Characterization and mechanism of influenza A virus induced cell death.
Item
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Title
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Characterization and mechanism of influenza A virus induced cell death.
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Identifier
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AAI3159233
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identifier
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3159233
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Creator
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Matassov, Demetrius.
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Contributor
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Adviser: Zahra Zakeri
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Date
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2005
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Cell | Biology, Microbiology
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Abstract
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Virus induced host cell death is an important process as it contributes to the pathogenesis of the virus. Many viruses can induce cell death by interacting with the host's cell death machinery in different ways. The influenza virus is one such virus whose mechanism of induction of cell death has not been elucidated. The aim of this study was to characterize the type of cell death induced by the influenza virus and determine the cell death components that are activated and/or needed during influenza induced cell death.;Identifying the type of cell death induced by the virus is of great value as it can give insight to the pathways used by the virus to induce cell death. We started our study by characterizing the type of cell death in MDCK (Madin Darby canine kidney) and A549 human lung epithelial cells. We found that in both cell types influenza induced an apoptotic type of cell death albeit with different kinetics. Using UV inactivation of the virus we determined that the induction of cell death required the replication of the virus and not the mere attachment and internalization, hence the extrinsic pathway alone may not be the activated target by virus attachment. In this line we showed that the Fas molecule, which is part of the extrinsic cell death pathway, is not necessary for virus induced cell death, but appears to enhance the killing.;We found that mitochondria, which are part of the intrinsic cell death pathway, are altered during influenza induced cell death and contribute to the demise of the cell. With the aid of different knockout cell lines we evaluated the need of certain cell death components associated with mitochondria during influenza induced cell death. Pro-apoptotic Bcl-2 family members BAK, BAX and BIM are not needed for cell death induction by the virus but enhance cell killing by the virus while the anti-apoptotic BCl-2 shows limited protection against influenza induced cell death. P53, another intrinsic cell death component, appears not to be required for cell death but can enhance its activation.;As to the activation of caspases we find that caspases are activated in both A549 and MDCK cells after virus infection, but are not required for the cell killing of the infected cells and are therefore dispensable. Lastly, we show that another class of proteases called cathepsins can affect the level of cell death as well as the replication of the virus.;We have shown from our data that both components of intrinsic and extrinsic pathways are involved in influenza induced cell death. We also show that when different parts of the pathways are deleted the virus still kills the cells perhaps by redirecting its use of other components of the same or other pathways. In addition some of the cell death components also affect the efficiency of viral replication. Our findings give support to the possibility that influenza virus is a good killer since it can use a multitude of different components of the cell death machinery.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
