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

Abstract

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.

Cytomegalovirus Retinitis in HIV and Non-HIV Individuals

“…MAIDS induced mice when infected with CMV revealed up to 90% development of necrotizing retinitis within 10 days of infection. Interestingly, the pathogenesis of CMVR in MAIDS mice was similar to those observed in human counterparts [13,16].…”

“…Through sub-retinally injected MCMV in MAIDS mice, one could not only observe the progression of CMVR disease but could analyze for the presence and absence thereof for various cytokines, immune cell infiltration, immune-activation and antigen presentation, and mode of cell death during active and latent infection. One of the most important findings from these studies includes the upregulation of suppressor of cytokine signaling (SOCS) proteins SOCS1 and SOCS3 [16,17]. SOCS stimulation triggers a negative feedback in cell signaling via the regulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways initiated by antiviral interferons (IFN) and other cytokines such as interleukin (IL)-6 [16,17].…”

“…One of the most important findings from these studies includes the upregulation of suppressor of cytokine signaling (SOCS) proteins SOCS1 and SOCS3 [16,17]. SOCS stimulation triggers a negative feedback in cell signaling via the regulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways initiated by antiviral interferons (IFN) and other cytokines such as interleukin (IL)-6 [16,17]. Viral activation of these host proteins help dysregulate host antiviral strategies and thereby assist virally-infected cells in evading immune destruction.…”

SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

“…In various infectious disease, SOCS regulates the activation of cell by pro-inflammatory cytokines (2).Post natal death of SOCS1 knockdown mice have been reported within three weeks due to IFN-γinduced hyper-inflammation (3). Contrary to this, there are few infectious diseases wherein parasite inhibits activation of immune cells through selective expression of few SOCS (4). One such example is Leishmaniasis wherein expression of SOCS isoforms plays a crucial role in the establishment of infection (5).…”

SOCS and Herpesviruses, With Emphasis on Cytomegalovirus Retinitis

“…As with humans and AIDS, mice with murine AIDS (MAIDS) experience retrovirus-induced immune suppression and become susceptible to diseases of opportunistic pathogens (26). For many years our laboratory has used MAIDS-related MCMV retinitis as a clinically relevant mouse model with high face validity and predictive validity [per (27, 28)] to AIDS-related HCMV retinitis to elucidate the role of potential candidates contributing to this disease (29), including host SOCS proteins (21, 23). Thus, the purposes of this review are to explore briefly the model systems under which herpesviruses manipulate SOCS proteins and to review the effects of SOCS manipulation on virologic, immunologic, or pathologic outcomes, with a focus on experimental cytomegalovirus retinitis.…”