Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques.
HIV infiltrates the CNS soon after an individual has become infected with the virus, and can cause dementia and encephalitis in late-stage disease. Here, a global metabolomics approach was used to find and identify metabolites differentially regulated in the cerebrospinal fluid (CSF) of rhesus macaques with SIV-induced CNS disease, as we hypothesized that this might provide biomarkers of virus-induced CNS damage. The screening platform used a non-targeted, mass-based metabolomics approach beginning with capillary reverse phase chromatography and electrospray ionization with accurate mass determination, followed by novel, nonlinear data alignment and online database screening to identify metabolites. CSF was compared before and after viral infection. Significant changes in the metabolome specific to SIV-induced encephalitis were observed. Metabolites that were increased during infection-induced encephalitis included carnitine, acyl-carnitines, fatty acids, and phospholipid molecules. The elevation in free fatty acids and lysophospholipids correlated with increased expression of specific phospholipases in the brains of animals with encephalitis. One of these, a phospholipase A2 isoenzyme, is capable of releasing a number of the fatty acids identified. It was expressed in different areas of the brain in conjunction with glial activation, rather than linked to regions of SIV infection and inflammation, indicating widespread alterations in infected brains. The identification of specific metabolites as well as mechanisms of their increase illustrates the potential of mass-based metabolomics to address problems in CNS biochemistry and neurovirology, as well as neurodegenerative diseases.
Department of Molecular Biology and Center for Mass Spectrometry, The Scripps Research Institute, La Jolla, California 92037, USA.
William R
WR
Wikoff
Gurudutt
G
Pendyala
Gary
G
Siuzdak
Howard S
HS
Fox
D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid; D002490:Central Nervous System / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D005227:Fatty Acids / Q000134:cerebrospinal fluid; D015971:Gene Expression Regulation, Enzymologic; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D017403:In Situ Hybridization; D008244:Lysophosphatidylcholines / Q000134:cerebrospinal fluid; D008253:Macaca mulatta; D010740:Phospholipases / Q000235:genetics* / Q000378:metabolism; D054466:Phospholipases A1 / Q000235:genetics / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000134:cerebrospinal fluid* / Q000378:metabolism; D015302:Simian Immunodeficiency Virus; D021241:Spectrometry, Mass, Electrospray Ionization; D015854:Up-Regulation / Q000235:genetics
D005227:Fatty Acids; D008244:Lysophosphatidylcholines; D010740:Phospholipases; D054466:Phospholipases A1; D054513:Group IV Phospholipases A2; D002331:Carnitine