Depletion of microglia leads to severe impairment in virus elimination and increased mortality in a mouse model of viral encephalitis-induced epilepsy
Inken Waltl1,2,Christopher Käufer1, Ingo Gerhauser3, Chintan Chhatbar4, Luca Ghita4, Ulrich Kalinke4, Wolfgang Löscher1,2 1Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; 2Center for Systems Neuroscience, Hannover, Germany; 3Department of Pathology, University of Veterinary Medicine Hannover, Germany; 4Institute for Experimental Infection Research, TWINCORE, Hannover, Germany
Infections of the central nervous system (CNS) can lead to various long-term impairments and cognitive deficits including epilepsy, which represents one of the most common neurological diseases among humans. The risk to develop epilepsy after survival of viral encephalitis is up to 21%, but the mechanisms of acute seizure development and epileptogenesis are rarely known. We hypothesized that cells of the innate immune system, especially myeloid cells - either CNS invading monocytes or activated resident microglia within the CNS - play a major role in these processes. To investigate the role of these cells in acute seizure development and epileptogenesis, we studied intracerebral infection with Theiler's virus, a Cardiovirus of the Picornaviridae family, in C57BL/6 (B6) mice as a model of acute seizure induction and epilepsy development (Libbey et al. Epilepsia 2008). We tested the effects of prior depletion of microglial cells, using a specific colony stimulating factor 1 receptor inhibitor (PLX5622). Interestingly, the lack of microglia did not have an effect on acute seizure occurrence, but did reduce virus clearance and increased virus distribution within the CNS. Animals had severe encephalitis including viral spread through the spinal cord, causing hind limb paralysis and increased mortality, as evidenced by clinical examination and seizure monitoring, immunohistology, flow cytometry and quantitative PCR analysis. Our data demonstrate that depletion of microglia prior to viral intracerebral infection does not alter acute seizure occurrence, but reveals a crucial role of these cells in virus elimination and prevention of CNS damage following Theiler's virus infection.
Acknowledgement: We thank Plexxikon for kindly providing the food chow containing PLX5622. Supported by the N-RENNT network (Lower Saxony Ministry of Science and Culture).
Credits: None available.
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