Burkholderia pseudomallei Penetrates the Brain via Destruction of the Olfactory and Trigeminal Nerves: Implications for the Pathogenesis of Neurological Melioidosis

Abstract

Melioidosis is a potentially fatal disease that is endemic to tropical northern Australia and Southeast Asia, with a mortality rate of 14 to 50%. The bacterium Burkholderia pseudomallei is the causative agent which infects numerous parts of the human body, including the brain, which results in the neurological manifestation of melioidosis. The olfactory nerve constitutes a direct conduit from the nasal cavity into the brain, and we have previously reported that B. pseudomallei can colonize this nerve in mice. We have now investigated in detail the mechanism by which the bacteria penetrate the olfactory and trigeminal nerves within the nasal cavity and infect the brain. We found that the olfactory epithelium responded to intranasal B. pseudomallei infection by widespread crenellation followed by disintegration of the neuronal layer to expose the underlying basal layer, which the bacteria then colonized. With the loss of the neuronal cell bodies, olfactory axons also degenerated, and the bacteria then migrated through the now-open conduit of the olfactory nerves. Using immunohistochemistry, we demonstrated that B. pseudomallei migrated through the cribriform plate via the olfactory nerves to enter the outer layer of the olfactory bulb in the brain within 24 h. We also found that the bacteria colonized the thin respiratory epithelium in the nasal cavity and then rapidly migrated along the underlying trigeminal nerve to penetrate the cranial cavity. These results demonstrate that B. pseudomallei invasion of the nerves of the nasal cavity leads to direct infection of the brain and bypasses the blood-brain barrier.

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…During our initial studies in mice, we also demonstrated that B. pseudomallei was present in the brain stem, increasing in number for up to 48 h postinfection, indicating, though not definitively demonstrating, that bacteria may enter via the trigeminal nerve after intranasal inoculation (105). We have now confirmed that B. pseudomallei penetrates the intact respiratory epithelium in mice and migrates along Schwann cell-encased trigeminal nerve bundles to the cranial cavity (326). Figure 4B to D demonstrate B. pseudomallei localized within the branches of the trigeminal nerve.…”

“…The mechanisms by which B. pseudomallei migrates along the olfactory nerves were recently investigated (326). In BALB/c mice, we demonstrated that intranasally delivered B. pseudomallei was associated with widespread crenellation of the olfactory epithelium and loss of the neuron cell bodies.…”

“…This neuronal loss led to the degeneration of olfactory axons within 24 to 48 h, and the axon-devoid, hollow olfactory nerve fascicles, surrounded by olfactory ensheathing cells, provided an open conduit for bacterial passage from the nasal cavity through the cribriform plate and into the nerve fiber layer of the olfactory bulb. No bacteria were observed within the supporting sustentacular cells of the olfactory epithelium, nor within the Bowman's glands (326). By migrating within the nerve sheath, B. pseudomallei would be shielded from the flow of CSF out of the brain.…”

“…However, following mild detergent damage to the nasal epithelium of C57BL/6 mice, intranasally delivered S. aureus was detected in the olfactory epithelium, olfactory nerve, and olfactory bulb, as early as 6 h postinfection (325). Indeed, damage to the olfactory epithelium within the nasal cavity appears to be an important and common event in bacterial spread to the CNS via the olfactory nerve (324)(325)(326)(327).…”

Listeria monocytogenes Spreads within the Brain by Actin-Based Intra-Axonal Migration

“…Such an intra-axonal migration pathway has long been known for neurotropic viruses such as rabies virus, herpesviruses, morbilliviruses, West Nile virus, and poliovirus (45)(46)(47), and also, the bacterium Burkholderia pseudomallei is suspected to migrate along cranial nerves (48). Although, once L. monocytogenes has entered the brain, the intrathecal immune response is intense and develops rapidly, L. monocytogenes is able to efficiently replicate and spread within the brain, causing a progressive and frequently fatal neurological disease (17,29).…”