The long term experimental objective of this competitive renewal is to evaluate the functional roles of chemokines and their receptors in contributing to viral clearance, immunopathology and repair in a murine model of WNV encephalitis. Murine WNV infection is well-accepted flavivirus encephalitis model whereby subcutaneous infection with low inoculum of virulent strains leads to neuroinvasive disease in individuals with depressed or dysregulated immune function. Thus, murine experimental studies have identified viral and host factors that determine the neuropathogenesis and outcome of WNV encephalitis in humans, including several chemokine receptors that determine the entry and fate of infiltrating immune cells. In published studies we have determined that the chemokines CXCL12 and CXCL10 control leukocyte access to the central nervous system (CNS) parenchyma at the blood-brain barrier (BBB) and within the CNS parenchyma in a region-specific manner, respectively. In preliminary studies we have also observed that WNV infection led to increased BrDU incorporation within neurogenic zones, suggesting that adult neurogenesis is affected by viral infection. In addition, we have determined that TLR3 signaling affects the expression of neural precursor cell transcription factors Pax6 and nestin in several brain regions, providing a link between viral infection and activation of innate immune molecules known to regulate both chemokine expression and neurogenesis. The present proposal seeks to understand the immunological basis of BBB trafficking for protective versus pathogenic leukocytes and for virus entry. Because chemokine up-regulation also recruits neural precursor cells for repair, we will additionally evaluate how chemokines influence neurogenesis within the WNV-damaged CNS. We will address these questions in three aims: 1) Identify the proinflammatory pathways responsible for the migration of protective versus pathogenic leukocytes across the BBB during WNV encephalitis.
This aim will determine molecular cues for leukocyte entry at the BBB and trafficking within specific CNS regions. Additionally, we will determine the role of CXCR4 in T cell subset entry at the BBB;2) Identify molecular mechanisms involved in WNV entry and effects at the BBB.
This aim will use in vitro and in vivo approaches to determine WNV effects on CNS endothelium and viral invasion;and 3) Examine chemokine receptor-mediated strategies for neuroprotection and repair during WNV encephalitis.
This aim will determine how WNV infection affects the generation of neural cells in the adult CNS and the chemokines that control this process. Together, these studies will extend our current understanding of how chemokines and their receptors control CNS inflammation and ultimately repair during WNV encephalitis.
Viral encephalitis is an emerging global health threat without effective therapeutic strategies. In particular, the arthropod-borne flaviviruses, West Nile (WNV), Japanese encephalitis (JEV), Tick-borne encephalitis (TBEV, Murray Valley encephalitis (MVEV) and St. Louis encephalitis (SLEV) viruses, cause outbreaks of encephalitis worldwide, with a total annual case rate of over 50,000 (www.who.int). Among the important questions regarding the neuropathogenesis of flavivirus encephalitis is whether individuals that develop neuroinvasive disease do so because of impaired virologic control in the periphery and/or because of fundamental differences in blood-brain barrier (BBB) biology and whether viral-mediated effects on endogenous repair mechanisms alter functional outcomes. In addition, although central nervous system infections (CNS) with these cytopathic neurotropic viruses require the parenchymal penetration of T lymphocytes for virus clearance, there are also data suggesting that the presence of these immune cells within the CNS induces immunopathologic damage. Thus, understanding the mechanisms that govern the entry of virus and leukocyte subsets at the BBB is essential for developing treatments that can prevent neuroinvasion in patients at risk and promote appropriate antiviral immune responses within the CNS after neuroinvasion has occurred. The present proposal seeks to understand the immunological basis of BBB trafficking for protective versus pathogenic leukocytes and for virus entry and to additionally evaluate adult neurogenesis within the WNV-damaged CNS. These studies will extend our current understanding of the molecular mechanisms that control CNS inflammation and repair during WNV encephalitis. Further, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with flavivirus encephalitides.
|Cruz-Orengo, Lillian; Daniels, Brian P; Dorsey, Denise et al. (2014) Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest 124:2571-84|
|Sun, Tony; Vasek, Michael J; Klein, Robyn S (2014) Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone. PLoS One 9:e96442|
|Reddy, Adarsh S; Patel, Jigisha R; Vogler, Carole et al. (2014) Central nervous system pathology progresses independently of KC and CXCR2 in globoid-cell leukodystrophy. PLoS One 8:e64647|
|Daniels, Brian P; Holman, David W; Cruz-Orengo, Lillian et al. (2014) Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals. MBio 5:e01476-14|
|Durrant, Douglas M; Daniels, Brian P; Klein, Robyn S (2014) IL-1R1 signaling regulates CXCL12-mediated T cell localization and fate within the central nervous system during West Nile Virus encephalitis. J Immunol 193:4095-106|
|Durrant, Douglas M; Robinette, Michelle L; Klein, Robyn S (2013) IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis. J Exp Med 210:503-16|
|Daniels, Brian P; Cruz-Orengo, Lillian; Pasieka, Tracy Jo et al. (2013) Immortalized human cerebral microvascular endothelial cells maintain the properties of primary cells in an in vitro model of immune migration across the blood brain barrier. J Neurosci Methods 212:173-9|
|Holman, David W; Klein, Robyn S; Ransohoff, Richard M (2011) The blood-brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta 1812:220-30|
|Reddy, Adarsh S; Kim, Joong H; Hawkins-Salsbury, Jacqueline A et al. (2011) Bone marrow transplantation augments the effect of brain- and spinal cord-directed adeno-associated virus 2/5 gene therapy by altering inflammation in the murine model of globoid-cell leukodystrophy. J Neurosci 31:9945-57|
|Szretter, Kristy J; Daffis, Stephane; Patel, Jigisha et al. (2010) The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system. J Virol 84:12125-38|
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