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1.
Glia ; 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39359232

RESUMEN

Microglial cells are the phagocytic cells of the brain that under physiological conditions participate in brain homeostasis and surveillance. Under pathogenic states, microglia undergoes strong morphological and transcriptional changes potentially leading to sustained neuroinflammation, brain damage, and cognitive disorders. Postnatal and adult Zika virus (ZIKV) brain infection is characterized by the induction of reactive microglia associated with brain inflammation, synapse loss and neuropathogenesis. Contrary to neurons, microglial cells are not infected by ZIKV thus raising the question of the mechanism governing ZIKV-induced microglia's reactivity. In this work, we have questioned the role of exogenous, neuronal type I interferons (IFNs-I) in regulating ZIKV-induced microglia's reactivity. Primary cultured microglial cells were either treated with conditioned media from ZIKV-infected mature neurons or co-cultured with ZIKV-infected neurons. Using either an antibody directed against the IFNAR receptor that neutralizes the IFNs-I response or Ifnar-/-microglial cells, we demonstrate that IFNs-I produced by ZIKV-infected neurons are the main regulators of the phagocytic capacity and the pro-inflammatory gene expression profile of reactive, non-infected microglial cells. We identify protein kinase R (PKR), whose expression is activated by IFNs-I, as a major regulator of the phagocytic capacity, pro-inflammatory response, and morphological changes of microglia induced by IFNs-I while up-regulating STAT1 phosphorylation and IRF1 expression. Results obtained herein in vitro with primary cultured cells and in vivo in ZIKV-infected adult immunocompetent mice, unravel a role for IFNs-I and PKR in directly regulating microglia's reactivity that could be at work in other infectious and non-infectious brain pathologies.

2.
J Neuroinflammation ; 19(1): 307, 2022 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-36539803

RESUMEN

BACKGROUND: Zika virus (ZIKV) infection at postnatal or adult age can lead to neurological disorders associated with cognitive defects. Yet, how mature neurons respond to ZIKV remains substantially unexplored. METHODS: The impact of ZIKV infection on mature neurons and microglia was analyzed at the molecular and cellular levels, in vitro using immunocompetent primary cultured neurons and microglia, and in vivo in the brain of adult immunocompetent mice following intracranial ZIKV inoculation. We have used C57BL/6 and the genetically diverse Collaborative Cross mouse strains, displaying a broad range of susceptibility to ZIKV infection, to question the correlation between the effects induced by ZIKV infection on neurons and microglia and the in vivo susceptibility to ZIKV. RESULTS: As a result of a delayed induction of interferon beta (IFNB) expression and response, infected neurons displayed an inability to stop ZIKV replication, a trait that was further increased in neurons from susceptible mice. Alongside with an enhanced expression of ZIKV RNA, we observed in vivo, in the brain of susceptible mice, an increased level of active Iba1-expressing microglial cells occasionally engulfing neurons and displaying a gene expression profile close to the molecular signature of disease-associated microglia (DAM). In vivo as well as in vitro, only neurons and not microglial cells were identified as infected, raising the question of the mechanisms underlying microglia activation following brain ZIKV infection. Treatment of primary cultured microglia with conditioned media from ZIKV-infected neurons demonstrated that type-I interferons (IFNs-I) secreted by neurons late after infection activate non-infected microglial cells. In addition, ZIKV infection induced pathological phosphorylation of Tau (pTau) protein, a hallmark of neurodegenerative tauopathies, in vitro and in vivo with clusters of neurons displaying pTau surrounded by active microglial cells. CONCLUSIONS: We show that ZIKV-infected mature neurons display an inability to stop viral replication in link with a delayed IFNB expression and response, while signaling microglia for activation through IFNs-I secreted at late times post-infection. In the brain of ZIKV-infected susceptible mice, uninfected microglial cells adopt an active morphology and a DAM expression profile, surrounding and sometimes engulfing neurons while ZIKV-infected neurons accumulate pTau, overall reflecting a tauopathy-like phenotype.


Asunto(s)
Tauopatías , Infección por el Virus Zika , Virus Zika , Ratones , Animales , Infección por el Virus Zika/metabolismo , Virus Zika/genética , Interferón beta/genética , Ratones Endogámicos C57BL , Neuronas/metabolismo , Tauopatías/patología , Replicación Viral , Fenotipo
3.
J Virol ; 95(1)2020 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-33087469

RESUMEN

Rift Valley fever virus (RVFV) is a highly pathogenic zoonotic arbovirus endemic in many African countries and the Arabian Peninsula. Animal infections cause high rates of mortality and abortion among sheep, goats, and cattle. In humans, an estimated 1 to 2% of RVFV infections result in severe disease (encephalitis, hepatitis, or retinitis) with a high rate of lethality when associated with hemorrhagic fever. The RVFV NSs protein, which is the main virulence factor, counteracts the host innate antiviral response to favor viral replication and spread. However, the mechanisms underlying RVFV-induced cytopathic effects and the role of NSs in these alterations remain for the most part unknown. In this work, we have analyzed the effects of NSs expression on the actin cytoskeleton while conducting infections with the NSs-expressing virulent (ZH548) and attenuated (MP12) strains of RVFV and the non-NSs-expressing avirulent (ZH548ΔNSs) strain, as well as after the ectopic expression of NSs. In macrophages, fibroblasts, and hepatocytes, NSs expression prevented the upregulation of Abl2 (a major regulator of the actin cytoskeleton) expression otherwise induced by avirulent infections and identified here as part of the antiviral response. The presence of NSs was also linked to an increased mobility of ZH548-infected cells compared to ZH548ΔNSs-infected fibroblasts and to strong changes in cell morphology in nonmigrating hepatocytes, with reduction of lamellipodia, cell spreading, and dissolution of adherens junctions reminiscent of the ZH548-induced cytopathic effects observed in vivo Finally, we show evidence of the presence of NSs within long actin-rich structures associated with NSs dissemination from NSs-expressing toward non-NSs-expressing cells.IMPORTANCE Rift Valley fever virus (RVFV) is a dangerous human and animal pathogen that was ranked by the World Health Organization in 2018 as among the eight pathogens of most concern for being likely to cause wide epidemics in the near future and for which there are no, or insufficient, countermeasures. The focus of this work is to address the question of the mechanisms underlying RVFV-induced cytopathic effects that participate in RVFV pathogenicity. We demonstrate here that RVFV targets cell adhesion and the actin cytoskeleton at the transcriptional and cellular level, affecting cell mobility and inducing cell shape collapse, along with distortion of cell-cell adhesion. All these effects may participate in RVFV-induced pathogenicity, facilitate virulent RVFV dissemination, and thus constitute interesting potential targets for future development of antiviral therapeutic strategies that, in the case of RVFV, as with several other emerging arboviruses, are presently lacking.


Asunto(s)
Citoesqueleto de Actina/genética , Proteínas Tirosina Quinasas/genética , Fiebre del Valle del Rift/patología , Virus de la Fiebre del Valle del Rift/patogenicidad , Proteínas no Estructurales Virales/metabolismo , Citoesqueleto de Actina/metabolismo , Animales , Adhesión Celular , Línea Celular , Movimiento Celular , Forma de la Célula , Interacciones Huésped-Patógeno , Inmunidad Innata , Ratones , Mutación , Proteínas Tirosina Quinasas/metabolismo , Fiebre del Valle del Rift/metabolismo , Fiebre del Valle del Rift/virología , Virus de la Fiebre del Valle del Rift/genética , Virus de la Fiebre del Valle del Rift/metabolismo , Proteínas no Estructurales Virales/genética , Factores de Virulencia/genética , Factores de Virulencia/metabolismo , Replicación Viral
4.
Nucleic Acids Res ; 46(21): 11405-11422, 2018 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-30321409

RESUMEN

Tauopathies such as Alzheimer's Disease (AD) are neurodegenerative disorders for which there is presently no cure. They are named after the abnormal oligomerization/aggregation of the neuronal microtubule-associated Tau protein. Besides its role as a microtubule-associated protein, a DNA-binding capacity and a nuclear localization for Tau protein has been described in neurons. While questioning the potential role of Tau-DNA binding in the development of tauopathies, we have carried out a large-scale analysis of the interaction of Tau protein with the neuronal genome under physiological and heat stress conditions using the ChIP-on-chip technique that combines Chromatin ImmunoPrecipitation (ChIP) with DNA microarray (chip). Our findings show that Tau protein specifically interacts with genic and intergenic DNA sequences of primary culture of neurons with a preference for DNA regions positioned beyond the ±5000 bp range from transcription start site. An AG-rich DNA motif was found recurrently present within Tau-interacting regions and 30% of Tau-interacting regions overlapped DNA sequences coding for lncRNAs. Neurological processes affected in AD were enriched among Tau-interacting regions with in vivo gene expression assays being indicative of a transcriptional repressor role for Tau protein, which was exacerbated in neurons displaying nuclear pathological oligomerized forms of Tau protein.


Asunto(s)
ADN Intergénico/genética , ADN/química , Neuronas/metabolismo , Proteínas tau/genética , Enfermedad de Alzheimer/genética , Animales , Encéfalo/embriología , Inmunoprecipitación de Cromatina , Hipertermia Inducida , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación , Unión Proteica , Tauopatías , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
5.
J Virol ; 86(20): 11333-44, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22896612

RESUMEN

Rift Valley fever virus (RVFV) is a highly pathogenic Phlebovirus that infects humans and ruminants. Initially confined to Africa, RVFV has spread outside Africa and presently represents a high risk to other geographic regions. It is responsible for high fatality rates in sheep and cattle. In humans, RVFV can induce hepatitis, encephalitis, retinitis, or fatal hemorrhagic fever. The nonstructural NSs protein that is the major virulence factor is found in the nuclei of infected cells where it associates with cellular transcription factors and cofactors. In previous work, we have shown that NSs interacts with the promoter region of the beta interferon gene abnormally maintaining the promoter in a repressed state. In this work, we performed a genome-wide analysis of the interactions between NSs and the host genome using a genome-wide chromatin immunoprecipitation combined with promoter sequence microarray, the ChIP-on-chip technique. Several cellular promoter regions were identified as significantly interacting with NSs, and the establishment of NSs interactions with these regions was often found linked to deregulation of expression of the corresponding genes. Among annotated NSs-interacting genes were present not only genes regulating innate immunity and inflammation but also genes regulating cellular pathways that have not yet been identified as targeted by RVFV. Several of these pathways, such as cell adhesion, axonal guidance, development, and coagulation were closely related to RVFV-induced disorders. In particular, we show in this work that NSs targeted and modified the expression of genes coding for coagulation factors, demonstrating for the first time that this hemorrhagic virus impairs the host coagulation cascade at the transcriptional level.


Asunto(s)
Factores de Coagulación Sanguínea/genética , ADN/genética , Regiones Promotoras Genéticas , Secuencias Reguladoras de Ácidos Nucleicos , Virus de la Fiebre del Valle del Rift/genética , Virus de la Fiebre del Valle del Rift/metabolismo , Proteínas no Estructurales Virales/metabolismo , Animales , Chlorocebus aethiops , Inmunoprecipitación de Cromatina , ADN/metabolismo , Estudio de Asociación del Genoma Completo , Interacciones Huésped-Patógeno/genética , Interferón beta/genética , Análisis por Matrices de Proteínas , ARN Mensajero/genética , Fiebre del Valle del Rift/genética , Fiebre del Valle del Rift/patología , Virus de la Fiebre del Valle del Rift/patogenicidad , Transcripción Genética , Células Vero , Proteínas no Estructurales Virales/análisis
6.
J Biol Chem ; 286(6): 4566-75, 2011 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-21131359

RESUMEN

Tau, a neuronal protein involved in neurodegenerative disorders such as Alzheimer disease, which is primarily described as a microtubule-associated protein, has also been observed in the nuclei of neuronal and non-neuronal cells. However, the function of the nuclear form of Tau in neurons has not yet been elucidated. In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wild-type and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. These results highlight a novel role for nuclear Tau as a key player in early stress response.


Asunto(s)
Núcleo Celular/metabolismo , ADN/metabolismo , Respuesta al Choque Térmico , Neuronas/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Núcleo Celular/genética , Núcleo Celular/patología , Células Cultivadas , ADN/genética , Humanos , Ratones , Ratones Noqueados , Neuronas/patología , Fosforilación/genética , Proteínas tau/genética
7.
PLoS Pathog ; 4(1): e13, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18225953

RESUMEN

Rift Valley fever virus (RVFV) nonstructural protein NSs acts as the major determinant of virulence by antagonizing interferon beta (IFN-beta) gene expression. We demonstrate here that NSs interacts with the host protein SAP30, which belongs to Sin3A/NCoR/HDACs repressor complexes and interacts with the transcription factor YY1 that regulates IFN-beta gene expression. Using confocal microscopy and chromatin immunoprecipitation, we show that SAP30, YY1, and Sin3A-associated corepressor factors strongly colocalize with nuclear NSs filaments and that NSs, SAP30 and Sin3A-associated factors are recruited on the IFN-beta promoter through YY1, inhibiting CBP recruitment, histone acetylation, and transcriptional activation. To ascertain the role of SAP30, we produced, by reverse genetics, a recombinant RVFV in which the interacting domain in NSs was deleted. The virus was unable to inhibit the IFN response and was avirulent for mice. We discuss here the strategy developed by the highly pathogenic RVFV to evade the host antiviral response, affecting nuclear organization and IFN-beta promoter chromatin structure.


Asunto(s)
Histona Desacetilasas/metabolismo , Interferón beta/metabolismo , Proteínas Represoras/metabolismo , Virus de la Fiebre del Valle del Rift/fisiología , Proteínas no Estructurales Virales/metabolismo , Factor de Transcripción YY1/metabolismo , Animales , Núcleo Celular/metabolismo , Células Cultivadas , Chlorocebus aethiops , Regulación Viral de la Expresión Génica , Histona Desacetilasas/genética , Interferón beta/genética , Ratones , Microscopía Confocal , Mutación , Complejo Correpresor Histona Desacetilasa y Sin3 , Técnicas del Sistema de Dos Híbridos , Células Vero , Proteínas no Estructurales Virales/genética , Virulencia
8.
Mol Cell Biol ; 26(22): 8551-61, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16954376

RESUMEN

Virus-induced activation of the beta interferon (IFN-beta) gene requires orderly recruitment of chromatin-remodeling complexes and time-regulated acetylation of histone residues K8H4 and K14H3 on the promoter region. We have previously shown that transcription factor Yin Yang 1 (YY1) binds the murine IFN-beta promoter at two sites (-122 and -90) regulating promoter transcriptional capacity with a dual activator/repressor role. In this work we demonstrate that both YY1 -122 and -90 sites are required for CBP recruitment and K8H4/K14H3 acetylation to take place on the IFN-beta promoter region after virus infection. A single point mutation introduced at either one of these two sites inhibiting YY1 binding completely disrupted CBP recruitment and K8H4/K14H3 acetylation independently of HMGI or IRF3 binding to the promoter. We have previously demonstrated that YY1 represses the transcriptional capacity of the IFN-beta promoter through its -90 site via histone deacetylation. Here we demonstrate that, in vivo, the binding of YY1 to the -90 site is constant all through virus infection whereas the binding of YY1 to the -122 site is activated after infection. We discuss here the capacity of YY1 to either repress (through histone deacetylase recruitment) or activate (through CBP recruitment) IFN-beta gene expression according to the occupancy of either only its -90 site or both its -122 and -90 sites.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Histona Acetiltransferasas/metabolismo , Histonas/genética , Interferón beta/genética , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Factor de Transcripción YY1/genética , Acetilación , Secuencias de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Proteínas de Ciclo Celular/genética , Regulación de la Expresión Génica , Histona Acetiltransferasas/genética , Histonas/metabolismo , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Ratones , Datos de Secuencia Molecular , Factores de Transcripción/genética , Transcripción Genética , Transfección , Factor de Transcripción YY1/metabolismo , Factores de Transcripción p300-CBP
9.
Nucleic Acids Res ; 32(14): 4390-9, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15316102

RESUMEN

Pericentromeric gamma-satellite DNA is organized in constitutive heterochromatin structures. It comprises a 234 bp sequence repeated several thousands times surrounding the centromeric sequence of all murine chromosomes. Potential binding sites for transcription factor Yin Yang 1 (YY1), a repressor or activator of several cellular and viral genes, are present in pericentromeric gamma-satellite DNA. Using gel retardation and chromatin immunoprecipitation, we demonstrate in this work that YY1 specifically interacts in vitro and in vivo with gamma-satellite DNA. Using immunoFISH and confocal microscopy we show that YY1 specifically co-localizes with pericentromeric gamma-satellite DNA clusters organized in constitutive heterochromatin in murine L929 and 3T3 fibroblasts cell lines. Immunoelectron microscopy experiments further confirmed YY1 localization in heterochromatic areas. Overall, our results demonstrate for the first time that a fraction of YY1 is directly associated with constitutive heterochromatin structures. This association appears physiologically relevant since the association of YY1 with pericentromeric gamma-satellite DNA observed in cycling 3T3 fibroblasts strongly diminished in quiescent (G0) 3T3 fibroblasts. We discuss the implications of these results in the context of heterochromatin formation as well as with regard to the YY1-induced repression of euchromatic genes.


Asunto(s)
ADN Satélite/análisis , Proteínas de Unión al ADN/análisis , Heterocromatina/química , Factores de Transcripción/análisis , Animales , Ciclo Celular , División Celular , Núcleo Celular/química , Centrómero , ADN Satélite/metabolismo , Proteínas de Unión al ADN/metabolismo , Factores de Unión al ADN Específico de las Células Eritroides , Eucromatina/química , Eucromatina/ultraestructura , Heterocromatina/ultraestructura , Ratones , Modelos Genéticos , Células 3T3 NIH , Fase de Descanso del Ciclo Celular , Factores de Transcripción/metabolismo , Factor de Transcripción YY1
10.
Mol Cell Biol ; 36(1): 13-29, 2016 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-26459757

RESUMEN

Rapid upregulation of interferon beta (IFN-ß) expression following virus infection is essential to set up an efficient innate antiviral response. Biological roles related to the antiviral and immune response have also been associated with the constitutive production of IFN-ß in naive cells. However, the mechanisms capable of modulating constitutive IFN-ß expression in the absence of infection remain largely unknown. In this work, we demonstrate that inhibition of the kinase glycogen synthase kinase 3 (GSK-3) leads to the upregulation of the constitutive level of IFN-ß expression in noninfected cells, provided that GSK-3 inhibition is correlated with the binding of ß-catenin to the IFN-ß promoter. Under these conditions, IFN-ß expression occurred through the T-cell factor (TCF) binding sites present on the IFN-ß promoter independently of interferon regulatory factor 3 (IRF3). Enhancement of the constitutive level of IFN-ß per se was able to confer an efficient antiviral state to naive cells and acted in synergy with virus infection to stimulate virus-induced IFN-ß expression. Further emphasizing the role of ß-catenin in the innate antiviral response, we show here that highly pathogenic Rift Valley fever virus (RVFV) targets the Wnt/ß-catenin pathway and the formation of active TCF/ß-catenin complexes at the transcriptional and protein level in RVFV-infected cells and mice.


Asunto(s)
Interferón beta/metabolismo , Regiones Promotoras Genéticas , Linfocitos T/metabolismo , Activación Transcripcional/fisiología , Regulación hacia Arriba , beta Catenina/metabolismo , Animales , Sitios de Unión , Glucógeno Sintasa Quinasa 3/metabolismo , Interferón beta/genética , Ratones , Virus de la Fiebre del Valle del Rift , Transducción de Señal/genética , Transducción de Señal/fisiología , Factores de Transcripción TCF/genética , Activación Transcripcional/genética
11.
Sci Rep ; 6: 33047, 2016 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-27605042

RESUMEN

Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer's disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons.


Asunto(s)
Centrómero/genética , Reparación del ADN/genética , Heterocromatina/genética , Neuronas/metabolismo , Transcripción Genética/genética , Proteínas tau/genética , Animales , Encéfalo/metabolismo , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Roturas del ADN , Epigénesis Genética/genética , Histonas/genética , Humanos , Lisina/genética , Ratones , Ratones Noqueados
12.
J Cell Sci ; 119(Pt 10): 2025-34, 2006 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-16638814

RESUMEN

The microtubule-associated tau protein participates in the organization and integrity of the neuronal cytoskeleton. A nuclear form of tau has been described in neuronal and non-neuronal cells, which displays a nucleolar localization during interphase but is associated with nucleolar-organizing regions in mitotic cells. In the present study, based on immunofluorescence, immuno-FISH and confocal microscopy, we show that nuclear tau is mainly present at the internal periphery of nucleoli, partially colocalizing with the nucleolar protein nucleolin and human AT-rich alpha-satellite DNA sequences organized as constitutive heterochromatin. By using gel retardation, we demonstrate that tau not only colocalizes with, but also specifically binds to, AT-rich satellite DNA sequences apparently through the recognition of AT-rich DNA stretches. Here we propose a functional role for nuclear tau in relation to the nucleolar organization and/or heterochromatinization of a portion of RNA genes. Since nuclear tau has also been found in neurons from patients with Alzheimer's disease (AD), aberrant nuclear tau could affect the nucleolar organization during the course of AD. We discuss nucleolar tau associated with AT-rich alpha-satellite DNA sequences as a potential molecular link between trisomy 21 and AD.


Asunto(s)
Nucléolo Celular/metabolismo , ADN Satélite/metabolismo , Proteínas tau/metabolismo , Animales , Ensayo de Cambio de Movilidad Electroforética , Fibroblastos/metabolismo , Células HeLa , Humanos , Hibridación Fluorescente in Situ , Linfocitos/metabolismo , Ratones , Microscopía Confocal , Unión Proteica
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