RESUMEN
Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel components of the TRAF3 interactome network. Notably, in non-infected cells, TRAF3 was found associated with markers of the ER-Exit-Sites (ERES), ER-to-Golgi intermediate compartment (ERGIC) and the cis-Golgi apparatus. Upon dsRNA and dsDNA sensing however, the Golgi apparatus fragmented into cytoplasmic punctated structures containing TRAF3 allowing its colocalization and interaction with Mitochondrial AntiViral Signaling (MAVS), the essential mitochondria-bound RIG-I-like Helicase (RLH) adaptor. In contrast, retention of TRAF3 at the ER-to-Golgi vesicular transport system blunted the ability of TRAF3 to interact with MAVS upon viral infection and consequently decreased type I IFN response. Moreover, depletion of Sec16A and p115 led to a drastic disorganization of the Golgi paralleled by the relocalization of TRAF3, which under these conditions was unable to associate with MAVS. Consequently, upon dsRNA and dsDNA sensing, ablation of Sec16A and p115 was found to inhibit IRF3 activation and anti-viral gene expression. Reciprocally, mild overexpression of Sec16A or p115 in Hec1B cells increased the activation of IFNß, ISG56 and NF-κB -dependent promoters following viral infection and ectopic expression of MAVS and Tank-binding kinase-1 (TBK1). In line with these results, TRAF3 was found enriched in immunocomplexes composed of p115, Sec16A and TBK1 upon infection. Hence, we propose a model where dsDNA and dsRNA sensing induces the formation of membrane-bound compartments originating from the Golgi, which mediate the dynamic association of TRAF3 with MAVS leading to an optimal induction of innate immune responses.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Inmunidad Innata , Factor 3 Asociado a Receptor de TNF/genética , Factor 3 Asociado a Receptor de TNF/metabolismo , Línea Celular , ADN/metabolismo , Perfilación de la Expresión Génica , Proteínas de la Matriz de Golgi , Células HEK293 , Células HeLa , Humanos , Factor 3 Regulador del Interferón/antagonistas & inhibidores , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/biosíntesis , Interferón beta/genética , Mitocondrias/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Proteoma , Interferencia de ARN , ARN Bicatenario/metabolismo , ARN Interferente Pequeño , Proteínas de Unión al ARN , Transducción de Señal , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
A growing proportion of critically ill patients admitted in ICUs are older adults. The need for improving care provided to older adults in critical care settings to optimize functional status and quality of life for survivors is acknowledged, but the optimal model of care remains unknown. We aimed to identify and describe reported models of care. DATA SOURCES: We conducted a scoping review on critically ill older adults hospitalized in the ICU. Medline (PubMed), Embase (OvidSP), Cumulative Index to Nursing and Allied Health Literature (Ebsco), and Web of Science (Clarivate) were searched from inception to May 5, 2020. STUDY SELECTION: We included original articles, published abstracts, review articles, editorials, and commentaries describing or discussing the implementation of geriatric-based models of care in critical care, step-down units, and trauma centers. The organization of care had to be described. Articles only discussing geriatric syndromes and specific interventions were not included. DATA EXTRACTION: Full texts of included studies were obtained. We collected publication and study characteristics, structures of care, human resources used, interventions done or proposed, results, and measured outcomes. Data abstraction was done by two investigators and reconciled, and disagreements were resolved by discussion. DATA SYNTHESIS: Our search identified 3,765 articles, and we found 19 reporting on the implementation of geriatric-based models of care in the setting of critical care. Four different models of care were identified: dedicated geriatric beds, geriatric assessment by a geriatrician, geriatric assessment without geriatrician, and a fourth model called "other approaches" including geriatric checklists, bundles of care, and incremental educational strategies. We were unable to assess the superiority of any model due to limited data. CONCLUSIONS: Multiple models have been reported in the literature with varying degrees of resource and labor intensity. More data are required on the impact of these models, their feasibility, and cost-effectiveness.
RESUMEN
Vitamin C is a novel treatment currently under investigation in the management of sepsis. Adverse renal effects of vitamin C through hyperoxaluria have been described in the past. DATA SOURCES: We report the case of a 63-year-old man admitted in a community-based hospital with a diagnosis of sepsis of pulmonary origin. DATA EXTRACTION: On day 19, despite a having developed oligoanuric acute kidney injury, a regimen of IV vitamin C, hydrocortisone, and thiamine was undertaken for 4 days. On day 23, the patient required renal replacement therapy with an estimated glomerular filtration rate of 7 mL/min. Renal biopsy revealed extensive acute tubular necrosis associated with the presence of intratubular crystal of calcium oxalate. CONCLUSION: Although vitamin C seems to be a possible therapeutic asset in the supportive care of sepsis patients, larger cohorts are required to ensure its safety and underlying or novel kidney injury should forewarn clinicians as to its use.