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Reactive oxygen species-induced parthanatos of immunocytes by human cytomegalovirus-associated substance
- Reactive oxygen species-induced parthanatos of immunocytes by human cytomegalovirus-associated substance
- Kim J.H.; Kim J.; Roh J.; Park C.-S.; Seoh J.-Y.; Hwang E.-S.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- Microbiology and Immunology
- Microbiology and Immunology vol. 62, no. 4, pp. 229 - 242
- human cytomegalovirus; parthanatos; reactive oxygen species
- Blackwell Publishing Asia
- SCI; SCIE; SCOPUS
- Document Type
- Previous studies have examined various immune evasion strategies of human cytomegalovirus (HCMV) to gain understanding of its pathogenesis. Although the mechanism that underlies immunocyte destruction near HCMV-infected lesions has yet to be established, it is here shown that substances produced by HCMV-infected cells induce death in several types of immunocytes, but not in fibroblasts or astrocytomas. These substances contain HCMV proteins and were termed HCMV-associated insoluble substance (HCMVAIS). The mechanism by which HCMVAIS induces cell death was characterized to improve understanding the death of immunocytes near HCMV-infected lesions. HCMVAIS were found to trigger production of intracellular nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species (ROS), resulting in cell death, this effect being reversed following treatment with ROS inhibitors. Cell death was not induced in splenocytes from NOX-2 knockout mice. It was hypothesized that DNA damage induced by oxidative stress initiates poly ADP-ribose polymerase-1 (PARP-1)-mediated cell death, or parthanatos. HCMVAIS-induced cell death is accompanied by PARP-1 activation in a caspase-independent manner, nuclear translocation of apoptosis-inducing factor (AIF), and DNA fragmentation, which are typical features of parthanatos. Treatment with an AIF inhibitor decreased the rate of HCMVAIS-induced cell death, this being confirmed by hematoxylin and eosin staining; cell death in most HCMV-positive foci in serial section samples of a large intestine with HCMV infection was TUNEL-positive, cleaved caspase 3-negative and CD45-positive. Taken together, these data suggest that HCMV inhibits local immune responses via direct killing of immunocytes near HCMV-infected cells through ROS-induced parthanatos by HCMVAIS. © 2018 The Authors. Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd
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