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-acces
