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1.
Invest Ophthalmol Vis Sci ; 55(11): 7137-46, 2014 Oct 08.
Article in English | MEDLINE | ID: mdl-25298417

ABSTRACT

PURPOSE: Extensive death of uninfected bystander neuronal cells is an important component of the pathogenesis of cytomegalovirus retinitis. Our previous results have shown that caspase 3-dependent and -independent pathways are involved in death of uninfected bystander cells during murine cytomegalovirus (MCMV) retinitis and also that Bcl-2, an important inhibitor of apoptosis via the Bax-mediated mitochondrial pathway, is downregulated during this process. The purpose of this study was to determine whether Bax-mediated mitochondrial damage has a significant role in the death of uninfected retinal cells. METHODS: BALB/c mice, Bax(-/-) mice, or Bax(+/+) mice were immunosuppressed with methylprednisolone and infected with 5 × 10(3) plaque-forming units (PFU) of the K181 strain of MCMV via the supraciliary route. Injected eyes were analyzed by plaque assay, electron microscopy, hematoxylin and eosin (H&E) staining, TUNEL assay, Western blot (for caspase 3, caspase 12, Bax, receptor interacting protein-1 [RIP1] and receptor interacting protein-3 [RIP3]), as well as immunohistochemical staining for MCMV early antigen and cleaved caspase 3. RESULTS: Significantly more Bax was detected in mitochondrial fractions of MCMV-infected eyes than in mitochondrial fractions of mock-infected control eyes. Furthermore, the level of cleaved caspase 3 was significantly lower in MCMV-infected Bax(-/-) eyes than in MCMV-infected Bax(+/+) eyes. However, more caspase 3-independent cell death of uninfected bystander retinal cells and more cleaved RIP1 were observed in Bax(-/-) than in Bax(+/+) eyes. CONCLUSIONS: During MCMV retinitis, Bax is activated and has an important role in death of uninfected bystander retinal cells by caspase 3-dependent apoptosis. Although the exact mechanism remains to be deciphered, active Bax might also prevent death of some types of uninfected retinal cells by a caspase 3-independent pathway.


Subject(s)
Cell Death , Cytomegalovirus Retinitis/pathology , Retinal Ganglion Cells/ultrastructure , bcl-2-Associated X Protein/physiology , Animals , Blotting, Western , Caspase 3/metabolism , Cytomegalovirus Retinitis/metabolism , Cytomegalovirus Retinitis/virology , Disease Models, Animal , Immunohistochemistry , In Situ Nick-End Labeling , Mice , Mice, Inbred BALB C , Microscopy, Electron , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/virology
2.
J Neuroimmunol ; 260(1-2): 82-91, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23611643

ABSTRACT

The autophagy response induced by HSV-1 infection is antagonized by the Beclin-binding domain (BBD). The purpose of this study was to determine if lack of the BBD affects viral spread and immune response in the eyes and brain. Our results showed that lack of the BBD increases autophagy response and activation of NLRP3 inflammasome, which in turn induces a more rapid innate immune response mediated by macrophage/microglia and NK cells in the injected eye, limiting virus replication and retinal damage. We conclude that autophagy plays a role in controlling HSV-1 infection by more rapid induction of the innate immune response.


Subject(s)
Apoptosis Regulatory Proteins/immunology , Herpes Simplex/immunology , Herpesvirus 1, Human/growth & development , Herpesvirus 1, Human/immunology , Membrane Proteins/immunology , Retinitis/virology , Animals , Apoptosis Regulatory Proteins/chemistry , Autophagy/immunology , Beclin-1 , Encephalitis, Viral/immunology , Encephalitis, Viral/virology , Female , Herpesvirus 1, Human/genetics , Immunity, Innate/immunology , Inflammasomes/immunology , Membrane Proteins/chemistry , Mice , Mice, Inbred BALB C , Protein Structure, Tertiary , Retinitis/immunology , Virus Replication/immunology
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