PATTERN OF DISEASE AFTER MURINE HEPATITIS-VIRUS STRAIN-3 INFECTION CORRELATES WITH MACROPHAGE ACTIVATION AND NOT VIRAL REPLICATION

Murine hepatitis virus strain 3 (MHV-3) produces a strain-dependent pa ttern of disease which has been used as a model for fulminant viral he patitis. This study was undertaken to examine whether there was a corr elation between macrophage activation and susceptibility or resistance to MHV-3 infection. Peritoneal macrophages were isolated from resista nt A/J and susceptible BALB/cJ mice and, following stimulation with MH V-3 or lipopolysaccharide (LPS), analyzed for transcription of mRNA an d production of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF -alpha), transforming growth factor beta (TGF-beta), mouse fibrinogen- like protein (musfiblp), tissue factor (TF), leukotriene B-4, and pros taglandin E(2) (PGE(2)). Macrophages from BALB/cJ mice produced greate r amounts of IL-1, TNF-alpha, TGF-beta, leukotriene B-4, and musfiblp following MHV-3 infection than macrophages from resistant A/J mice, wh ereas in response to LPS, equivalent amounts of IL-1, TNF-alpha, TGF-b eta, and TF were produced by macrophages from both strains of mice. Le vels of mRNA of IL-1, TNF-alpha, and musfiblp were greater and more pe rsistent in BALB/cJ than in A/J macrophages, whereas the levels and ki netics of IL-1, TNF-alpha, and TF mRNA following LPS stimulation were identical in macrophages from both strains of mice. Levels of producti on of PGE(2) by MHV-3-stimulated macrophages from resistant and suscep tible mice were equivalent; however, the time course for induction of PGE(2) differed, but the total quantity of PGE, produced was insuffici ent to inhibit induction of musfiblp, a procoagulant known to correlat e with development of fulminant hepatic necrosis in susceptible mice. These results demonstrate marked differences in production of inflamma tory mediators to MHV-3 infection in macrophages from resistant A/J an d susceptible BALB/cJ mice, which may explain the marked hepatic necro sis and fibrin deposition and account for the lethality of MHV-3 in su sceptible mice.