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1.
Cell ; 186(22): 4818-4833.e25, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37804831

RESUMO

MXRA8 is a receptor for chikungunya (CHIKV) and other arthritogenic alphaviruses with mammalian hosts. However, mammalian MXRA8 does not bind to alphaviruses that infect humans and have avian reservoirs. Here, we show that avian, but not mammalian, MXRA8 can act as a receptor for Sindbis, western equine encephalitis (WEEV), and related alphaviruses with avian reservoirs. Structural analysis of duck MXRA8 complexed with WEEV reveals an inverted binding mode compared with mammalian MXRA8 bound to CHIKV. Whereas both domains of mammalian MXRA8 bind CHIKV E1 and E2, only domain 1 of avian MXRA8 engages WEEV E1, and no appreciable contacts are made with WEEV E2. Using these results, we generated a chimeric avian-mammalian MXRA8 decoy-receptor that neutralizes infection of multiple alphaviruses from distinct antigenic groups in vitro and in vivo. Thus, different alphaviruses can bind MXRA8 encoded by different vertebrate classes with distinct engagement modes, which enables development of broad-spectrum inhibitors.


Assuntos
Alphavirus , Animais , Humanos , Febre de Chikungunya , Vírus Chikungunya/química , Mamíferos , Receptores Virais/metabolismo
2.
Mol Ecol ; 27(8): 1860-1873, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29533484

RESUMO

A mechanistic understanding of community ecology requires tackling the nonadditive effects of multispecies interactions, a challenge that necessitates integration of ecological and molecular complexity-namely moving beyond pairwise ecological interaction studies and the "gene at a time" approach to mechanism. Here, we investigate the consequences of multispecies mutualisms for the structure and function of genomewide differential coexpression networks for the first time, using the tractable and ecologically important interaction between legume Medicago truncatula, rhizobia and mycorrhizal fungi. First, we found that genes whose expression is affected nonadditively by multiple mutualists are more highly connected in gene networks than expected by chance and had 94% greater network centrality than genes showing additive effects, suggesting that nonadditive genes may be key players in the widespread transcriptomic responses to multispecies symbioses. Second, multispecies mutualisms substantially changed coexpression network structure of 18 modules of host plant genes and 22 modules of the fungal symbionts' genes, indicating that third-party mutualists can cause significant rewiring of plant and fungal molecular networks. Third, we found that 60% of the coexpressed gene sets that explained variation in plant performance had coexpression structures that were altered by interactive effects of rhizobia and fungi. Finally, an "across-symbiosis" approach identified sets of plant and mycorrhizal genes whose coexpression structure was unique to the multiple mutualist context and suggested coupled responses across the plant-mycorrhizal interaction to rhizobial mutualists. Taken together, these results show multispecies mutualisms have substantial effects on the molecular interactions in host plants, microbes and across symbiotic boundaries.


Assuntos
Medicago truncatula/genética , Micorrizas/genética , Rhizobiaceae/genética , Simbiose/genética , Ecologia , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes/genética , Medicago truncatula/microbiologia , Transcriptoma/genética
3.
Cell Rep ; 43(10): 114809, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39369384

RESUMO

The very-low-density lipoprotein receptor (VLDLR) has been reported as an entry receptor for Semliki Forest (SFV) and Eastern equine encephalitis (EEEV) alphaviruses in cell cultures. However, the role of VLDLR in alphavirus pathogenesis and the extent to which other alphaviruses can engage VLDLR remains unclear. Here, using a surface protein-targeted CRISPR-Cas9 screen, we identify VLDLR as a receptor for Western equine encephalitis virus (WEEV) and demonstrate that it promotes the infection of multiple viruses in the WEE antigenic complex. In vivo studies show that the pathogenicity of WEEV, EEEV, and SFV, but not the distantly related Venezuelan equine encephalitis virus, is markedly diminished in VLDLR-deficient mice and that mice treated with a soluble VLDLR-Fc decoy molecule are protected against disease. Overall, these results expand our understanding of the role of VLDLR in alphavirus pathogenesis and provide a potential path for developing countermeasures against alphaviruses from different antigenic complexes.


Assuntos
Receptores de LDL , Animais , Receptores de LDL/metabolismo , Receptores de LDL/genética , Camundongos , Humanos , Camundongos Endogâmicos C57BL , Internalização do Vírus , Infecções por Alphavirus/virologia , Infecções por Alphavirus/patologia , Alphavirus/patogenicidade , Vírus da Encefalite Equina do Oeste/metabolismo , Vírus da Encefalite Equina do Oeste/patogenicidade , Camundongos Knockout , Células HEK293
4.
J Clin Invest ; 133(13)2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37279078

RESUMO

Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-Seq revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET- and EOMES-deleted CD56bright NK cells acquired an innate lymphoid cell precursor-like (ILCP-like) profile with increased expression of the ILC-3-associated TFs RORC and AHR, revealing a role for T-box TFs in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity.


Assuntos
Imunidade Inata , Proteínas com Domínio T , Humanos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Matadoras Naturais/metabolismo , Fatores de Transcrição/metabolismo , Citocinas/metabolismo
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