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1.
Cell ; 184(6): 1440-1454, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33450204

RESUMEN

Food is simultaneously a source of essential nutrients and a potential source of lethal toxins and pathogens. Consequently, multiple sensory mechanisms evolved to monitor the quality of food based on the presence and relative abundance of beneficial and harmful food substances. These include the olfactory, gustatory, and gut chemosensory systems. Here we argue that, in addition to these systems, allergic immunity plays a role in food quality control by mounting allergic defenses against food antigens associated with noxious substances. Exaggeration of these defenses can result in pathological food allergy.


Asunto(s)
Hipersensibilidad a los Alimentos/patología , Alimentos/efectos adversos , Alérgenos/inmunología , Hipersensibilidad a los Alimentos/inmunología , Humanos , Inmunidad , Modelos Biológicos , Control de Calidad
2.
Cell ; 175(5): 1198-1212.e12, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30293866

RESUMEN

Although chronic gastrointestinal dysmotility syndromes are a common worldwide health problem, underlying causes for these disorders are poorly understood. We show that flavivirus infection of enteric neurons leads to acute neuronal injury and cell death, inflammation, bowel dilation, and slowing of intestinal transit in mice. Flavivirus-primed CD8+ T cells promote these phenotypes, as their absence diminished enteric neuron injury and intestinal transit delays, and their adoptive transfer reestablished dysmotility after flavivirus infection. Remarkably, mice surviving acute flavivirus infection developed chronic gastrointestinal dysmotility that was exacerbated by immunization with an unrelated alphavirus vaccine or exposure to a non-infectious inflammatory stimulus. This model of chronic post-infectious gastrointestinal dysmotility in mice suggests that viral infections with tropism for enteric neurons and the ensuing immune response might contribute to the development of bowel motility disorders in humans. These results suggest an opportunity for unique approaches to diagnosis and therapy of gastrointestinal dysmotility syndromes.


Asunto(s)
Infecciones por Flavivirus/patología , Flavivirus/patogenicidad , Motilidad Gastrointestinal , Intestinos/patología , Animales , Linfocitos T CD8-positivos/inmunología , Flavivirus/genética , Infecciones por Flavivirus/inmunología , Infecciones por Flavivirus/virología , Intestinos/virología , Leucocitos/citología , Leucocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/patología , Neuronas/ultraestructura , ARN Viral/aislamiento & purificación , ARN Viral/metabolismo , Síndrome
3.
Cell ; 166(5): 1247-1256.e4, 2016 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-27565347

RESUMEN

Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.


Asunto(s)
Encefalopatías/virología , Encéfalo/virología , Retardo del Crecimiento Fetal/virología , Complicaciones Infecciosas del Embarazo/virología , Vagina/virología , Replicación Viral , Infección por el Virus Zika/transmisión , Virus Zika/fisiología , Aborto Habitual/virología , Animales , Encefalopatías/inmunología , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/inmunología , Factor 3 Regulador del Interferón/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Receptor de Interferón alfa y beta/genética
4.
J Virol ; 94(22)2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-32878886

RESUMEN

Herpes simplex virus 1 (HSV-1) and HSV-2 can efficiently establish lifelong, transcriptionally silent latency states in sensory neurons to escape host detection. While host factors have previously been associated with long-range insulators in the viral genome, it is still unknown whether host transcription factors can repress viral genes more proximately to promote latency in dorsal root ganglion (DRG) neurons. Here, we assessed whether RUNX (runt-related transcription factor) transcription factors, which are critical in the development of sensory neurons, could be binding HSV-1 genome directly to suppress viral gene expression and lytic infection. Using previously published transcriptome sequencing data, we confirmed that mouse DRG neurons highly express Runx1 mRNA. Through computational analysis of HSV-1 and HSV-2 genomes, we observed that putative RUNX consensus binding sites (CBSs) were more enriched and more closely located to viral gene transcription start sites than would be expected by chance. We further found that RUNX CBSs were significantly more enriched among genomes of herpesviruses compared to those of nonherpesviruses. Utilizing an in vitro model of HSV-1 infection, we found that overexpressed RUNX1 could bind putative binding sites in the HSV-1 genome, repress numerous viral genes spanning all three kinetic classes, and suppress productive infection. In contrast, knockdown of RUNX1 in neuroblastoma cells induced viral gene expression and increased HSV-1 infection in vitro In sum, these data support a novel role for RUNX1 in directly binding herpesvirus genome, silencing the transcription of numerous viral genes, and ultimately limiting overall infection.IMPORTANCE Infecting 90% of the global population, HSV-1 and HSV-2 represent some of the most prevalent viruses in the world. Much of their success can be attributed to their ability to establish lifelong latent infections in the dorsal root ganglia (DRG). It is still largely unknown, however, how host transcription factors are involved in establishing this latency. Here, we report that RUNX1, expressed highly in DRG, binds HSV-1 genome, represses transcription of numerous viral genes, and suppresses productive in vitro infection. Our computational work further suggests this strategy may be used by other herpesviruses to reinforce latency in a cell-specific manner.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Herpesviridae/genética , Herpesviridae/fisiología , Herpesvirus Humano 1/efectos de los fármacos , Animales , Sitios de Unión , Subunidad alfa 2 del Factor de Unión al Sitio Principal/farmacología , Ganglios Espinales/virología , Regulación Viral de la Expresión Génica , Técnicas de Silenciamiento del Gen , Genoma Viral , Células HEK293 , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Humanos , Ratones , Células Receptoras Sensoriales/virología , Ganglio del Trigémino/virología , Activación Viral/fisiología , Latencia del Virus/fisiología
5.
Nature ; 520(7548): 553-7, 2015 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-25642965

RESUMEN

Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.


Asunto(s)
ADN Mitocondrial/metabolismo , Herpesvirus Humano 1/inmunología , Inmunidad Innata/inmunología , Estrés Fisiológico , Animales , Línea Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Proteínas del Grupo de Alta Movilidad/deficiencia , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Factor 3 Regulador del Interferón/metabolismo , Interferón Tipo I/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Nucleotidiltransferasas/metabolismo
6.
PLoS Biol ; 12(1): e1001758, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24409098

RESUMEN

Type III interferon (IFN-λ) exhibits potent antiviral activity similar to IFN-α/ß, but in contrast to the ubiquitous expression of the IFN-α/ß receptor, the IFN-λ receptor is restricted to cells of epithelial origin. Despite the importance of IFN-λ in tissue-specific antiviral immunity, the molecular mechanisms responsible for this confined receptor expression remain elusive. Here, we demonstrate that the histone deacetylase (HDAC) repression machinery mediates transcriptional silencing of the unique IFN-λ receptor subunit (IFNLR1) in a cell-type-specific manner. Importantly, HDAC inhibitors elevate receptor expression and restore sensitivity to IFN-λ in previously nonresponsive cells, thereby enhancing protection against viral pathogens. In addition, blocking HDAC activity renders nonresponsive cell types susceptible to the pro-apoptotic activity of IFN-λ, revealing the combination of HDAC inhibitors and IFN-λ to be a potential antitumor strategy. These results demonstrate that the type III IFN response may be therapeutically harnessed by epigenetic rewiring of the IFN-λ receptor expression program.


Asunto(s)
Epigénesis Genética , Interferón gamma/genética , Receptores de Citocinas/genética , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Islas de CpG , Cricetinae , Citomegalovirus/efectos de los fármacos , Citomegalovirus/fisiología , Metilación de ADN/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatocitos/virología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 1/fisiología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Interferón gamma/metabolismo , Ratones , Células 3T3 NIH , Especificidad de Órganos , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Citocinas/antagonistas & inhibidores , Receptores de Citocinas/metabolismo , Receptores de Interferón , Transducción de Señal , Vesiculovirus/efectos de los fármacos , Vesiculovirus/fisiología
7.
Neuron ; 110(4): 613-626.e9, 2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-34921782

RESUMEN

The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking. Here, we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.


Asunto(s)
Macrófagos , Células Receptoras Sensoriales , Animales , Ganglios Espinales/metabolismo , Humanos , Macrófagos/metabolismo , Ratones , Mitocondrias , Dolor/metabolismo , Células Receptoras Sensoriales/metabolismo
8.
Front Psychol ; 12: 582083, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33981265

RESUMEN

In this interdisciplinary article, we investigate the relationship between creativity and the immune system; the creative features of the immune system and how the immune system and its role in regulating homeostasis might be related to creative cognition. We argue that within a multivariate approach of creativity, the immune system is a contributing factor. New directions for research are also discussed. When astronauts and cosmonauts venture into the new and extreme environment of outer space, their immune system needs to instantly adapt and find new answers to survive biologically and psychologically. Many astronauts report interest in creative activities and therefore represent an interesting group to investigate creativity in relation with the immune system. Little is known regarding (1) how the immune system interacts with and supports creative cognition and behavior, (2) if an individual's immune system, interacting with cognition, adapts more originally to a new environment compared to another's; in other words, if there is creativity in the domain of the immune system, and (3) the creative properties and functions of the immune system itself.

9.
Science ; 371(6535)2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33737460

RESUMEN

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The "on-demand" induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.


Asunto(s)
Carbohidratos de la Dieta/administración & dosificación , Carbohidratos de la Dieta/metabolismo , Enterocitos/fisiología , Interleucinas/metabolismo , Mucosa Intestinal/fisiología , Receptores de Antígenos de Linfocitos T gamma-delta , Subgrupos de Linfocitos T/fisiología , Adaptación Fisiológica , Animales , Comunicación Celular , Proteínas en la Dieta/administración & dosificación , Digestión , Regulación de la Expresión Génica , Interleucinas/genética , Absorción Intestinal , Mucosa Intestinal/citología , Intestino Delgado/citología , Intestino Delgado/metabolismo , Ratones Endogámicos C57BL , Nutrientes/administración & dosificación , Nutrientes/metabolismo , Subgrupos de Linfocitos T/inmunología , Transcripción Genética , Transcriptoma , Interleucina-22
10.
Sci Signal ; 14(704): eabb4324, 2021 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-34637328

RESUMEN

CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)­induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP. Upon pretreatment of cells with increasing concentrations of IFN-α, CD200R switched from inhibiting to potentiating the TLR7- and TLR8-induced expression of the gene encoding IFN-γ, a cytokine that is important for innate and adaptive immunity and is implicated in systemic lupus erythematosus (SLE) pathogenesis. PBMC from patients with SLE, a prototypic type I IFN disease, had an increased abundance of cleaved p120-RasGAP compared to that in cells from healthy controls. In a subset of SLE patients, CD200R stopped functioning as an inhibitory receptor or potentiated TLR-induced IFNG mRNA expression. Thus, our data suggest that type I IFN rewires CD200R signaling to be proinflammatory, which could contribute to the perpetuation of inflammation in patients with SLE.


Asunto(s)
Interferón Tipo I , Leucocitos Mononucleares , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , Interferón Tipo I/genética , Interferón-alfa , Leucocitos Mononucleares/metabolismo , Transducción de Señal
11.
Cell Host Microbe ; 19(1): 9-11, 2016 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-26764592

RESUMEN

Autophagy is a well-known cell-intrinsic antiviral defense mechanism. Two new studies published in this issue of Cell Host & Microbe (Lu et al., 2016; Park et al., 2016) demonstrate that deletion of autophagy in myeloid cells leads paradoxically to better control of viral infection in vivo through enhanced inflammation, leading to antiviral resistance.


Asunto(s)
Autofagia , Macrófagos , Inflamación , Células Mieloides
12.
Cell Host Microbe ; 19(6): 788-99, 2016 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-27281569

RESUMEN

Herpes simplex virus 1 (HSV-1), a leading cause of genital herpes, infects oral or genital mucosal epithelial cells before infecting the peripheral sensory nervous system. The spread of HSV-1 beyond the sensory nervous system and the resulting broader spectrum of disease are not well understood. Using a mouse model of genital herpes, we found that HSV-1-infection-associated lethality correlated with severe fecal and urinary retention. No inflammation or infection of the brain was evident. Instead, HSV-1 spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system (ENS) in the colon. ENS infection led to robust viral gene transcription, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons, ultimately resulting in permanent loss of peristalsis and the development of toxic megacolon. Laxative treatment rescued mice from lethality following genital HSV-1 infection. These results reveal an unexpected pathogenesis of HSV associated with ENS infection.


Asunto(s)
Sistema Nervioso Entérico/virología , Herpes Genital/virología , Herpesvirus Humano 1/patogenicidad , Megacolon Tóxico/virología , Neuronas/virología , Enfermedades Vaginales/virología , Animales , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/patología , Femenino , Ganglios/patología , Ganglios/ultraestructura , Ganglios/virología , Ganglios Espinales/patología , Ganglios Espinales/virología , Genoma Viral , Herpes Genital/patología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiología , Intestinos/virología , Megacolon Tóxico/patología , Ratones , Ratones Endogámicos C57BL , Neuronas/patología , Neutrófilos/virología , Nociceptores/virología , Vagina/virología , Enfermedades Vaginales/patología , Replicación Viral/fisiología
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