Characterization of Virus‐Induced Interferon‐γ Responses in Mice Previously Infected with Murine Cytomegalovirus

Shanley, John D.; Albert, Greg; Biegel, Diane

doi:10.1086/318830

Cited by 5 publications

(2 citation statements)

References 38 publications

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“…These results are consistent with previous studies demonstrating that IFN‐γ, TNF‐α, IL‐12 and IFN‐α/β are produced in response to MCMV infection and are critical to effective anti‐viral defences [24–33]. Production of proinflammatory cytokines, especially IFN‐γ, in response to MCMV and their importance in control of MCMV replication is demonstrated here and is also supported by previous in vitro and in vivo studies [21,34,35]. However, little is known about the mechanisms by which the production of proinflammatory cytokines is curtailed after effective host response to MCMV infection; our studies were designed to address this question.…”

Section: Discussionsupporting

confidence: 92%

Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus

Oakley¹,

Garvy

Humphreys³

et al. 2007

Clinical and Experimental Immunology

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SummaryThe anti-inflammatory cytokine interleukin (IL)-10 plays an important role in the regulation of host-immune responses. Here we studied the role IL-10 plays in host responses to cytomegalovirus (CMV) infection. We demonstrate that manifestations of murine CMV (MCMV) disease are more severe in IL-10 knock-out mice, despite significantly reduced levels of viral replication. Cytokine analysis of serum revealed increased levels of interferon (IFN)-g, monocyte chemotactic protein 1 (MCP-1) and IL-6, all of which are potent stimulators of inflammatory responses. Depletion of IFN-g by monoclonal antibodies in IL-10 knock-out mice failed to improve the physical condition of the mice, while increasing viral replication. In contrast, serum levels of IL-6 in the knock-out animals were unaffected by IFN-g depletion and remained significantly elevated early in the course of infection. These data suggest that increased weight loss observed in IL-10 knock-out mice may be attributed to the uncontrolled production of proinflammatory cytokines, including IL-6.

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Section: Discussionsupporting

confidence: 92%

Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus

Oakley¹,

Garvy

Humphreys³

et al. 2007

Clinical and Experimental Immunology

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“…Many viruses are capable of directly and/or indirectly inducing SOCS proteins, exploiting their function to enhance virus replication by inhibiting the antiviral functions of the JAK/STAT pathway (82). MCMV infection of immunologically normal mice results in the induction of IL-6 as well as type I and type II IFNs (98)(99)(100)(101)(102)(103)(104)(105)(106). Our findings indicate that both IFN-␥ and IL-6 are candidate inducers of SOCS expression during acute MCMV infection of healthy mice and during subretinal MCMV infection of retinitis-susceptible MAIDS-10 mice.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression

Chien

Alston

Dix

2018

J Virol

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AIDS-related human cytomegalovirus retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. To study mechanisms of this disease, we used a clinically relevant animal model of murine cytomegalovirus (MCMV) retinitis with retrovirus-induced murine AIDS (MAIDS) that mimics the progression of AIDS in humans. We found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling 1 (SOCS1) and SOCS3, host proteins which hinder immune-related signaling by cytokines, including antiviral type I and type II interferons. The present study demonstrates that in the absence of retinal disease, systemic MCMV infection of mice without MAIDS, but not in mice with MAIDS, leads to mild stimulation of splenic SOCS1 mRNA. In sharp contrast, when MCMV is directly inoculated into the eyes of retinitis-susceptible MAIDS mice, high levels of intraocular SOCS1 and SOCS3 mRNA and protein are produced which are associated with significant intraocular upregulation of gamma interferon (IFN-γ) and interleukin-6 (IL-6) mRNA expression. We also show that infiltrating macrophages, granulocytes, and resident retinal cells are sources of intraocular SOCS1 and SOCS3 protein production during development of MAIDS-related MCMV retinitis, and SOCS1 and SOCS3 mRNA transcripts are detected in retinal areas histologically characteristic of MCMV retinitis. Furthermore, SOCS1 and SOCS3 are found in both MCMV-infected cells and uninfected cells, suggesting that these SOCS proteins are stimulated via a bystander mechanism during MCMV retinitis. Taken together, our findings suggest a role for MCMV-related stimulation of SOCS1 and SOCS3 in the progression of retinal disease during ocular, but not systemic, MCMV infection. Cytomegalovirus infection frequently causes blindness in untreated HIV/AIDS patients. This virus manipulates host cells to dysregulate immune functions and drive disease. Here, we use an animal model of this disease to demonstrate that cytomegalovirus infection within eyes during retinitis causes massive upregulation of immunosuppressive host proteins called SOCS. As viral overexpression of SOCS proteins exacerbates infection with other viruses, they may also enhance cytomegalovirus infection. Alternatively, the immunosuppressive effect of SOCS proteins may be protective against immunopathology during cytomegalovirus retinitis, and in such a case SOCS mimetics or overexpression treatment strategies might be used to combat this disease. The results of this work therefore provide crucial basic knowledge that contributes to our understanding of the mechanisms of AIDS-related cytomegalovirus retinitis and, together with future studies, may contribute to the development of novel therapeutic targets that could improve the treatment or management of this sight-threatening disease.

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Murine Cytomegalovirus and Other Herpesviruses

Shellam¹,

Redwood²,

Smith³

et al. 2007

The Mouse in Biomedical Research

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Characterization of Virus‐Induced Interferon‐γ Responses in Mice Previously Infected with Murine Cytomegalovirus

Cited by 5 publications

References 38 publications

Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus

Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus

Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression

Murine Cytomegalovirus and Other Herpesviruses

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