Who is killing whom? Hantaviruses vs programmed cell death
Author: Gupta, Shawon
Date: 2016-03-10
Location: Hillarp, Retzius väg 8, Karolinska Institutet, Campus Solna
Time: 13.00
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
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Thesis (795.1Kb)
Abstract
Hantaviruses belong to the Bunyaviridae family of negative stranded RNA viruses. They
carry a tri-segmented genome and consist of four structural proteins. The four structural
proteins are two glycoproteins Gn and Gc, a nucleocapsid (N) protein and an RNA-dependent
RNA-polymerase. An additional nonstructural protein can be expressed by some
hantaviruses. Hantavirus-infection cause two severe diseases in humans with potential deadly
outcome, namely hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS). One main target for hantavirus-infection is the endothelial
cells and vascular leakage is a hallmark for both HFRS and HCPS. In patients strong
cytotoxic lymphocyte responses are seen. Cytotoxic lymphocytes, such as natural killer (NK)
cells and cytotoxic T lymphocytes, cause apoptosis in virus-infected cells via the cytotoxic
granule pathway or the death receptor pathway. The cytotoxic granule pathway uses
granzyme B to facilitate programmed cell death (PCD) in the target. The death receptor
pathway uses death ligands, among them tumor necrosis factor related apoptosis-inducing
ligand (TRAIL) binds to death receptor (DR) 4 or 5, to induce PCD.
One potential mechanism regarding hantavirus pathogenesis might be killing of infected endothelial cells by cytotoxic lymphocytes, thus causing leakage of the endothelium. This is contradicted by findings showing that in patient autopsy, hantavirus-infected cells are intact. The aim of this PhD thesis is to give a possible explanation of this dichotomy and to better understand hantavirus pathogenesis.
The first part of this thesis (paper I and II) shows that hantavirus-infection protects cells from cytotoxic lymphocytes via inhibiting granzyme B activity and by down-regulating DR5 from the cell surface. Granzyme B and caspase 3, enzymes needed for apoptosis (a type of PCD), both interacts with hantavirus N protein, and they are both inhibited by the N protein. Further, hantavirus-infection of primary endothelial cells causes miss-localization of DR5. In infected cells DR5 is found in the nucleus instead of on the cell surface. Taken together, hantavirus-infection blocks the two major pathways used by cytotoxic lymphocytes to induce cell death, suggesting that hantavirus pathogenesis is not due to killing of infected cells by cytotoxic lymphocytes. The last part of this thesis (paper III) focuses on hantavirus activated NK cell mediated killing of uninfected endothelial cells. NK cells co-incubated with hantavirus-infected endothelial cells are activated. This activation is contact dependent and was attributed to IL-15 and IL-15Rα expression on hantavirus-infected cells’ surface. Interestingly, these activated NK cells induce cell death in uninfected cells with normal HLA class I levels, indicating that hantavirus might cause NK cell mediated killing of uninfected bystander cells.
Taken together, the papers I, II and III included in this thesis shows that hantavirusinfection protects cells from cytotoxic lymphocyte mediated killing, while infected cells can cause NK cell activation and possibly subsequent NK cell killing of uninfected cells.http://kib.ki.se/en/publish-analyse/open-access
One potential mechanism regarding hantavirus pathogenesis might be killing of infected endothelial cells by cytotoxic lymphocytes, thus causing leakage of the endothelium. This is contradicted by findings showing that in patient autopsy, hantavirus-infected cells are intact. The aim of this PhD thesis is to give a possible explanation of this dichotomy and to better understand hantavirus pathogenesis.
The first part of this thesis (paper I and II) shows that hantavirus-infection protects cells from cytotoxic lymphocytes via inhibiting granzyme B activity and by down-regulating DR5 from the cell surface. Granzyme B and caspase 3, enzymes needed for apoptosis (a type of PCD), both interacts with hantavirus N protein, and they are both inhibited by the N protein. Further, hantavirus-infection of primary endothelial cells causes miss-localization of DR5. In infected cells DR5 is found in the nucleus instead of on the cell surface. Taken together, hantavirus-infection blocks the two major pathways used by cytotoxic lymphocytes to induce cell death, suggesting that hantavirus pathogenesis is not due to killing of infected cells by cytotoxic lymphocytes. The last part of this thesis (paper III) focuses on hantavirus activated NK cell mediated killing of uninfected endothelial cells. NK cells co-incubated with hantavirus-infected endothelial cells are activated. This activation is contact dependent and was attributed to IL-15 and IL-15Rα expression on hantavirus-infected cells’ surface. Interestingly, these activated NK cells induce cell death in uninfected cells with normal HLA class I levels, indicating that hantavirus might cause NK cell mediated killing of uninfected bystander cells.
Taken together, the papers I, II and III included in this thesis shows that hantavirusinfection protects cells from cytotoxic lymphocyte mediated killing, while infected cells can cause NK cell activation and possibly subsequent NK cell killing of uninfected cells.http://kib.ki.se/en/publish-analyse/open-access
List of papers:
I. Gupta S, Braun M, Tischler ND, Stoltz M, Sundström KB, Björkström NK, Ljunggren HG, Klingström J. Hantavirus-infection Confers Resistance to Lymphocyte-Mediated Apoptosis. PLoS Pathogens, 2013 9(3):e1003272.
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II. Gupta S, Solà Riera C, Braun M, Björkström NK, Ljunggren HG, Klingström J. Hantavirus Causes Nuclear Translocation of Death Receptor 5 and Protects Infected Cells from TRAIL-Induced Apoptosis. [Manuscript]
III. Braun M, Björkström NK, Gupta S, Sundström K, Ahlm C, Klingström J, Ljunggren HG. NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL-15Rα Expression. PLoS Pathogens, 2014 20;10(11):e1004521.
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View record in Web of Science®
I. Gupta S, Braun M, Tischler ND, Stoltz M, Sundström KB, Björkström NK, Ljunggren HG, Klingström J. Hantavirus-infection Confers Resistance to Lymphocyte-Mediated Apoptosis. PLoS Pathogens, 2013 9(3):e1003272.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Gupta S, Solà Riera C, Braun M, Björkström NK, Ljunggren HG, Klingström J. Hantavirus Causes Nuclear Translocation of Death Receptor 5 and Protects Infected Cells from TRAIL-Induced Apoptosis. [Manuscript]
III. Braun M, Björkström NK, Gupta S, Sundström K, Ahlm C, Klingström J, Ljunggren HG. NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL-15Rα Expression. PLoS Pathogens, 2014 20;10(11):e1004521.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Klingström, Jonas
Issue date: 2016-02-17
Rights:
Publication year: 2016
ISBN: 978-91-7676-150-2
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