Abstract
Purpose :
The inflammasome is a multiprotein complex that activates pyroptosis, a proinflammatory programmed cell death pathway of innate immunity. We have shown previously that several key molecules of the pyroptosis pathway (Caspase-1, Gasdermin D, IL-1b, and IL-18) are all significantly stimulated within the eye during progression of MCMV retinitis in mice with MAIDS [J Virol 2012; EER 2021]. We have also shown that MCMV-infected eyes of knockout (KO) MAIDS mice deficient in either Caspase-1, Gasdermin D, or IL-18 all exhibit the same atypical pattern of retinal disease different from full-thickness retinal necrosis of MCMV-infected eyes of wildtype (WT) MAIDS mice [EER 2021]. Herein, we test the hypothesis that pyroptosis-associated inflammasomes are necessary for development of MAIDS-related MCMV full-thickness retinal necrosis.
Methods :
MCMV-infected eyes of groups of WT MAIDS mice collected at 3, 6, and 10 days postinfection (dpi) were subjected to RT-PCR assay for quantification of mRNAs for pyroptosis-associated AIM2, NLRP3, NLRP-1b, and NLRC4 inflammasomes. MCMV-infected eyes of additional groups of WT or KO MAIDS mice deficient in AIM2 or NLRP3 were collected at 10 dpi and subjected to histopathologic analysis or infectious virus quantification.
Results :
MCMV-infected eyes of WT MAIDS mice showed significant amounts of mRNAs for AIM2, NLRP3, NLRP-1b, and NLRC4 that peaked at 6 dpi prior to retinitis development at 10 dpi. Whereas MCMV-infected eyes of WT MAIDS mice showed full-thickness retinal necrosis, MCMV-infected eyes of both AIM2-/- and NLRP3-/- MAIDS mice showed atypical retinal disease characterized by RPE proliferation and sparing of the neurosensory retina. Intraocular amounts of infectious MCMV were also significantly lower in both AIM2 and NLRP3-deficient MAIDS mice when compared with WT MAIDS mice.
Conclusions :
Results suggest that multiple pyroptosis-associated inflammasomes are stimulated within MCMV-infected eyes of WT MAIDS mice. Loss of either AIM2 or NLRP3 inflammasome during MAIDS leads to development of the same pattern of atypical retinal disease and not unlike that observed for MCMV-infected eyes of MAIDS mice deficient in other key molecules of the pyroptosis pathway. Multiple pyroptosis-associated inflammasomes appear to contribute to MAIDS-related MCMV retinitis pathogenesis.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.