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New Insights into the Pathogenesis of Experimental Cytomegalovirus Retinal Necrosis with an Emphasis on Inflammasomes
Richard D Dix1,2, Jessica J Carter1, Heather Koehler3
1Viral Immunology Center, Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Abstract:
Pyroptosis is a programmed cell death pathway that initiates and sustains inflammation to protect the host against invading pathogens or stress. Activation of caspase-1-mediated canonical pyroptosis takes place via formation of multi-protein cytoplasmic immune signaling complexes known as inflammasomes. Because we have shown previously that the canonical pyroptosis pathway plays a significant role in the pathogenesis of experimental murine cytomegalovirus (MCMV) retinal necrosis in mice with retrovirus-induced immunosuppression (MAIDS), we performed additional studies to determine whether this pathogenic involvement extends to inflammasomes as initiators of the canonical pyroptosis pathway. Initial studies demonstrated significant transcription of three different pyroptosis-associated inflammasomes, NLRP3, NLRP1b, and AIM2, within the ocular compartments of MCMV-infected eyes of MAIDS mice. Subsequent histopathologic findings revealed MCMV-infected eyes of groups of NLRP3-/- MAIDS mice, NLRP1b-/- MAIDS mice, or AIM2-/- MAIDS mice each exhibited a similar atypical retinal pathology characterized by loss of photoreceptors and proliferation and/or loss of retinal pigmented epithelium but with relative sparing of the neurosensory retina, an outcome different from typical full-thickness retinal necrosis of MCMV-infected eyes of wildtype MAIDS mice. We conclude that multiple inflammasomes are individually stimulated within MCMV-infected eyes of MAIDS mice and each independently contributes to MAIDS-related MCMV full-thickness retinal necrosis pathogenesis.
Insights
Multiple inflammasomes, including NLRP3, NLRP1b, and AIM2, independently drive pyroptosis and retinal necrosis in mice with cytomegalovirus-induced immunosuppression.
Area of Science:
- Immunology
- Ophthalmology
- Virology
Background:
- Pyroptosis is a programmed cell death pathway crucial for host defense against pathogens.
- Canonical pyroptosis is initiated by inflammasomes, multi-protein complexes activating caspase-1.
- Previous work implicated pyroptosis in experimental murine cytomegalovirus (MCMV) retinal necrosis in mice with acquired immunodeficiency (MAIDS).
Purpose of the Study:
- To investigate the role of inflammasomes as initiators of canonical pyroptosis in MCMV retinal necrosis pathogenesis in MAIDS mice.
- To determine if specific inflammasomes (NLRP3, NLRP1b, AIM2) contribute to MCMV-induced retinal pathology.
Main Methods:
- Quantification of inflammasome transcription in ocular tissues of MCMV-infected MAIDS mice.
- Histopathological analysis of MCMV-infected eyes from wildtype, NLRP3-/-, NLRP1b-/-, and AIM2-/- MAIDS mice.
- Comparison of retinal pathology between different knockout mouse models and wildtype controls.
Main Results:
- Significant transcription of NLRP3, NLRP1b, and AIM2 inflammasomes was observed in MCMV-infected eyes of MAIDS mice.
- Mice lacking NLRP3, NLRP1b, or AIM2 exhibited atypical retinal pathology with photoreceptor loss and retinal pigmented epithelium changes, but relative sparing of the neurosensory retina.
- This atypical pathology contrasted with the full-thickness retinal necrosis seen in wildtype MAIDS mice.
Conclusions:
- Multiple inflammasomes (NLRP3, NLRP1b, AIM2) are individually activated in MCMV-infected eyes of MAIDS mice.
- Each of these inflammasomes independently contributes to the pathogenesis of MCMV-induced retinal necrosis in MAIDS mice.
- These findings highlight the complex inflammasome-mediated immune response in viral-induced ocular disease.
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