict which genes from within this 182-gene superfamily of adhesin-encoding genes play an essential role in the host-pathogen interaction. Targeted gene deletion experiments with predicted candidate surface antigens identified SRS29C as an important negative regulator of acute virulence in murine models of Toxoplasma infection. Our integrated computational and experimental approach provides a comprehensive framework, or road map, for the assembly and discovery of additional key pathogenesis genes contained within other large surface coat gene superfamilies from a broad array of eukaryotic pathogens.James D. WasmuthViviana PszennySimon HaileEmily M. JansenAlexandra T. GastAlan SherJon P. BoyleMartin J. BoulangerJohn ParkinsonMichael E. GriggAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 3, Iss 6 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 James D. Wasmuth Viviana Pszenny Simon Haile Emily M. Jansen Alexandra T. Gast Alan Sher Jon P. Boyle Martin J. Boulanger John Parkinson Michael E. Grigg Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence
description	ABSTRACT The Toxoplasma gondii SRS gene superfamily is structurally related to SRS29B (formerly SAG1), a surface adhesin that binds host cells and stimulates host immunity. Comparative genomic analyses of three Toxoplasma strains identified 182 SRS genes distributed across 14 chromosomes at 57 genomic loci. Eight distinct SRS subfamilies were resolved. A core 69 functional gene orthologs were identified, and strain-specific expansions and pseudogenization were common. Gene expression profiling demonstrated differential expression of SRS genes in a developmental-stage- and strain-specific fashion and identified nine SRS genes as priority targets for gene deletion among the tissue-encysting coccidia. A Δsag1 ∆sag2A mutant was significantly attenuated in murine acute virulence and showed upregulated SRS29C (formerly SRS2) expression. Transgenic overexpression of SRS29C in the virulent RH parent was similarly attenuated. Together, these findings reveal SRS29C to be an important regulator of acute virulence in mice and demonstrate the power of integrated genomic analysis to guide experimental investigations. IMPORTANCE Parasitic species employ large gene families to subvert host immunity to enable pathogen colonization and cause disease. Toxoplasma gondii contains a large surface coat gene superfamily that encodes adhesins and virulence factors that facilitate infection in susceptible hosts. We generated an integrated bioinformatic resource to predict which genes from within this 182-gene superfamily of adhesin-encoding genes play an essential role in the host-pathogen interaction. Targeted gene deletion experiments with predicted candidate surface antigens identified SRS29C as an important negative regulator of acute virulence in murine models of Toxoplasma infection. Our integrated computational and experimental approach provides a comprehensive framework, or road map, for the assembly and discovery of additional key pathogenesis genes contained within other large surface coat gene superfamilies from a broad array of eukaryotic pathogens.
format	article
author	James D. Wasmuth Viviana Pszenny Simon Haile Emily M. Jansen Alexandra T. Gast Alan Sher Jon P. Boyle Martin J. Boulanger John Parkinson Michael E. Grigg
author_facet	James D. Wasmuth Viviana Pszenny Simon Haile Emily M. Jansen Alexandra T. Gast Alan Sher Jon P. Boyle Martin J. Boulanger John Parkinson Michael E. Grigg
author_sort	James D. Wasmuth
title	Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence
title_short	Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence
title_full	Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence
title_fullStr	Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence
title_full_unstemmed	Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence
title_sort	integrated bioinformatic and targeted deletion analyses of the srs gene superfamily identify srs29c as a negative regulator of <italic toggle="yes">toxoplasma</italic> virulence
publisher	American Society for Microbiology
publishDate	2012
url	https://doaj.org/article/29c657891aca450c82653a06a7d1225a
work_keys_str_mv	AT jamesdwasmuth integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT vivianapszenny integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT simonhaile integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT emilymjansen integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT alexandratgast integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT alansher integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT jonpboyle integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT martinjboulanger integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT johnparkinson integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence AT michaelegrigg integratedbioinformaticandtargeteddeletionanalysesofthesrsgenesuperfamilyidentifysrs29casanegativeregulatorofitalictoggleyestoxoplasmaitalicvirulence
_version_	1718427754540564480

Integrated Bioinformatic and Targeted Deletion Analyses of the SRS Gene Superfamily Identify SRS29C as a Negative Regulator of <italic toggle="yes">Toxoplasma</italic> Virulence

Ejemplares similares