SOCS and Herpesviruses, With Emphasis on Cytomegalovirus Retinitis.

Christine I Alston,Richard D Dix

doi:10.3389/fimmu.2019.00732

Christine I Alston, Richard D Dix

Open Access

https://doi.org/10.3389/fimmu.2019.00732

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Abstract

Suppressor of cytokine signaling (SOCS) proteins provide selective negative feedback to prevent pathogeneses caused by overstimulation of the immune system. Of the eight known SOCS proteins, SOCS1 and SOCS3 are the best studied, and systemic deletion of either gene causes early lethality in mice. Many viruses, including herpesviruses such as herpes simplex virus and cytomegalovirus, can manipulate expression of these host proteins, with overstimulation of SOCS1 and/or SOCS3 putatively facilitating viral evasion of immune surveillance, and SOCS suppression generally exacerbating immunopathogenesis. This is particularly poignant within the eye, which contains a diverse assortment of specialized cell types working together in a tightly controlled microenvironment of immune privilege. When the immune privilege of the ocular compartment fails, inflammation causing severe immunopathogenesis and permanent, sight-threatening damage may occur, as in the case of AIDS-related human cytomegalovirus (HCMV) retinitis. Herein we review how SOCS1 and SOCS3 impact the virologic, immunologic, and/or pathologic outcomes of herpesvirus infection with particular emphasis on retinitis caused by HCMV or its mouse model experimental counterpart, murine cytomegalovirus (MCMV). The accumulated data suggests that SOCS1 and/or SOCS3 can differentially affect the severity of viral diseases in a highly cell-type-specific manner, reflecting the diversity and complexity of herpesvirus infection and the ocular compartment.

Highlights

Herpesviruses skillfully manipulate their hosts by various mechanisms while viral lytic and latent cycles maintain a lifelong, Sisyphean struggle with host innate, and adaptive immune systems
Stimulation of SOCS1 and SOCS3 during experimental murine AIDS (MAIDS)-related murine cytomegalovirus (MCMV) retinitis suggests that one or both of these contribute to the severity of the disease, at this time it remains unknown whether SOCS1 and/or SOCS3 inhibition or overexpression would improve the clinical outcome of AIDS-related human cytomegalovirus (HCMV) retinitis
The virologic, immunologic, and pathologic effects of SOCS1 or SOCS3 stimulation during herpesvirus infection frequently depend on cell type, virus strain, and host or host organ system

Summary

Introduction

Herpesviruses skillfully manipulate their hosts by various mechanisms while viral lytic and latent cycles maintain a lifelong, Sisyphean struggle with host innate, and adaptive immune systems. These studies demonstrate pathways whereby HCMV indirectly stimulates SOCS1 and/or SOCS3 in various cell types, which functionally change host and/or bystander cells to contribute to viral immune evasion. During persistent EBV infection of the HK-1 and NP69 human nasopharyngeal epithelial cell lines, signaling pathways including STAT3 and NF-κB are activated compared with uninfected cells, resulting in transcriptional upregulation of downstream targets, including SOCS1 and SOCS3 [169].

Results

Conclusion