No abstract

Currently, it is unclear whether a neuron that undergoes viral reactivation and produces infectious particles survives and resumes latency or is killed, which is intriguing even if still unanswered. Previous reports have shown that herpes simplex virus type 1 (HSV-1) inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. These effects could be accomplished through deacetylation of pro-apoptotic protein p53 and regulation of the master regulator of mitochondrial biogenesis and function PGC-1α and its target gene TFAM. Accordingly, we evaluated the AMPK/Sirt1 axis and its targets p53, PGC-1α, and acetyl CoA carboxylase in mice neuronal cultures infected with HSV-1 by western blot, RT-qPCR, and immunofluorescence analyses. Herein, we show that HSV-1 differentially modulates the AMPK/Sirt1 axis during the course of infection. In fact, during early infection (2 hpi) activated AMPK (p-AMPK) was down-regulated, but thereafter recovered gradually. In contrast, the levels of acetylated-p53 increased during the first hours post infection, but afterwards were reduced in parallel with the activation of Sirt1. However, acetylated-p53 peaked again at 18 hpi during productive infection, suggesting an activation of apoptosis. Strikingly, acetylated-p53, Sirt1, and p-AMPK apparently translocate from the nucleus to the cytoplasm after 4 hpi, where they accumulate in discrete foci in the perinuclear region. These results suggest that HSV-1 modulates the AMPK/Sirt1 axis differentially during the course of infection interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that establishes a latent persistent neuronal infection in humans. The pathogenic effects of repeated viral reactivation in infected neurons are still unknown. Several studies have reported that during HSV-1 epithelial infection, the virus could modulate diverse cell signaling pathways remodeling the Golgi apparatus (GA) membranes, but the molecular mechanisms implicated, and the functional consequences to neurons is currently unknown. Here we report that infection of primary neuronal cultures with HSV-1 triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 GTPase, two players with a role in GA integrity maintenance. Immunofluorescence analyses showed that HSV-1 productive neuronal infection caused a scattered and fragmented distribution of the GA through the cytoplasm, contrasting with the uniform perinuclear distribution pattern observed in control cells. In addition, transmission electron microscopy revealed swollen cisternae and disorganized stacks in HSV-1 infected neurons compared to control cells. Interestingly, PP2, a selective inhibitor for Src-family kinases markedly reduced these morphological alterations of the GA induced by HSV-1 infection strongly supporting the possible involvement of Src tyrosine kinase. Finally, we showed that HSV-1 tegument protein VP11/12 is necessary but not sufficient to induce Dyn2 phosphorylation. Altogether, these results show that HSV-1 neuronal infection triggers activation of Src tyrosine kinase, phosphorylation of Dynamin 2 GTPase, and perturbation of GA integrity. These findings suggest a possible neuropathogenic mechanism triggered by HSV-1 infection, which could involve dysfunction of the secretory system in neurons and central nervous system.

10%), presenta: S: 25%, E: 98%, VPP: 37%, VPN: 97%. Paratrombocitopenia se obtuvo: S: 98%, E: 74%, VPP: 16%, VPN: 100%. Conclusión: Se hace necesario reiterar a nivel del sistema sanitario chileno la importancia de contar con datos completos en los formularios de notificación. La presencia de trombocitopenia e inmunoblastos (> 10%) fue altamente sensible y especifica, respectivamente, en la detección de pacientes con SCPH. Con el fin de optimizar la sospecha de infección por hantavirus, según la definición de caso sospechoso, se plantea la necesidad de desarrollar programas de capacitación para la sospecha clínica y lectura de parámetros de laboratorio, tales como presencia de inmunoblastos en el hemograma, así como incluir un algoritmo con el fin de optimizar la sospecha y el uso adecuado de los recursos sanitarios.]]>