Abstracts (complete list) - Wissenschaft Online

Claudia N. Detje, Hauke Schmidt, Thomas Meyer, Marco Prinz, Ulrich Kalinke
Early type I interferon responses exclude nerotropic viruses
from central nervous system
Mice infected with vesicular stomatitis virus (VSV) mount a protective anti-viral immune
response. It is generally believed that if clearance of the pathogen in the periphery fails,
neurotropic virus can enter the central nervous system (CNS) to replicate and cause
severe brain damage that ultimately leads to death. This concept is supported by the
observation that type I interferon receptor deficient mice (IFNAR-/-) that usually
succumb to VSV infection within 2-3 days are protected if they have been immunized
with UV-inactivated VSV before challenge.
To investigate whether in IFNAR-/- mice viral infection of the CNS was primarily
associated with the failure of the peripheral immune system to control the virus or with
the failure of the interferon system to protect neurons against virus infection, we are
studying the pathogenesis of VSV infection in mice with a cell type-specific IFNAR
deletion in neurons of the CNS (NesCre+/-IFNARflox/flox). In recent experiments we
verified the specificity and efficiency of IFNAR deletion in NesCre+/-IFNARflox/flox mice.
Unlike IFNAR-/- mice that died within 3 days after VSV infection, NesCre+/-IFNARflox/
flox mice did not show signs of disease before 5-6 days after infection. Then, NesCre+/-
IFNARflox/flox mice became hemiplegic, started to move around in circles and
eventually died. In contrast, wild type mice did not show any sign of disease and
survived VSV infection. The different courses of disease observed correlated with a
severe infection of basically any type of tissue in IFNAR-/- mice, whereas in NesCre+/-
IFNARflox/flox mice only CNS was infected. Terminally diseased NesCre+/-IFNARflox/
flox mice showed approximately 10 to 100-fold higher virus loads in the brain than
IFNAR-/- mice, whereas only very little or no virus was found in liver, kidney and
spleen. In contrast IFNAR-/- mice showed high virus titers in all tissues analyzed.
In conclusion, the data collected so far suggest that early type I interferon responses
play a crucial role in excluding virus from CNS. It will be a matter of future research to
determine whether early type I interferon crosses the blood brain barrier or whether it
is produced within the CNS.