Fingerote R J, Cruz B M, Gorczynski R M, Fung L S, Hubbell H R, Suhadolnik R J, Levy G A
Toronto General Hospital, Ontario, Canada.
J Gen Virol. 1995 Feb;76 ( Pt 2):373-80. doi: 10.1099/0022-1317-76-2-373.
Exposure of inbred mice to murine hepatitis virus strain 3 (MHV-3) causes a strain dependent spectrum of disease symptoms which correlates with induction of procoagulant activity (PCA) by macrophages. Previous studies have demonstrated a role for interferons in resistance to MHV-3 infection. These cytokines have both antiviral and immunoregulatory effects which may be crucial for MHV-3 resistance. One of their antiviral effects is the ability to induce 2',5'-oligoadenylate (2-5A) synthetase leading to activation of the latent endoribonuclease RNase L. Once activated, RNase L degrades ssRNA thereby inhibiting viral-induced protein synthesis. These studies were undertaken to determine the effects of Oragen 0004 (Oragen), an RNase L activating 2-5A analogue, on MHV-3 replication and induction of PCA in vitro and on the course of MHV-3 infection in susceptible BALB/cJ mice in vivo. Oragen inhibited MHV-3 replication in peritoneal macrophages derived from resistant A/J and susceptible BALB/cJ mice in a dose-dependent fashion. Concentrations of Oragen greater than 110 micrograms/2 x 10(6) macrophages decreased viral replication by greater than 89% in peritoneal macrophages in vitro obtained from both BALB/cJ and A/J mice and by 86% in livers from MHV-3-infected mice in vivo. However, Oragen failed to inhibit induction of PCA following in vitro exposure of BALB/cJ mice-derived peritoneal macrophages to MHV-3 and failed to prevent the development of fulminant hepatitis in BALB/cJ mice in vivo. Thus, these studies demonstrate clearly that induction of 2-5A synthase and inhibition of viral replication is not sufficient to prevent MHV-3-related hepatocellular injury, and these data further support the role of PCA in the pathogenesis of MHV-3 infection.
将近交系小鼠暴露于鼠肝炎病毒3型（MHV-3）会引发一系列与品系相关的疾病症状，这些症状与巨噬细胞诱导的促凝血活性（PCA）相关。先前的研究表明干扰素在抵抗MHV-3感染中发挥作用。这些细胞因子具有抗病毒和免疫调节作用，这可能对抵抗MHV-3至关重要。它们的抗病毒作用之一是能够诱导2',5'-寡腺苷酸（2-5A）合成酶，从而激活潜伏的核糖核酸酶RNase L。一旦激活，RNase L会降解单链RNA，从而抑制病毒诱导的蛋白质合成。进行这些研究是为了确定一种激活RNase L的2-5A类似物Oragen 0004（Oragen）对体外MHV-3复制和PCA诱导的影响，以及对易感的BALB/cJ小鼠体内MHV-3感染进程的影响。Oragen以剂量依赖的方式抑制了源自抗性A/J和易感BALB/cJ小鼠的腹腔巨噬细胞中MHV-3的复制。在体外从BALB/cJ和A/J小鼠获得的腹腔巨噬细胞中，浓度大于110微克/2×10(6)巨噬细胞的Oragen使病毒复制减少了89%以上，在体内感染MHV-3的小鼠肝脏中减少了86%。然而，在体外将源自BALB/cJ小鼠的腹腔巨噬细胞暴露于MHV-3后，Oragen未能抑制PCA的诱导，并且在体内未能预防BALB/cJ小鼠暴发性肝炎的发展。因此，这些研究清楚地表明，诱导2-5A合成酶和抑制病毒复制不足以预防与MHV-3相关的肝细胞损伤，并且这些数据进一步支持了PCA在MHV-3感染发病机制中的作用。
