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

Abstract

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.

Lymphocytes have a role in protection, but not in pathogenesis, during La Crosse Virus infection in mice

“…Additionally, even though these cells were not detected in the brain, they could still be influencing pathogenesis through actions elicited by soluble immunoglobulin (Ig) entering the brain [27, 28]. Blood-brain barrier breakdown occurs in areas of LACV infection [9], which may allow anti-LACV antibodies to enter the CNS. Immunohistochemistry for mouse IgG in the CNS was completed using LACV-infected mice that had received Evans Blue dye to identify areas of a blood-brain barrier leakage (Fig.…”

“…Furthermore, the adaptive immune response may be more suited to controlling LACV infection in a minor cell population in the periphery, rather than a massive infection of neurons in the CNS. Indeed, when adult mice are infected either through the intranasal route or by direct intracranial injection, they develop neurological disease with similar speed and frequency as weanling mice despite having a fully developed adaptive immune response [9, 22]. This insufficiency of response may be related in part to lymphocyte accessibility to the brain compared to the peripheral tissues as well as to the extremely responsiveness of the brain to injury [34].…”

“…However, the make-up of this infiltrating population and their potential role in LACV pathogenesis remains unknown. We have previously established that circulating leukocytes do not contribute to virus neuroinvasion [9] as has been suggested for other encephalitic viruses [10, 11]. However, these cells may have other roles in influencing viral pathogenesis.…”

“…Following peripheral infection, adult mice are resistant to neurological disease and have low CNS titers [19], while weanlings are susceptible and have high CNS titers [18, 20]. This age-related resistance in adults appears to be due to the inability of LACV to replicate in the periphery and/or invade the CNS, as administration of LACV to the CNS by intracerebral [18] or intranasal inoculation [9] results in neurological disease in adult mice. Suppression of type I interferon (IFN) signaling in the periphery or depletion of myeloid dendritic cells (DCs) in adult animals can result in neurological disease [21, 22], suggesting that an efficient anti-viral type I IFN response is necessary for preventing disease in adult animals.…”

Congenital Cytomegalovirus Infection Alters Olfaction Before Hearing Deterioration In Mice

“…Axons from OSNs project to the OB, where they form synapses on the dendrites of mitral/tufted cells, the main projection neurons of the OB, in organized structures called glomeruli. The OB constitutes a usual entry portal for many neurotropic viruses, including CMV, via anterograde transport along OSNs from the nasal epithelium or OB capillaries (Monath et al, 1983;Winkler et al, 2015;Farrell et al, 2016;Wheeler et al, 2017). Fetal OB infection might cause irreversible neuron damage and thus immediate olfactory deficits, preceding the delayed hearing loss that is usually observed.…”