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1.
Mamm Genome ; 20(7): 414-23, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19641964

RESUMO

NK cell-mediated resistance to viruses is subject to genetic control in humans and mice. Here we used classical and quantitative genetic strategies to examine NK-mediated murine cytomegalovirus (MCMV) control in genealogically related New Zealand white (NZW) and black (NZB) mice. NZW mice display NK cell-dependent MCMV resistance while NZB NK cells fail to limit viral replication after infection. Unlike Ly49H(+) NK resistance in C57BL/6 mice, NZW NK-mediated MCMV control was Ly49H-independent. Instead, MCMV resistance in NZW (Cmv2) involves multiple genetic factors. To establish the genetic basis of Cmv2 resistance, we further characterized a major chromosome X-linked resistance locus (DXMit216) responsible for innate MCMV control in NZW x NZB crosses. We found that the DXMit216 locus affects early MCMV control in New Zealand F(2) crosses and demonstrate that the NZB-derived DXMit216 allele enhances viral resistance in F(2) males. The evolutionary conservation of the DXMit216 region in mice and humans suggests that a Cmv2-related mechanism may affect human antiviral responses.


Assuntos
Infecções por Herpesviridae/veterinária , Imunidade Inata , Camundongos/genética , Muromegalovirus/imunologia , Locos de Características Quantitativas , Doenças dos Roedores/genética , Cromossomo X/genética , Animais , Mapeamento Cromossômico , Feminino , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos/imunologia , Camundongos/virologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Muromegalovirus/fisiologia , Doenças dos Roedores/imunologia , Caracteres Sexuais
2.
J Virol ; 81(1): 229-36, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17050600

RESUMO

NK cells are key effectors of innate immunity and host survival during cytomegalovirus (CMV) infection. Innate murine CMV (MCMV) resistance in MA/My mice requires Ly49H/m157-independent H-2k-linked NK cell control. Here we show that replacement of MA/My H-2k with C57L H-2b susceptibility genes led to a remarkable loss of innate virus immunity, though NK gamma interferon was induced in H-2b and H-2k strains shortly after infection. Thus, H-2b genes expressed in C57L or MA/My.L-H2b are sufficient in alerting NK cells to intrusion but fail to support NK restraint of viral infection. In addition, novel H-2 recombinant strains were produced and utilized in a further refinement of a critical genetic interval controlling innate H-2k-linked MCMV resistance. Importantly, this analysis excluded the gene interval from Kk class I through class II. The responsible gene(s) therefore resides in an interval spanning Dk class Ia and more-distal major histocompatibility complex (MHC) nonclassical class Ib genes. Recently, the NK activation receptor Ly49P and MHC class I Dk proteins were genetically implicated in MCMV resistance, in part because Ly49P-expressing reporter T cells could specifically bind Dk molecules on MCMV-infected mouse embryonic fibroblasts (MEFs). However, as we found that H-2k innate resistance differs in the C57L or MA/My backgrounds and because MCMV very efficiently downregulates H-2k class I proteins in L929 cells and primary MEFs shortly after infection, a Ly49P/Dk model should not fully explain H-2k-linked MCMV resistance.


Assuntos
Antígenos H-2/metabolismo , Infecções por Herpesviridae/imunologia , Imunidade Inata , Complexo Principal de Histocompatibilidade , Muromegalovirus/imunologia , Animais , Regulação para Baixo , Antígenos H-2/genética , Infecções por Herpesviridae/genética , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos , Muromegalovirus/patogenicidade , Muromegalovirus/fisiologia , Replicação Viral
3.
J Immunol ; 175(10): 6820-8, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16272339

RESUMO

Human CMV infections are a major health risk in patients with dysfunctional or compromised immunity, especially in patients with NK cell deficiencies, as these are frequently associated with high morbidity and mortality. In experimental murine CMV (MCMV) infections, Ly49H activation receptors on C57BL/6 (B6) NK cells engage m157 viral ligands on MCMV-infected cells and initiate dominant virus control. In this study, we report that MCMV resistance in MA/My relies on Ly49H-independent NK cell-mediated control of MCMV infection as NK cells in these mice do not bind anti-Ly49H mAb or soluble m157 viral ligands. We genetically compared MA/My resistance with MCMV susceptibility in genealogically and NK gene complex-Ly49 haplotype-related C57L mice. We found that MCMV resistance strongly associated with polymorphic H2k-linked genes, including MHC and non-MHC locations by analysis of backcross and intercross progeny. The H2b haplotype most frequently, but not absolutely, correlated with MCMV susceptibility, thus confirming a role for non-MHC genes in MCMV control. We also demonstrate a definite role for NK cells in H2k-type MCMV resistance because their removal from C57L.M-H2k mice before MCMV infection diminished immunity. NK gene complex-linked polymorphisms, however, did not significantly influence MCMV control. Taken together, effective NK cell-mediated MCMV control in this genetic system required polymorphic H2k genes without need of Ly49H-m157 interactions.


Assuntos
Infecções por Citomegalovirus/imunologia , Antígenos H-2/metabolismo , Células Matadoras Naturais/imunologia , Muromegalovirus/imunologia , Animais , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Feminino , Antígenos H-2/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Muromegalovirus/patogenicidade , Polimorfismo Genético
4.
J Immunol ; 173(10): 6312-8, 2004 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-15528370

RESUMO

Ly49H(+) NK cells play a critical role in innate antiviral immune responses to murine CMV (MCMV). Ly49H(b6) recognition of MCMV-encoded m157 on infected cells activates natural killing required for host resistance. We show that mAb 3D10 (anti-Ly49H) recognizes comparable subsets of NK cells from New Zealand White (NZW), New Zealand Black (NZB), and C57BL/6 spleens. However, virus levels in the spleens of MCMV-infected NZW and NZB mice differed greatly. We found that MCMV replication in infected NZW spleens was limited through NK cells. Alternately, NZB mice were profoundly susceptible to MCMV infection. Although 3D10 mAb injections given before infection interfere with Cmv1-type resistance in C57BL/6 mice, similar mAb injections did not affect NZW resistance, likely because NZW NK cell receptors did not bind MCMV-encoded m157. Instead, anti-MCMV host defenses in hybrid NZ offspring were associated with multiple chromosome locations including several putative quantitative trait loci that did not overlap with H-2 or NK gene complex loci. This study revealed a novel pathway used by NK cells to defend against MCMV infection. Thus, the importance of Ly49H in MCMV infection may be shaped by other additional background genes.


Assuntos
Antígenos Ly/fisiologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Muromegalovirus/imunologia , Doença Aguda , Animais , Antígenos Ly/biossíntese , Antígenos Ly/genética , Antígenos de Superfície/biossíntese , Antígenos de Superfície/genética , Linhagem Celular , Citotoxicidade Imunológica/genética , Marcadores Genéticos , Predisposição Genética para Doença , Infecções por Herpesviridae/genética , Humanos , Hibridomas , Imunidade Inata/genética , Células Matadoras Naturais/virologia , Lectinas Tipo C/biossíntese , Lectinas Tipo C/genética , Ativação Linfocitária/genética , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB , Muromegalovirus/genética , Células NIH 3T3 , Subfamília A de Receptores Semelhantes a Lectina de Células NK , Subfamília B de Receptores Semelhantes a Lectina de Células NK , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Receptores Semelhantes a Lectina de Células NK
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