Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor

Lučin, Pero; Jonjić, Stipan; Messerle, Martin; Polić, Bojan; Hengel, Hartmut; Koszinowski, Ulrich H.

doi:10.1099/0022-1317-75-1-101

Cited by 130 publications

(115 citation statements)

References 29 publications

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“…Synergistic antiviral activity of mIFN-␥ and mTNF-␣ has long been recognized (34). Indeed, synergistic activity of these cytokines has been shown to affect early steps in herpes simplex virus replication at the level of early gene transcription and translation (8), while they inhibit murine cytomegalovirus late gene transcription and DNA replication (20). Our results add HBV to the list of viruses whose gene expression is synergistically suppressed by IFN-␥ and TNF-␣.…”

Section: Discussionmentioning

confidence: 59%

Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures

Pasquetto

Wieland

Uprichard

et al. 2002

J Virol

119

120

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We have previously shown that alpha/beta interferon (IFN-␣/␤) and gamma interferon (IFN-␥) inhibit hepatitis B virus (HBV) replication by eliminating pregenomic RNA containing viral capsids from the hepatocyte. We have also shown that HBV-specific cytotoxic T lymphocytes that induce IFN-␥ and tumor necrosis factor alpha (TNF-␣) in the liver can inhibit HBV gene expression by destabilizing preformed viral mRNA. In order to further study the antiviral activity of IFN-␣/␤, IFN-␥, and TNF-␣ at the molecular level, we sought to reproduce these observations in an in vitro system. Accordingly, hepatocytes were derived from the livers of HBV-transgenic mice that also expressed the constitutively active cytoplasmic domain of the human hepatocyte growth factor receptor (c-Met). Here, we show that the resultant well-differentiated, continuous hepatocyte cell lines (HBV-Met) replicate HBV and that viral replication in these cells is efficiently controlled by IFN-␣/␤ or IFN-␥, which eliminate pregenomic RNA-containing capsids from the cells as they do in the liver. Furthermore, we demonstrate that IFN-␥, but not IFN-␣/␤, is capable of inhibiting HBV gene expression in this system, especially when it acts synergistically with TNF-␣. These cells should facilitate the analysis of the intracellular signaling pathways and effector mechanisms responsible for these antiviral effects.Hepatitis B virus (HBV) is a hepatotropic DNA virus that causes acute and chronic hepatitis and hepatocellular carcinoma (5). We have previously shown that the intrahepatic induction of alpha/beta interferon (IFN-␣/␤), gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣) by various stimuli can inhibit HBV gene expression and/or HBV replication in the livers of HBV-transgenic mice (3,9,10,23). More recently, we demonstrated that similar noncytopathic antiviral events probably occur in the livers of chimpanzees acutely infected with HBV (15).Although it is now well documented that HBV replication can be inhibited by these cytokines (11,19), in vivo systems are by nature difficult to manipulate and control. Therefore, studies designed to determine which cytokines primarily inhibit HBV replication and to decipher the antiviral intracellular mechanism(s) they induce would be greatly facilitated by an in vitro cell culture system that accurately reflects the cytokinedependent control of HBV observed in vivo. Unfortunately, primary cultures of HBV-transgenic hepatocytes are not suitable for these studies because they rapidly become less well differentiated in vitro. Recently, however, well-differentiated immortalized mouse hepatocyte cell lines were established from transgenic mice expressing the constitutively active cytoplasmic domain of the human hepatocyte growth factor receptor (c-Met) in their livers (2). Cells prepared from these mice are not transformed, and they can be induced to a stable, highly differentiated hepatocyte phenotype by dimethyl sulfoxide (DMSO) (29).In this report, we describe the establishment and characterization of an i...

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Section: Discussionmentioning

confidence: 59%

Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures

Pasquetto

Wieland

Uprichard

et al. 2002

J Virol

119

120

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“…CD4+ T cell-independent, antiviral CD8+ T cells are generated in these mice, and are eVective in eliminating virus from other target organs, such as spleen and lung, and from Wbroblasts within the SG [26]. CD4+ T cells mediate their protective function through a combination of TNF and IFN , as revealed through cytokine neutralization assays [32,46]. These cytokines could have direct antiviral activity, and/or could assist in the activation or recruitment of other eVector cells.…”

Section: Immunological Features Of the Cellular Immune Response To MCmentioning

confidence: 99%

The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence

Campbell

Cavanaugh

Slater

2008

Med Microbiol Immunol

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The salivary glands (SG) provide a haven for persistent cytomegalovirus replication, and in this regard are a privileged site of virus immune evasion. The murine cytomegalovirus (MCMV) model has provided insight into the immunological environment of the SG and the unqiue virus-host relationship of this organ. In response to MCMV infection, a robust T cell-mediated immune response is elicited, comprised predominantly of CD8+ T cells that phenotypically and functionally appear activated. However, they fail to clear virus by an unknown evasion mechanism that is independent of inhibitory NKG2A-or Programmed Death 1-mediated signaling. Virus is eventually eliminated from the SG by eVector CD4+ T cells expressing antiviral cytokines. However, this mechanism is severely dampened by high levels of the immunosuppressive cytokine IL-10, selectively expressed by SG CD4+ T cells.

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“…Ϫ/Ϫ mice showed a successive production of IFN-␥ after acute infection Th1-associated cytokine IFN-␥, especially produced by NK cells (13) or CD4 ϩ T cells (9), is also important for MCMV clearance early or late in infection. Moreover, the T cell-dependent IFN-␥ production has been found to play a critical role in the augmentation of NK cell activity (15).…”

Section: Nos2mentioning

confidence: 99%

Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

Noda

Tanaka

Sawamura

et al. 2001

The Journal of Immunology

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Whether or not NO plays a critical role in murine CMV (MCMV) infection has yet to be elucidated. In this study, we examined the role of NO in acute infection with MCMV using NO synthase type 2 (NOS2)-deficient mice. NOS2−/− mice were more susceptible to lethal infection with MCMV than NOS2+/+ mice and generated a much higher peak virus titer in the salivary gland after acute infection. A moderate increase in the MCMV titer was also observed in other organs of NOS2−/− mice such as the spleen, lung, and liver. The immune responses to MCMV infection including NK cell cytotoxicity and CTL response in NOS2−/− mice were comparable with those of NOS2+/+ mice. Moreover, the ability to produce IFN-γ is not impaired in NOS2−/− mice after MCMV infection. The peritoneal macrophages from NOS2−/− mice, however, exhibited a lower antiviral activity than those from NOS2+/+ mice, resulting in an enhanced viral replication in macrophages themselves. Treatment of these cells from NOS2+/+ mice with a selective NOS2 inhibitor decreased the antiviral activity to a level below that obtained with NOS2−/− mice. In addition, the absence of NOS2 and NOS2-mediated antiviral activity of macrophages resulted in not only an enhanced MCMV replication and a high mortality but also a consequent risk of the latency. It was thus concluded that the NOS2-mediated antiviral activity of macrophages via NO plays a protective role against MCMV infection at an early and late stage of the infection.

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Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor

Cited by 130 publications

References 29 publications

Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures

Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures

The salivary glands as a privileged site of cytomegalovirus immune evasion and persistence

Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

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