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Institute of Experimental Immunology, Department of Pathology, University Hospital Zurich, Zurich, Switzerland
The immune system has to be optimally balanced to be highly
effective against infections with cytopathic microbial pathogens and
must guarantee efficient destruction of cells infected with
noncytopathic agents while leaving the integrity of noninfected cells
largely unaltered. We describe here the effects of genetically induced
hypercholesterolemia on cellular immunity in apolipoprotein E
(ApoE-/-) and low density lipoprotein receptor-deficient
(LDLR-/-) mice during infection with the hepatotropic
lymphocytic choriomeningitis virus WE strain. In both
ApoE-/- and LDLR-/- mice
hypercholesterolemia aggravated virus-induced immunopathologic liver
disease. ApoE-/- mice exhibited a higher susceptibility
to virus-induced immunopathology than LDLR-/- mice and
usually succumbed to immunopathologic disease when infected with high
doses of virus. Initial virus spread was not influenced by the
hypercholesterolemia, whereas clearance of the virus from spleen and
nonlymphoid organs, including liver, was delayed. Activation of
antiviral CTL, measured by ex vivo cytotoxicity and IFN-
production,
and recruitment of specific CTL into blood and liver were impaired in
hypercholesterolemic mice, indicating that hypercholesterolemia had a
significant suppressive effect on cellular immunity. Taken together,
these data provide evidence that hypercholesterolemia suppresses
antiviral immune responses, thereby changing the host-virus balance,
and can increase susceptibility to acute or chronic and potentially
lethal virus-induced immunopathologic disease. These findings impinge
on our understanding of hypercholesterolemia as a disease parameter and
may explain aspects of the frequent association of persistent pathogens
with hypercholesterolemia-induced diseases, such as
atherosclerosis.
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