INHIBITION OF NITRIC-OXIDE SYNTHESIS INCREASES MORTALITY IN SINDBIS VIRUS ENCEPHALITIS

Sindbis virus (ST? is an alphavirus that causes acute encephalomyeliti s in mice, The outcome is determined by the strain of virus and by the age and genetic background of the host, The mortality rates after inf ection with NSV, a neurovirulent strain of SV, were as follows: 81% (1 7 of 21) in BALB/cJ mice; 20% (4 of 20) in BALB/cByJ mice (P < 0.001); 100% in A/J, C57BL/6J, SJL, and DBA mice; and 79% (11 of 14) in immun odeficient scid/CB17 mice, Treatment with N omega-nitro-L-arginine met hyl ester (L-NAME), a nitric oxide synthetase (NOS) inhibitor, increas ed mortality to 100% (P < 0.05) in NSV-infected BALB/cJ mice, to 95% ( P < 0.001) in BALB/cByJ mice, and to 100% in scid/CB17 mice, BALB/cJ a nd BALB/cByJ mice had similar levels of inducible NOS mRNA in their br ains, which were not affected by L-NAME or NSV infection, Brain NOS ac tivity was similar in BALB/cJ and BALB/cByJ mice before and after infe ction and was markedly inhibited by L-NAME. NSV replication in the bra ins of BALB/cJ mice, BALB/cByJ mice, and mice treated with L-NAME was similar, Treatment of N18 neuroblastoma cells with NO donors S-nitroso -N-acetylpenicillamine or sodium nitroprusside in vitro before infecti on increased cell viability at 42 to 48 h compared with untreated NSV- infected N18 cells with little effect on virus replication, These data suggest that NO protects mice from fatal encephalitis by a mechanism that does not directly involve the immune response or inhibition of vi rus growth but rather may enhance survival of the infected neuron unti l the immune response can control virus replication.