Leukotrienes play protective roles early during experimental VSV encephalitis.
Leukotrienes (LT) are potent lipid mediators of inflammation. 5-Lipoxygenase (5-LO) is the key enzyme in the conversion of arachidonic acid to LT. There are four LT: LTB(4), LTC(4), LTD(4) and LTE(4). LT have been extensively studied in airway inflammation but little is known about their roles in viral infection in the CNS. LTB(4) is a chemoattractant for neutrophils. In this work, we studied the roles of LT in acute vesicular stomatitis virus (VSV) encephalitis. Two methods were used to disrupt 5-LO activity: mice were treated with Zileuton, an enzyme antagonist, or 5-LO genetic knockout mice were used. We found that inhibition or deletion of 5-LO resulted in: (a) impaired process of neutrophil infiltration into the CNS early during viral infection; (b) fewer neurons expressed nitric oxide synthase-1 (NOS-1); (c) higher viral titers 1 day after viral infection; and (d) increased disruption of blood brain barrier (BBB). Our studies suggest that LT are important innate immune players during VSV pathogenesis and are beneficial to the host in early control of viral replication in the CNS.
Chen
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Department of Biology, New York University, New York, NY 10003-6688, USA.
Restivo
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Reiss
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D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology*; D001921:Brain / Q000201:enzymology / Q000276:immunology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D016466:CHO Cells; D006224:Cricetinae; D018792:Encephalitis, Viral / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis / Q000276:immunology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000276:immunology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D019562:Viral Load
D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase; D019001:Nitric Oxide Synthase; C063449:zileuton; D006918:Hydroxyurea