Resistance to murine hepatitis virus strain 3 is dependent on production of nitric oxide.
The strain-specific spectrum of liver disease following murine hepatitis virus type 3 (MHV-3) infection is dependent on inflammatory mediators released by macrophages. Production of nitric oxide (NO) by macrophages has been implicated in resistance to a number of viruses, including ectromelia virus, vaccinia virus, and herpes simplex virus type 1. This study was undertaken to define the role of NO in MHV-3 infection. Gamma interferon-induced production of NO inhibited growth of MHV-3 in a murine macrophage cell line (RAW 264.7). Viral inhibitory activity was reproduced by the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP), whereas N-acetyl-DL-pencillamine (NAP), an inactive analog of SNAP, had no effect. Electron microscopy studies confirmed the inhibitory effects of NO on viral replication. Peritoneal macrophages isolated from A/J mice known to be resistant to MHV-3 produced a fivefold-higher level of NO and higher levels of mRNA transcripts of inducible NO synthase in response to gamma interferon than macrophages from susceptible BALB/cJ mice. SNAP inhibited growth of MHV-3 in macrophages from both strains of mice to similar degrees. In vivo inhibition of NO by N-monomethyl-L-arginine resulted in loss of resistance to MHV-3 in A/J mice. These results collectively demonstrate a defect in the production of NO in macrophages from susceptible BALB/cJ mice and define the importance of endogenous NO in resistance to MHV-3 infection in resistant A/J mice.
Departments of Surgery, The University of Toronto, Toronto, Ontario, Canada.
M
M
Pope
P A
PA
Marsden
E
E
Cole
S
S
Sloan
L S
LS
Fung
Q
Q
Ning
J W
JW
Ding
J L
JL
Leibowitz
M J
MJ
Phillips
G A
GA
Levy
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D018352:Coronavirus Infections / Q000276:immunology*; D005260:Female; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000276:immunology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D014771:Virion; D014779:Virus Replication / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology
C110881:S-nitro-N-acetylpenicillamine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D010396:Penicillamine