ß-Catenin Restricts Zika Virus Internalization by Downregulating Axl.

The latest outbreak of Zika virus (ZIKV) in the Americas was associated with significant neurologic complications, including microcephaly of newborns. We evaluated mechanisms that regulate ZIKV entry into human fetal astrocytes (HFAs). Astrocytes are key players in maintaining brain homeostasis. We show that the central mediator of canonical Wnt signaling, ß-catenin, regulates Axl, a receptor for ZIKV infection of HFAs, at the transcriptional level. In turn, ZIKV inhibited ß-catenin, potentially as a mechanism to overcome its restriction of ZIKV internalization through regulation of Axl. This was evident with three ZIKV strains tested but not with a laboratory-adapted strain which has a large deletion in its envelope gene. Finally, we show that ß-catenin-mediated Axl-dependent internalization of ZIKV may be of increased importance for brain cells, as it regulated ZIKV infection of astrocytes and human brain microvascular cells but not kidney epithelial (Vero) cells. Collectively, our studies reveal a role for ß-catenin in ZIKV infection and highlight a dynamic interplay between ZIKV and ß-catenin to modulate ZIKV entry into susceptible target cells. IMPORTANCE ZIKV is an emerging pathogen with sporadic outbreaks throughout the world. The most recent outbreak in North America was associated with small brains (microcephaly) in newborns. We studied the mechanism(s) that may regulate ZIKV entry into astrocytes. Astrocytes are a critical resident brain cell population with diverse functions that maintain brain homeostasis, including neurogenesis and neuronal survival. We show that three ZIKV strains (and not a heavily laboratory-adapted strain with a large deletion in its envelope gene) require Axl for internalization. Most importantly, we show that ß-catenin, the central mediator of canonical Wnt signaling, negatively regulates Axl at the transcriptional level to prevent ZIKV internalization into human fetal astrocytes. To overcome this restriction, ZIKV downregulates ß-catenin to facilitate Axl expression. This highlights a dynamic host-virus interaction whereby ZIKV inhibits ß-catenin to promote its internalization into human fetal astrocytes through the induction of Axl.

Caracterización de los pacientes con diagnóstico presuntivo de síndrome coronario agudo sin elevación del segmento ST que asisten a un servicio de urgencias / Profile of patients with non-ST elevation acute coronary syndrome that attend an Emergency Department

Resumen El dolor torácico es uno de los principales motivos de consulta al sistema de urgencias, y este es secundario a condiciones como el síndrome coronario agudo entre otras. Para su diagnóstico se requiere no sólo el resultado de la troponina, sino una evaluación clínica completa en la que se tengan en cuenta factores de riesgo cardiovascular, características del dolor y hallazgos electrocardiográficos. La interpretación inadecuada de las troponinas ultrasensibles lleva a que se someta al paciente a riesgos innecesarios a causa de estudios como el cateterismo cardiaco. Se llevó a cabo un estudio de corte trasversal en un hospital de Bogotá, en el que la causa principal de consulta en el servicio de urgencias fue el dolor torácico, y la primera causa de hospitalización en Cardiología el síndrome coronario agudo. Se recolectaron datos de 411 pacientes a quienes se les realizó arteriografía coronaria, la mayoría hombres con factores de riesgo como hipertensión arterial, tabaquismo y un evento coronario previo. Dentro de los estudios paraclínicos, la fracción de eyección promedio estuvo cercana al 50% y sólo en 201 pacientes se encontraron lesiones epicárdicas significativas.De la muestra analizada, el 13% tenía creatinina mayor de 1,5 mg/dl como causa alterna de elevación del biomarcador y 28% tenía disfunción ventricular izquierda de algún grado. La mayoría de los pacientes en quienes no se documentaron lesiones angiográficamente significativas en el cateterismo cardiaco, la troponina no cumplía criterios de positividad con base en el aumento del 20% respecto al valor inicial si este era positivo o de 50% en caso de que el primer valor fuese negativo. Adicionalmente, del grupo de pacientes con enfermedad coronaria angiográficamente significativa fue más frecuente la combinación de tres o más factores de riesgo cardiovascular en presencia de biomarcador positivo.

Abstract Chest pain is one of the main reasons for consulting the Emergency Department, and it is secondary to conditions, such as acute coronary syndrome. For its diagnosis, it not only requires a Troponin result, but also a full clinical evaluation, in which factors like cardiovascular risk have to be taken into account, as well as characteristics of the pain and the findings on the electrocardiogram. The poor interpretation of the ultrasensitive Troponins leads to the patient being subjected to unnecessary risks due to studies such as cardiac catheterisation. A cross-sectional study was conducted in a hospital in Bogota, in which chest pain was the main reason for consulting the Emergency Department, and acute coronary syndrome the first cause of admission to Cardiology. The study included a total of 411 patients on whom a coronary angiography was performed. The majority were males with risk factors such as arterial hypertension, smokers, and with a previous coronary event. Among the para-clinical studies, the mean ejection fraction was around 50%, and significant epicardial lesions were found in only 201 patients.Of the sample analysed, 13% had a creatinine greater than 1.5 mg/dl as an alternative cause of the elevation of the biomarker, and 28% had some degree of left ventricular function. the majority of patients that did not have significant angiographic lesions in the cardiac catheterisation documented, the Troponin did not meet the criteria for being positive, based on an increase of 20% as regards the initial value if this was positive or 50% in the case where the first value was negative. Furthermore, of the patient group with significant angiographic coronary disease, the combination of three or more cardiovascular risk factors was the most frequent in the presence of a positive biomarker.