Human T-cell lymphotropic virus type 1-infected T lymphocytes impair catabolism and uptake of glutamate by astrocytes via Tax-1 and tumor necrosis factor alpha.
Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of a chronic progressive myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In this disease, lesions of the central nervous system (CNS) are associated with perivascular infiltration by lymphocytes. We and others have hypothesized that these T lymphocytes infiltrating the CNS may play a prominent role in TSP/HAM. Here, we show that transient contact of human or rat astrocytes with T lymphocytes chronically infected by HTLV-1 impairs some of the major functions of brain astrocytes. Uptake of extracellular glutamate by astrocytes was significantly decreased after transient contact with infected T cells, while the expression of the glial transporters GLAST and GLT-1 was decreased. In two-compartment cultures avoiding direct cell-to-cell contact, similar results were obtained, suggesting possible involvement of soluble factors, such as cytokines and the viral protein Tax-1. Recombinant Tax-1 and tumor necrosis factor alpha (TNF-alpha) decreased glutamate uptake by astrocytes. Tax-1 probably acts by inducing TNF-alpha, as the effect of Tax-1 was abolished by anti-TNF-alpha antibody. The expression of glutamate-catabolizing enzymes in astrocytes was increased for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 transcripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T cells impair the ability of astrocytes to manage the steady-state level of glutamate, which in turn may affect neuronal and oligodendrocytic functions and survival.
Szymocha
R
R
Experimental Neurobiology and Physiopathology Unit, INSERM U433, Lyon, France.
Akaoka
H
H
Dutuit
M
M
Malcus
C
C
Didier-Bazes
M
M
Belin
M F
MF
Giraudon
P
P
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D001692:Biological Transport; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D058969:Contactin 2; D005333:Fetus; D018698:Glutamic Acid / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; C548674:CNTN2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C548676:Cntn2 protein, rat; D058969:Contactin 2; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid