My research interest is mainly focused on the study of the possible neurodegenerative effects, neuronal dysfunctions and innate immune activation on neurons and astrocytes infected with the neurotropic virus as HSV-1. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. The possibility that HSV-1 reactivates in CNS neurons causing chronic progressive damage at cellular level and altering the neuronal functionality has not yet been investigated. In fact, our group was the first to demonstrate that in vitro HSV-1 neuronal infection is associated with several neurodegenerative features, such as tau hyperphosphorylation and cleavage, modifications in the microtubular dynamics and damage in axonal and dendritic processes. In this moment we are focused to analyze virus-cell relationships, especially neuronal signaling and synaptic-plasticity function modify by HSV-1 infection. (Chilean grants: Fundación Andes C14060/05; Fondecyt: 11080067, 1120464, 1150574).

It has been described that during viral infection the protein synthesis is highly increased at the endoplasmic reticulum (ER), condition that in some cases trigger ER stress responses by the accumulation of misfolded proteins. Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that causes a latent persistent infection in humans. It has been postulated that during productive infection herpesvirus use the ERAD pathway to avoid the immune response; however, the contribution in the viral replication efficiency it is unknown. The aim of this study was to investigate the role of the ERAD enhancer EDEM1, an endoplasmic reticulum lectin protein that works in the recognition of misfolded glycoproteins during productive HSV-1 infection. Human neuroglioma cells (H4) stably expressing either luciferase shRNA or EDEM1 shRNA were infected with HSV-1 wild type or mutant null to ICP0 (protein with E3 ubiquitin ligase activity) or US3 (a protein kinase that modifies host cellular machinery). After infection, levels of EDEM1 were measure by either mRNA (RT-PCR) or protein levels (immunoblotting). Our results showed that HSV-1 infection decreases the levels of EDEM1 to favor viral replication efficiency. The relevance of this study is the elucidation of the contribution of the ERAD pathway in the productive infection of HSV-1 and the possible involvement of ICP0 and/or US3 in this pathway. Funding: FONDECYT 1150574.

Henri Alexandre Giblot Ducray has graduated cum laude from the St. Ambrose University, Iowa, with a B.Sc. in Biology with a Biomedical Science concentration and is currently pursuing a PhD at Auburn University, Alabama, in Anatomy, Physiology, and Pharmacology department. He is a graduate research assistant for Dr. Sorokulova and has been involved in several of her research projects.

The gut barrier integrity plays a crutial role in health, preventing the translocation of the luminal contents into circulation. One in particular are lipopolysaccharides (LPS), a toxic component of gram-negative bacteria that is a potent stimulator of inflammation. Increased intestinal permeability accompanies different pathological conditions. Heat stress was shown to disrupt the intestinal barrier function and change the expression of tight junction (TJ) proteins, responsible for maintaining the integrity of the gut. The gut barrier integrity is key for intestinal homeostasis and overall for the health status of the host. It was shown that microbiota and its metabolites can regulate the gut barrier function. Prebiotics have been proposed as a promising approach to normalize microbiota and, as a result, improve the gut barrier integrity. The main aim of this study was to evaluate the protective effect of a yeast fermentate product EpiCor (EH) on the intestinal barrier integrity during heat stress. Rats were orally treated with the EH prebiotic product (7 mg/kg in 1 mL of PBS) or with PBS for 14 days and exposed to heat stress conditions (45oC for 25 min). Control rats received the same treatment, but were kept at room temperature. Expression of tight junction (TJ) proteins (claudin 1, occludin, ZO-1 and JAM-A) in the intestine were analyzed by Western blot in all rats, a number of Paneth and goblet cells was also calculated in all samples. . Pre-treatment with EH prevented the adverse effects of heat: decrease in the number of Paneth and goblet cells, elevation of LPS in circulation, and decrease of TJ proteins expression. Our results demonstrated efficacy of EH treatment in protecting the integrity of the intestinal barrier in the heat stress model. We speculate that EH could be used for improvement of the gut barrier function in certain pathological conditions.

Mohamed Elgazzar, PhD, is a Molecular Immunologist and an Associate Professor. He Received his PhD in 2002 from Kumamoto University School of Medicine, Japan. He received his postdoctoral training in Immunology at the National Jewish Medical Center and University of Colorado in Denver and in Infectious Diseases at Wake Forest University School of Medicine in Winston-Salem before joining ETSU. He holds an adjunct assistant professor position in the Department of Biomedical Sciences. He has authored over 36 original research and review manuscripts.

Backgound: The immune response to sepsis rapidly shifts from an early/acute hyperinflammatory reaction to a protracted state of immuunosuppression. Sepsis accelerates myeloid cell generation to compensate for the rapid mobilization of the myeloid progenitors from the bone marrow. This inflammation-driven myelopoiesis, however, generates myeloid progenitors with immunosuppressive properites (MDSCs), which expand markedly in the later phases of sepsis. Repressor MDSCs contribute to high mortality rates in mouse and human sepsis. Purporse: To determine whether the myeloid related transcription factor C/EBP plays a role in MDSC expansion. Methods: We used a murine model with myeloid-restricted deletion of the C/EBP, where the Cebpb allele is only inactivated in the myeloid lineage. Sepsis was induced by cecal ligation and puncture, and mice received limited antibiotic treatment, which produces an acute/early phase followed by a chronic/late immunosuppressive phase. Findings: C/EBP myeloid cell-deficient mice did not generate MDSCs nor develop immunosuppression and survived sepsis. Surprisingly, septic survivor mice could generate Gr1+CD11b+ myeloid progenitors similar to control sham-operated mice. Morover, C/EBP-deficient Gr1+CD11b+ cells differentiated normally in response to growth factors and adoptive transfer of C/EBP-deficient Gr1+CD11b+ cells from late septic mice exacerbated inflammation in control mice undergoing early sepsis, confirming they were not immunosuppressive. Mechanistically, we found that C/EBP induction in myeloid cells promoted expression of miR-21 and miR-181b immune repressor mediators in sepsis MDSCs. Conclusion: Sepsis-induced C/EBP initiates myeloid progenitor reprogramming into MDSCs with chronic immunosuppressive properties. Targeting this pathway may inform a new therapeutic target for improving sepsis outcome.