Dissecting the role of different pattern recognition receptors for the activation of anti-viral immunity within the CNS
Luca Ghita1, Chintan Chhatbar1, Andreas Pavlou2, Pia-Katharina Tegtmeyer1, Katharina Borst1, Chittappen Kandiyil Prajeeth2, Stefan Lienenklaus3, Julia Spanier1, Martin Stangel2 and Ulrich Kalinke1
1Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hanover, Germany; 2Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany; 3Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
Pattern recognition receptors are critical for the induction of immune responses after infection. Neurotropic viruses such as rabies virus or tick borne encephalitis virus can cause severe encephalitis and death. Understanding protective mechanisms that are triggered within the CNS by different pattern recognition receptors (PRR) will help to develop novel treatment strategies. To evaluate the role of PRR in induction of anti-viral immunity within the CNS, we used a model of intranasal infection with vesicular stomatitis virus (VSV) in C57BL/6 (WT) mice, and mice lacking Toll-like receptor signaling (MyD88-/-TRIF-/-) or Rig I like helicase signaling (RLH-/-) and analyzed for survival, virus dissemination, IFN-β induction, and immune cell distribution in the CNS.
While VSV infected WT mice did not show signs of disease and cleared VSV in less than 6 days post infection (dpi) from the brain, RLH-/- mice succumbed to infection by day 7 and MyD88-/-TRIF-/- mice died between 8-10 dpi. Of note, no virus was detected in the peripheral organs of the different mouse genotypes analyzed. Surprisingly, IFN-β responses and ISG induction was similar in WT, and RLH-/- and MyD88-/-TRIF-/- mice. WT animals showed an increase of myeloid cells in the olfactory bulb on 6 dpi, however, TLR-/- animals did not show this increase. In contrast, RLH-/- animals showed massive infiltration of myeloid cells when compared to WT animals.
These data show that concomitant TLR and RLH signaling is important to elicit protective immune responses, while both signaling platforms play a different roles during CNS infection.