Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion
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Viral neuroinvasion is a critical step in the pathogenesis of viral encephalitis. Multiple mechanisms of neuroinvasion have been identified, but their relative contribution to central nervous system (CNS) infection remains unclear for many viruses. In this study, we examined neuroinvasion of the mosquito-borne bunyavirus La Crosse (LACV), the leading cause of pediatric viral encephalitis in the USA. We found that the olfactory bulb (OB) and tract were the initial areas of CNS virus infection in mice. Removal of the OB reduced the incidence of LACV-induced disease demonstrating the importance of this area to neuroinvasion. However, we determined that infection of the OB was not due to axonal transport of virus from olfactory sensory neurons as ablation of these cells did not affect viral pathogenesis. Instead, we found that OB capillaries were compromised allowing leakage of virus-sized particles into the brain. Analysis of OB capillaries demonstrated specific alterations in cytoskeletal and Rho GTPase protein expression not observed in capillaries from other brain areas such as the cortex where leakage did not occur. Collectively, these findings indicate that LACV neuroinvasion occurs through hematogenous spread in specific brain regions where capillaries are prone to virus-induced activation such as the OB. Capillaries in these areas may be “hot spots” that are more susceptible to neuroinvasion not only for LACV, but other neurovirulent viruses as well.
KeywordsBunyavirus Neuroinvasion Olfactory bulb Brain capillary endothelial cells Olfactory sensory neurons Blood brain barrier
This study was performed at Rocky Mountain Laboratories (RML) and funded by the Division of Intramural Research (DIR), as part of the Nation Institute of Allergy and Infectious Disease (NIAID) within the National Institutes of Health (NIH). We thank Suzette A. Priola, Byron Caughey, Lara M. Myers, Sonja M. Best, Roger A. Moore, Burhan A. Khan, Tyson A. Woods and Paul F. Policastro for critical reading of the manuscript. Also, we thank Dan Long, Vinod Nair, Nancy Kurtz and Aaron B. Carmody for technical assistance with experiments. Figure preparation and image presentation assistance were provided by Anita Mora and Ryan Kissinger.
Conflict of interest
All authors declare no conflict of interest.
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