Capillaries in the olfactory bulb but not the cortex are highly susceptible to virus-induced vascular leak and promote viral neuroinvasion

Acta Neuropathol. 2015 Aug;130(2):233-45. doi: 10.1007/s00401-015-1433-0. Epub 2015 May 9.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Capillaries / metabolism*
  • Capillaries / pathology
  • Capillaries / virology
  • Capillary Permeability / physiology*
  • Cerebral Cortex / blood supply
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Cerebral Cortex / virology
  • Cytoskeleton / metabolism
  • Disease Models, Animal
  • Encephalitis, California / metabolism*
  • Encephalitis, California / pathology
  • La Crosse virus / pathogenicity*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Olfactory Bulb / blood supply*
  • Olfactory Bulb / metabolism
  • Olfactory Bulb / pathology
  • Olfactory Bulb / virology*
  • Viral Load
  • Virus Internalization


  • Bacterial Proteins
  • Luminescent Proteins
  • yellow fluorescent protein, Bacteria