Virus Clearance through Apoptosis-Dependent Phagocytosis of Influenza A Virus-Infected Cells by Macrophages

Fujimoto, Ippei; Pan, Jiehong; Takizawa, Takenori; Nakanishi, Yoshinobu

doi:10.1128/jvi.74.7.3399-3403.2000

Cited by 136 publications

(124 citation statements)

References 22 publications

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“…The host uses apoptosis to limit virus replication and remove virus-infected cells (Fujimoto et al, 2000). Apoptosis can also assist in the dissemination of viral particles and is the cause of tissue damage observed following many viral infections (Lyles, 2000).…”

Section: Discussionmentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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The molecular mechanisms governing severe acute respiratory syndrome coronavirus-induced pathology are not fully understood. Virus infection and some individual viral proteins, including the 3a protein, induce apoptosis. However, the cellular targets leading to 3a protein-mediated apoptosis have not been fully characterized. This study showed that the 3a protein modulates the mitochondrial death pathway in two possible ways. Activation of caspase-8 through extrinsic signal(s) caused Bid activation. In the intrinsic pathway, there was activation of caspase-9 and cytochrome c release from the mitochondria. This was the result of increased Bax oligomerization and higher levels of p53 in 3a protein-expressing cells, which depended on the activation of p38 MAP kinase (MAPK) in these cells. For p38 activation and apoptosis induction, the 3a cytoplasmic domain was sufficient. In direct Annexin V staining assays, the 3a protein-expressing cells showed increased apoptosis that was attenuated with the p38 MAPK inhibitor SB203580. A block in nuclear translocation of the STAT3 transcription factor in cells expressing the 3a protein was also observed. These results have been used to present a model of 3a-mediated apoptosis. INTRODUCTIONThe aetiological agent for severe acute respiratory syndrome (SARS) was identified as a novel coronavirus (SARS-CoV) (Peiris et al., 2003). SARS-CoV has a polyadenylated, positive-sense RNA genome of approximately 30 kb (Marra et al., 2003). In addition to the prototypic coronavirus genes, the SARS-CoV genome also contains nine unique open reading frames (ORFs) (Marra et al., 2003). Of these, orf3a is the largest and encodes a protein of 274 aa, variously called ORF3A (Ito et al., 2005), X1 (Rota et al., 2003) or U274 (Tan et al., 2004b). The 3a protein has been predicted to contain an N-terminal signal peptide followed by three transmembrane domains and a C-terminal cytoplasmic domain of approximately 150 aa (Zeng et al., 2004).The 3a protein is associated with virus particles produced following infection of Vero E6 or Caco-2 cells (Ito et al., 2005;Shen et al., 2005) and can assemble into virus-like particles when co-expressed with the membrane and envelope proteins in insect cells (Shen et al., 2005). In vitro studies have also shown the 3a protein to interact with the viral envelope, membrane and spike proteins (Tan et al., 2004b;Tan, 2005) and the cellular protein caveolin-1 (Padhan et al., 2007). A deletion of orf3a was shown to reduce virus titres, but not to eliminate virus replication (Yount et al., 2005), and convalescent sera from SARS patients have antibodies to the 3a protein (Tan et al., 2004a), suggesting that it is expressed during virus infection of the host. The 3a protein was shown to upregulate the expression of fibrinogen in A549 lung epithelial cells and to possess an ionchannel activity selective for monovalent cations (Lu et al., 2006). Ectopic expression of the 3a protein has been shown to induce apoptosis in Vero E6 cells through activation of caspase-8, chromatin c...

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Section: Discussionmentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Padhan

Minakshi

Towheed

et al. 2008

Journal of General Virology

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“…Apoptosis coupled to phagocytosis by macrophages was suggested to function in that way and to efficiently clear influenza A virus. 58 High cytoplasmic dsRNA contents may function as an internal signal initiating such a cell death program. However, many viruses encode for caspase inhibitors, such as baculovirus p35 or cowpoxvirus CrmA, which are exploited to prevent apoptotic suicide of the cellular host.…”

Section: Discussionmentioning

confidence: 99%

Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

et al. 2002

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Interferons enhance the cellular antiviral response by inducing expression of protective proteins. Many of these proteins are activated by dsRNA, a typical by-product of viral infection. Here we show that type-I and type-II interferons can sensitize cells to dsRNA-induced cytotoxicity. In caspase-8-or FADD-deficient Jurkat cells dsRNA induces necrosis, instead of apoptosis. In L929sA cells dsRNA-induced necrosis involves high reactive oxygen species production. The antioxidant butylated hydroxyanisole protects cells from necrosis, but shifts the response to apoptosis. Treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-DLAsp(OMe)-fluoromethylketone or overexpression of Bcl-2 prevent this shift and promote necrosis. Our results suggest that a single stimulus can initiate different deathsignaling pathways, leading to either necrotic or apoptotic cell death. Inhibition of key events in these signaling pathways, such as caspase activation, cytochrome c release or mitochondrial reactive oxygen species production, tips the balance between necrosis and apoptosis, leading to dominance of one of these death programs.

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“…27 ± 29 On the other hand, macrophage phagocytosis of influenza virus-infected cells in an apoptosis-dependent manner leads to direct elimination of the virus. 30 Another role of the phagocytic clearance of apoptotic cells could be the prevention of autoimmune diseases. Macrophages phagocytose some types of apoptotic cells in a complement-mediated manner.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of sperm production in mice by annexin V microinjected into seminiferous tubules: possible etiology of phagocytic clearance of apoptotic spermatogenic cells and male infertility

et al. 2002

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Many differentiating spermatogenic cells die by apoptosis during the process of mammalian spermatogenesis. However, very few apoptotic spermatogenic cells are detected by histological examination of the testis, probably due to the rapid elimination of dying cells by phagocytosis. Previous in vitro studies showed that Sertoli cells selectively phagocytose dying spermatogenic cells by recognizing the membrane phospholipid phosphatidylserine (PS), which is exposed to the surface of spermatogenic cells during apoptosis. We examined here whether PS-mediated phagocytosis of apoptotic spermatogenic cells occurs in vivo. For this purpose, the PS-binding protein annexin V was microinjected into the seminiferous tubules of normal live mice, and their testes were examined. The injection of annexin V caused no histological changes in the testis, but significantly increased the number of apoptotic spermatogenic cells as assessed by the terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay. The number of Sertoli cells did not change in the annexin V-injected testes, and annexin V itself did not induce apoptosis in primary cultured spermatogenic cells. These results indicate that annexin V inhibited the phagocytic clearance of apoptotic spermatogenic cells and suggest that PS-mediated phagocytosis of those cells occurs in vivo. Furthermore, the injection of annexin V into the seminiferous tubules brought about a significant reduction in the number of spermatogenic cells and epididymal sperm in anticancer drug-treated mice. This suggests that the elimination of apoptotic spermatogenic cells is required for the production of sperm.

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Virus Clearance through Apoptosis-Dependent Phagocytosis of Influenza A Virus-Infected Cells by Macrophages

Cited by 136 publications

References 22 publications

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation

Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

Inhibition of sperm production in mice by annexin V microinjected into seminiferous tubules: possible etiology of phagocytic clearance of apoptotic spermatogenic cells and male infertility

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