Biography:

Jianrong Li is an Associate Professor in Neuroscience at Texas A&M University. She received her PhD in Biochemistry from University of Hawaii and Post-doctoral training from University of Pittsburgh and Children’s Hospital Boston, Harvard Medical School. Her research interests include elucidating the molecular basis of oligodendroglial cell injury in developmental and demyelinating diseases, and uncovering key pathways for myelin repair. She has been awarded multiple research grants from the National Multiple Sclerosis Society and National Institutes of Health and has authored over 40 peer-reviewed research articles. 

Abstract:

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Local inflammatory reactions induced by infiltrating leukocytes and activated glia are believed to be the main culprit for myelin destruction and axonal damage. Recent studies suggest that galectins, the ß-galactoside-binding lectins, can modulate immune tolerance and inflammatory responses. Galectin-9 is significantly elevated in MS lesions, however, its function in CNS immune responses and demyelination remains largely unexplored. We found that galectin-9 was markedly induced in microglia and reactive astrocytes during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as well as in reactive astrocytes and microglia/macrophages surrounding active MS lesions. Pro-inflammatory cytokines such as TNF and IL-1b triggered galectin-9 production from astrocytes, which in turn acted in a feed-forward fashion to further enhance microglial TNF production. TNF-stimulated Lgals9^+/+ astrocytes induced greater extent of encephalitogenic T-cell apoptosis and proliferation arrest than that of Lgals9^-/- astrocytes, indicating that galectin-9 negatively regulates encephalitogenic T cells. During MOG_35-55-induced EAE, Lgals9^-/- mice exhibited worse clinical symptoms, which were associated with heightened Th17 responses in the CNS and demyelination when compared with littermate Lgals9^+/+ controls. In autoimmunity-independent toxin models of CNS demyelination, spontaneous remyelination was delayed in Lgals9^-/- mice. Immunohistochemistry analyses revealed that although Lgals9^-/- mice had similar number of oligodendrocyte precursor cells in the lesions as control mice, the number of mature oligodendrocytes was significantly reduced. Consistently, recombinant galectin-9 promoted oligodendrocyte maturation in mixed glial cultures. Collectively, our data suggest a role for galectin-9 in suppressing T lymphocytes in the CNS and facilitating oligodendrocyte maturation and myelin repair

Biography:

William Tyor is a Professor of Neurology at the Emory University School of Medicine and the Atlanta VA Medical Center. He is the Co-Director of the Emory/Atlanta VA MS Center and the Emory Center for AIDS Research NeuroAIDS Scientific Work Group. His research has focused on basic and translational investigations of neuro-inflammatory diseases of the central nervous system including clinical trials in multiple sclerosis (MS) and translational studies in MS and HIV associated neurocognitive disorders (HAND). His NIH and VA grant funding has focused primarily on the pathogenesis and treatment of HAND using a mouse model and neuronal culture systems. He attends outpatient clinics in his subspecialty of CNS inflammatory disorders at the Atlanta VA and Emory Clinic as well as General Neurology Patient Management in the VA Residents’ Clinic and VA Inpatient Consult Service.

Abstract:

Interferon-alpha (IFNα) is a pleiotropic cytokine expressed by a wide variety of cell types during inflammatory events, especially viral infections. In the central nervous system IFNα can be expressed by infiltrating leukocytes, glia and even neurons. When IFNα has been used as therapy for various diseases (e.g., hepatitis) and can be measured in the cerebrospinal fluid (CSF), it invariably causes cognitive dysfunction that is reversible when treatment is discontinued. IFNα has been measured in the CSF of people living with HIV and correlates with cognitive dysfunction. Both animal studies and in vitro investigations indicate that IFNα is toxic to neurons. We have shown that in a mouse model of HIV associated neurocognitive disorders (HAND), brain IFNα levels correlate with errors made in maze testing. Furthermore, behavioral abnormalities and histopathology can be ameliorated by treating these mice with neutralizing antibody to IFNα. In vitro studies using rat neurons reveal that IFNα exposure leads to dendritic simplification, which is likely a cellular correlate to memory loss. This dendritic simplification is not only mediated through the Type I IFN receptor, but also through the GluN2A subunit of the N-methyl-D-aspartate receptor. Preliminary studies in the HAND mouse model suggest that combined antiretroviral therapy (cART) plus an IFNα binding protein, B18R, are superior to cART alone in improving neuropathological markers. Our most recent unpublished data show that B18R can reverse abnormal behavioral seen with object recognition testing in HAND mice. Treatment of IFNα neurotoxicity may not only be effective in humans with HAND, but in other neurological disorders associated with cognitive dysfunction.

Biography:

Dr. Yumin Zhang, is an Associate Professor in the Department of Anatomy, Physiology and Genetics and the Department of Neuroscience at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Dr. Zhang obtained his MD in Binzhou Medical School, China, PhD in Hebrew University of Jerusalem, Israel, and postdoc study in the Children’s Hospital, Harvard Medical School. The major research interest in Dr. Zhang’s lab is to study how modulation of the arachidonic acid metabolism and the endocannabinoid system can impact the pathogenesis and treatment for neurological diseases, including traumatic brain injury and multiple sclerosis.

Abstract:

Modulation of the endocannabinoid system has emerged as an attractive strategy for the treatment of many neurological diseases, but its role in the management of traumatic brain injury is still in its infancy. The endocannabinoids 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide, AEA) are elevated after brain injury and believed to be protective. However, the compensatory effect of the endocannabinoids is transient due to their rapid degradation by hydrolytic enzymes.  In a mouse model of traumatic brain injury (TBI), we found that post-injury chronic treatment with WWL70 and PF3845, the respective and selective inhibitors of the 2-AG and AEA hydrolytic enzymes alpha/beta hydrolase domain 6 (ABHD6) and fatty acid amide hydrolase (FAAH), improved locomotor function, working memory and anxiolytic behavior. The treatment reduced lesion volume in the cortex and neuronal death in the hippocampal dendate gyrus. It also suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 in the ipsilateral cortex at 3, 7 and 14 days post-TBI, suggesting microglia/macrophages are shifted from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype. Treatment with PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. The beneficial effects of WWL70 and PF3845 were mediated by activation of cannabinoid type 1 and type 2 receptors and might be attributable to the phosphorylation of the extracellular signal regulated kinase (ERK1/2) and the serine/threonine protein kinase (AKT). These results suggest that fine-tuning of 2-AG and AEA signaling by regulating ABHD6 and FAAH activity can afford anti-inflammatory and neuroprotective effects in TBI.

Biography:

Ahmad Bassiouny has completed his PhD in Medical Sciences from University of Nebraska Medical Center, USA and postdoctoral studies from Max-Plank Institute, Germany. He is a full professor of Molecular Therapeutics & Immunology. He is the contact person of International ISIS Master in Neuroscience and Biotechnology with Bordeaux University, France. He was the PI of GESP Grant with Professor Detlef Gabel, University of Bremen, Germany. April 2011-April 2013. He was also the principal investigator of national grant from STDF project # 513 and Co-PI of STDF project ID: 4237: "Study on possible APE1-mediated molecular mechanism(s) implication in neuroinflammation". He has been chosen to be included in the special 30th Pearl Anniversary Edition of Who's Who in the World, 2013. Presenting author details 

Abstract:

Parkinson's disease is a progressive disorder of the nervous system that affects motor function in basal ganglia. The aim of this study was to examine the effects of ginger extract on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) mouse C57/BL/6 models. Animals were injected intraperitoneally (IP) with a total cumulative dose of 150 mg/kg MPTP. The levels of dopamine were determined by HPLC. Chronic exposure to neurotoxins increase α-synuclein (αS) aggregation concomitant with upregulation of miR-155 and downregulation of miR-7 and -153 and increase in intracellular reactive oxygen species (ROS). Seven days after the last MPTP injection, behavioral testings were performed.  The levels of TNF-α, COX-2 and iNO and miR-7, miR-153, miR-155 were analyzed both in Substantia nigra pars compacta (SNpc) and globus pallidus (GP) by real time PCR. Results: Here we show that Ginger extract can alleviate αS-induced toxicity, downregulate miR-155, and upregulate miR-7 and miR-153, reduce ROS levels and protect cells against apoptosis. It significantly increased the level of dopamine in GP and striatum and suppressed TNF-α and NO levels. In C57/BL mice, treatment with Ginger extract reversed MPTP-induced changes in motor coordination and bradykinesia. Moreover, Ginger extract significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-α, NO, iNOS, and COX-2 in both SNpc and GP. It upregulated the level of miR-153 and miR-7 indicating a protective effect. Conclusion:  Our results may indicate that miR155 has a possible central role in the inflammatory response to αS and αS-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to αS. Our findings implicate miR-155, miR-153 and miR-7 are potential therapeutic targets for regulating the inflammatory response in PD. Ginger extract exerts neuroprotective effects on DA neurons in in vivo PD model. 

Biography:

Pooja Jain is a tenured Professor in the Department of Microbiology and Immunology at the Drexel University College of Medicine, USA. She also holds joint appointment as a Professor of Neurobiology and Anatomy at DrexelMed. She is well respected in the field of Neurovirology/Neuroimmunology and made seminal contributions with her studies on HTLV-associated cancer and neuroinflammation with prime focus on the dendritic cells. She provided first live in vivo imaging evidence of dendritic cells’ trafficking into the central nervous system during an active ongoing neuroinflammatory condition and extended her pioneering observations in defining the molecular events and mechanisms underlining cellular migration across the blood-brain barrier. She has authored more than 50 peer-reviewed publications, over 250 abstracts and numerous invited talks across United States and overseas. She has been bestowed with various honors and has served in several NIH study sections. She is currently a Member of AAI, ASM, SFN, ISNV, SNIP and a Life Member for the International Society for Dendritic Cell & Vaccine Science.

Abstract:

For last several years, our laboratory has placed tremendous efforts in understanding retroviral pathogenesis both in periphery and in CNS utilizing human T-cell leukemia virus (HTLV) as a model pathogen with prime focus on dendritic cells (DCs). HTLV-1 is not only a good model for human chronic viral infection but also of associated neurological complications. Therefore, through these studies we were able to provide new scientific insights and paradigms in the areas of neuroimmunology and neurovirology. Our long-standing research work with HTLV-1 helped in bridging two important fields of Neuroscience and Immunology while strengthening DCs’ presence and functions within CNS. This is by means of our original work providing direct evidence for the ability of circulating DCs to migrate across the inflamed blood-brain barrier during an active ongoing neuroinflammatory condition such as experimental autoimmune encephalitis (EAE) by live intravital video microscopy. This was further substantiated by a variety of non-invasive imaging tools such as NIR, SPECT-CT, MRI, PET, etc. These studies have identified lectins (i.e., CLEC12A) as key molecular targets for potentially new DC-based immunotherapeutic strategies against neuroinflammatory diseases such as MS. Fairly recently; we undertook similar approach toward HIV-1 CNS infection to investigate if follicular DCs (fDCs) within deep cerebral lymph nodes (CLNs) could be potential reservoir for HIV/SIV CNS infection. We are also interested in investigating novel means to inhibit HIV-fDC interactions as relate to the CNS pathogenesis. Taken together, our work on DC-CNS trafficking has helped changed the central dogma of CNS being the immune privileged site.

Biography:

Patricia Szot as a long-term member of the MIRECC research team at the VA Puget Sound Health care System has provided substantial information on the expression of receptors and transmitter-synthesizing enzymes in the human and rodent brain.  This has included autopsy brain material from Parkinson’s disease and Alzheimer’s or dementia patients.  Due to the in situ hybridization and slice autoradiography technical expertise he has worked on the localized quantitation of some important regulatory proteins.  These studies contribute to his understanding of the mechanisms of side effects and additional symptomatology observed, e.g., in Alzheimer’s disease and Parkinson’s disease- information which is of direct clinical relevance.

Abstract:

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer’s disease (AD), Parkinson’s disease (PD), and traumatic brain injury (TBI).  The intra-peritoneal (ip) administration of lipopolysaccharide (LPS) induces peripheral inflammation and neuroinflammation as evident be elevations in blood and brain levels of cytokines.  However, the cellular and anatomical sources of these cytokines are not known. Here, we used in situ hybridization to examine in brain and spleen the sources of cytokine production after 3-injection regime previously shown to elevate cytokine levels in brain and blood.  Administration of LPS significantly increased mRNA expression of interleukin (IL)-6 and -10 in the spleen, an important organ for an immune response, consistent with increases in blood levels for these cytokines after LPS.  LPS significantly decreased IL-6 receptor (-6R) mRNA in the spleen, but had no effect on IL-7 or IL-7R mRNA.  In the CNS, IL-6 mRNA was expressed in neurons prior to LPS in regions that include the cortex, cerebellum and hippocampus.  After LPS, IL-6 mRNA expression in these neuronal populations was unchanged, but a diffuse non-neuronal pattern appeared throughout the brain.  IL-6R mRNA showed a pattern of expression similar to IL-6 mRNA and LPS significantly elevated all regions, except cerebellum, mainly in animals which expressed the non-neuronal IL-6 mRNA after LPS.  IL-10 mRNA was widely expressed in neurons in many discrete brain regions, with LPS tending to decrease expression in forebrain regions and increase it in hindbrain regions.  IL-7 and IL-7R had limited expression mainly to the cerebellum.  LPS had no effect on IL-7 or IL-7R mRNA in the CNS.  These studies indicate that LPS induced neuroinflammation has unique effects on regional and cellular patterns in the CNBS and splenic cytokine expression.  It is apparent that LPS can affect neuronal and non-neuronal cells in the brain, with IL-6 demonstrating the greatest change.

Biography:

Audrey D Lafrenaye is a Research Associate Faculty Member in the Department of Anatomy and Neurobiology at Virginia Commonwealth University. She has received her PhD in Anatomy. Following her graduate work she transitioned into the Trauma field. Her research focuses on evaluating the diffuse pathologies following traumatic brain injury. In the conduct of her studies she utilizes both rodent and micro pig models of diffuse traumatic brain injury and has been particularly interested in the effects of elevated intracranial pressure without hypoperfusion on subacute pathology and morbidity following TBI. For the past few years she has explored the pathological progression of diffuse axonal injury and acute neuro-inflammation following mild diffuse traumatic brain injury in the pig. 

Abstract:

Mild traumatic brain injury (mTBI) is a highly prevalent disease with devastating costs. While one of the major pathological hallmarks of TBI is diffuse axonal injury (DAI), neuroinflammation occurring chronically, weeks to months following injury, has also been implicated in a variety of detrimental as well as regenerative functions. Currently, little is known regarding acute neuroinflammation occurring within the first day following mTBI, particularly within the gyrencephalic brain. Therefore, we assessed acute neuroinflammation at 6h and 1d in a unique model of diffuse mTBI in the micro pig. Mild TBI did not precipitate systemic physiological abnormalities or overt histopathological damage; however, this micropig model generated substantial DAI in the thalamus, an area commonly affected in human mTBI, at both 6h and 1d following injury. Extensive acute neuroinflammation was also observed following mTBI within the thalamic domain. Importantly, the processes of activated microglia converged on axons sustaining DAI at both time points following mTBI. Contacts between activated microglia processes and swellings of injured axons increased two fold at 6h and nearly fourfold at 1d following mTBI compared to associations with uninjured myelinated axons in sham animals. While active phagocytosis was observed in association with wallerian degeneration following mTBI, the microglia that contacted swellings from diffusely injured axons were not ultra-structurally phagocytic. This study shows direct physical correlation between injured axonal swellings and non-phagocytic acute neuroinflammation in a higher order animal, finding that could lead to novel diagnostics based on a more complete understanding of acute neuroinflammation following mTBI. 

Biography:

Juan Pablo de Rivero Vaccari has received his Bachelor of Science degree in Biology in 2004 from Florida International University, where he graduated Summa Cum Laude and became a Member of Phi Beta Kappa Honor Society. In 2004, he joined the University of Miami as a graduate student in the Department of Physiology and Biophysics where he worked in the laboratory of Dr. Robert W. Keane. He has obtained his PhD in 2007 and joined the laboratory of Dr. W. Dalton Dietrich at the Miami Project to Cure Paralysis as a Postdoctoral Fellow where he continued his studies on innate immune responses after brain trauma. In 2010, he became a Research Assistant Professor in the Department of Neurological Surgery and the Miami Project to Cure Paralysis at the University of Miami. Currently, he works on identifying biomarkers and therapeutic targets in the innate immune response to improve outcomes after central nervous system injury and disease. In addition, his work has resulted in the filing of several patents with the United States Patent and Trademark Office and abroad. To move inventions forward, he co-founded InflamaCORE, LLC, a company dedicated to treating and diagnosing inflammatory injury and disease, as a spin-off company from the University of Miami.

Abstract:

The inflammasome plays a key role in the regulation of the innate immune inflammatory response in the central nervous system (CNS). The inflammasome regulates the activation of the inflammatory caspase; caspase-1 and the pro-inflammatory cytokines IL-1beta and IL-18. The inflammatory response is regulated differently at different stages of the aging cycle. This presentation will cover the regulation of the inflammasome in the brain as a result of naturally occurring aging in the brain of aged mice (18 months) when compared to younger mice (3 months). In addition, I will discuss the regulation of the inflammasome in the brain of reproductive senescent female rats when compared to the brain of young female rats. Taken together, our data indicate that the inflammasome is up-regulated in the brain as a result of aging. Importantly, inhibition of the inflammasome in the aging brain results in improvement in cognitive performance as determined by water maze testing in rats. In conclusion, our findings indicate that the inflammasome is a potential therapeutic target to inhibit inflammation in the aging brain, which could further protect from the development of neurodegenerative diseases associated with aging such as Parkinson's disease and Alzheimer's disease.

Biography:

Khanyisile Kgoadi is a Clinical Science and Immunology PhD student at the University of Cape Town, South Africa. She has completed her BSc in Biochemistry at the University of Johannesburg and MSc studies in Biochemistry at the University of Pretoria, South Africa. She has published a joint first authorship paper in the current metabolomics journal. She has won the South African Women in Science Award in 2015. She was awarded the Margaret McNamara Education Grant for her strong leadership qualities and empowerment of children and women through education.

Abstract:

Mycobacterium bovis BCG causes inflammation of the CNS referred to as central nervous system tuberculosis (CNS-TB). CNS-TB is a lethal form of tuberculosis that constitutes approximately 5-10% of extra-pulmonary tuberculosis cases. Pathogenesis of CNS-TB is initiated as a secondary infection during haematogenous dissemination of pulmonary infection to the brain parenchyma. CNS-TB is associated with high morbidity and 50% mortality. The mechanisms associated with CNS-TB infection and cells targeted for invasion is mostly unknown. The regulatory role of dendritic cells (DCs) in CNS-TB has been neglected because of their absence during homeostasis. This study investigated DC recruitment kinetics and phenotype in context to CNS-TB. C57BL/6 mice were intracerebrally infected with BCG and sacrificed at different time intervals. Bacterial loads of samples were determined by plating homogenates of organs and counting colony-forming units. Brain DCs were quantified and their phenotype determined using flow cytometry. Bacterial loads showed dissemination of BCG from the brain to the spleen and to a lesser extent to the lungs. A significant increase was observed in the amount of dendritic cells recruited to the brain at week 4 post BCG infections. At week 6, there was a significant drop in the mount of BCG present in the brain. Recruitment of T cells to the brain following BCG infection shows that DCS are successful in presenting antigens to T cells and eliciting an adaptive immune response in CNS-TB. This shows that the CNS is not immune privileged but CNS inflammation caused by mycobacteria is a highly regulated process that limits potential pathology damage.

Biography:

Rina Aharoni is currently a Senior Staff Scientist at the Department of Immunology, The Weizmann Institute of Science, Israel. She has completed her BSc in Biology, Hebrew University, Jerusalem, Israel and MSc and PhD in Life Sciences from The Weizmann Institute of Science, Rehovot, Israel. She did Postdoctoral Research at Stanford University, USA. Her main research interests include neuroimmunology, autoimmunity, pathology and therapy of multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE), immunomodulation, neuroprotection and repair processes in the central nervous system, inflammatory bowel diseases (IBD). She has published more than 60 papers and reviews on these subjects and she is also an Editorial Board Member of 20 journals.

Abstract:

Multiple sclerosis (MS) is currently recognized as complex diseases in which inflammatory autoimmune reactivity in the central nervous system (CNS) results in demyelination, axonal and neuronal pathology. Treatment strategies thus aim to reduce the detrimental inflammation and induce neuroprotective repair processes. The synthetic copolymer Copaxone (Glatiramer acetate, GA), an approved drug for the treatment of MS, is the first and so far the only therapeutic agent to have a copolymer as its active ingredient. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the mechanism of action of GA was elucidated. These studies indicated that GA treatment generates immunomodulatory shift from the inflammatory towards the anti-inflammatory pathways, such as Th2-cells that cross the blood brain barrier (BBB) and secrete in situ anti-inflammatory cytokines as well as T-regulatory cells (Tregs) that suppress the disease. The consequences of GA treatment on the CNS injury inflicted by the disease were studied using immunohistochemistry, electron microscopy and magnetic resonance imaging. These analyses revealed reduced demyelination and neuro-axonal damages as well as neuroprotective repair processes such as neurotrophic factors secretion, remyelination and neurogenesis. These combined findings indicate that immunomodulatory treatment can counteract the neurodegenerative disease course, supporting linkage between immunomodulation, neuroprotection and therapeutic activity in the CNS.

Biography:

S Ghosh is currently pursuing his Postdoctoral research at Washington School of Medicine, St. Louis, USA. His research interest lies in understanding the neuro-immune signaling pathways that are disrupted during neurodegenerative diseases and autoimmune disorders in the brain. He/ has received his Bachelor’s degree in Technology in Genetic Engineering from SRM University, India. He has pursued his PhD at Purdue University, USA in kinase signaling examining the role of different kinases such as CDK5 in neuronal cell death, Aurora A kinase in breast and ovarian cancer and spleen tyrosine kinase in microglial cell activation.

Abstract:

Microglial cell is the primary immune cell of the central nervous system and maintains the brain homeostasis. In Alzheimer’s disease brain, microglial cell are recruited to amyloid beta (Aβ) plaques and exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. To explore the molecular basis for these phenomena, we hypothesized that defect in the functions of the protein-tyrosine kinase SYK, which is important both for macrophage activation and phagocytosis, might underlie much of this observation. Recent evidence from our lab indicates that SYK can associate with stress granules, ribonucleoprotein particles that form in stressed cells and contain inactive translation initiation complexes. In our study, we found that microglial cell line and primary mouse brain microglia, when stressed by exposure to sodium arsenite or Aβ(1-42) peptides or fibrils, form extensive stress granules to which SYK is recruited. SYK enhances the formation of stress granules as evidenced by the inhibition of stress granule formation by small molecule inhibitors, knockdown of SYK expression by shRNA and SYK haplo-insufficiency in mouse microglial cells. SYK is active within the resulting stress granules where it catalyzes the phosphorylation of stress granule-associated proteins on tyrosine. SYK-dependent stress granule formation stimulates the production of reactive oxygen and nitrogen species. These are toxic to neuronal cells as demonstrated by a co-culture assay using stressed microglial cells and HT22 neuronal cells. The ability of microglial cells to phagocytose E. coli is blocked by SYK inhibitors. The sequestration of SYK into stress granules inhibits the ability of microglial cells to phagocytose either E. coli or Aβ fibrils. Microglial cells from aged mice are more susceptible to the formation of stress granules than are cells from young animals. Stress granules containing SYK and phosphotyrosine are prevalent in the brains of patients with severe Alzheimer’s disease, suggesting that the sequestration of SYK into stress granules is part of the pathology of the disease. Phagocytic activity can be restored to stress microglial cells by treatment with IgG independent of the epitope specificity, suggesting a mechanism to explain the therapeutic efficacy of intravenous IgG.

Biography:

Abstract:

Persistent cognitive sequelae occur following neuro-invasive infection with neurotropic flaviviruses, including Japanese encephalitis virus, Saint Louis encephalitis virus, and West Nile virus (WNV). We used an established murine model of recovery from WNV in which animals display spatial learning defects and loss of presynaptic termini within the hippocampal CA3. Transcriptional profiling of the hippocampi of mice with poor learning revealed decreased expression of genes involved in adult neurogenesis and increased expression of innate immune molecules known to inhibit this process, including interleukin (IL)-1. WNV-infected adult mice exhibited decreased numbers of proliferating neuroblasts, which are not directly targeted by virus, and increased generation of astroblasts, within neurogenic zones, with limited recovery of neurogenesis in the sub-granular zone at 30 days. Accordingly, IL-1R1-deficient, WNV-infected mice exhibited normal neurogenesis, rapid recovery of presynaptic termini, and resistance to WNV-mediated impairment in spatial learning and memory compared with wild type mice. Our results reveal that alterations to neuronal progenitor cell homeostasis during adult neurogenesis may underlie long-term cognitive consequences of WNV infection and provide a therapeutic intervention to prevent these deficits.