Streptococcus agalactiae Infects Glial Cells and Invades the Central Nervous System via the Olfactory and Trigeminal Nerves.

Streptococcus agalactiae causes neonatal meningitis and can also infect the adult central nervous system (CNS). S. agalactiae can cross the blood-brain barrier but may also reach the CNS via other paths. Several species of bacteria can directly invade the CNS via the olfactory and trigeminal nerves, which extend between the nasal cavity and brain and injury to the nasal epithelium can increase the risk/severity of infection. Preterm birth is associated with increased risk of S. agalactiae infection and with nasogastric tube feeding. The tubes, also used in adults, can cause nasal injuries and may be contaminated with bacteria, including S. agalactiae. We here investigated whether S. agalactiae could invade the CNS after intranasal inoculation in mice. S. agalactiae rapidly infected the olfactory nerve and brain. Methimazole-mediated model of nasal epithelial injury led to increased bacterial load in these tissues, as well as trigeminal nerve infection. S. agalactiae infected and survived intracellularly in cultured olfactory/trigeminal nerve- and brain-derived glia, resulting in cytokine production, with some differences between glial types. Furthermore, a non-capsulated S. agalactiae was used to understand the role of capsule on glial cells interaction. Interestingly, we found that the S. agalactiae capsule significantly altered cytokine and chemokine responses and affected intracellular survival in trigeminal glia. In summary, this study shows that S. agalactiae can infect the CNS via the nose-to-brain path with increased load after epithelial injury, and that the bacteria can survive in glia.

Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer's disease risk.

Chlamydia pneumoniae is a respiratory tract pathogen but can also infect the central nervous system (CNS). Recently, the link between C. pneumoniae CNS infection and late-onset dementia has become increasingly evident. In mice, CNS infection has been shown to occur weeks to months after intranasal inoculation. By isolating live C. pneumoniae from tissues and using immunohistochemistry, we show that C. pneumoniae can infect the olfactory and trigeminal nerves, olfactory bulb and brain within 72 h in mice. C. pneumoniae infection also resulted in dysregulation of key pathways involved in Alzheimer's disease pathogenesis at 7 and 28 days after inoculation. Interestingly, amyloid beta accumulations were also detected adjacent to the C. pneumoniae inclusions in the olfactory system. Furthermore, injury to the nasal epithelium resulted in increased peripheral nerve and olfactory bulb infection, but did not alter general CNS infection. In vitro, C. pneumoniae was able to infect peripheral nerve and CNS glia. In summary, the nerves extending between the nasal cavity and the brain constitute invasion paths by which C. pneumoniae can rapidly invade the CNS likely by surviving in glia and leading to Aß deposition.

Antimicrobial responses of peripheral and central nervous system glia against Staphylococcus aureus.

Staphylococcus aureus infections of the central nervous system are serious and can be fatal. S. aureus is commonly present in the nasal cavity, and after injury to the nasal epithelium it can rapidly invade the brain via the olfactory nerve. The trigeminal nerve constitutes another potential route of brain infection. The glia of these nerves, olfactory ensheathing cells (OECs) and trigeminal nerve Schwann cells (TgSCs), as well as astrocytes populating the glia limitans layer, can phagocytose bacteria. Whilst some glial responses to S. aureus have been studied, the specific responses of different glial types are unknown. Here, we compared how primary mouse OECs, TgSCs, astrocytes and microglia responded to S. aureus. All glial types internalized the bacteria within phagolysosomes, and S. aureus-conjugated BioParticles could be tracked with subtle but significant differences in time-course of phagocytosis between glial types. Live bacteria could be isolated from all glia after 24 h in culture, and microglia, OECs and TgSCs exhibited better protection against intracellular S. aureus survival than astrocytes. All glial types responded to the bacteria by cytokine secretion. Overall, OECs secreted the lowest level of cytokines, suggesting that these cells, despite showing strong capacity for phagocytosis, have immunomodulatory functions that can be relevant for neural repair.

Neisseria meningitidis Induces Pathology-Associated Cellular and Molecular Changes in Trigeminal Schwann Cells.

Neisseria meningitidis, a common cause of sepsis and bacterial meningitis, infects the meninges and central nervous system (CNS), primarily via paracellular traversal across the blood-brain barrier (BBB) or blood-cerebrospinal fluid barrier. N. meningitidis is often present asymptomatically in the nasopharynx, and the nerves extending between the nasal cavity and the brain constitute an alternative route by which the meningococci may reach the CNS. To date, the cellular mechanisms involved in nerve infection are not fully understood. Peripheral nerve glial cells are phagocytic and are capable of eliminating microorganisms, but some pathogens may be able to overcome this protection mechanism and instead infect the glia, causing cell death or pathology. Here, we show that N. meningitidis readily infects trigeminal Schwann cells (the glial cells of the trigeminal nerve) in vitro in both two-dimensional and three-dimensional cell cultures. Infection of trigeminal Schwann cells may be one mechanism by which N. meningitidis is able to invade the CNS. Infection of the cells led to multinucleation and the appearance of atypical nuclei, with the presence of horseshoe nuclei and the budding of nuclei increasing over time. Using sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics followed by bioinformatics pathway analysis, we showed that N. meningitidis induced protein alterations in the glia that were associated with altered intercellular signaling, cell-cell interactions, and cellular movement. The analysis also suggested that the alterations in protein levels were consistent with changes occurring in cancer. Thus, infection of the trigeminal nerve by N. meningitidis may have ongoing adverse effects on the biology of Schwann cells, which may lead to pathology.

Burkholderia pseudomallei invades the olfactory nerve and bulb after epithelial injury in mice and causes the formation of multinucleated giant glial cells in vitro.

The infectious disease melioidosis is caused by the bacterium Burkholderia pseudomallei. Melioidosis is characterised by high mortality and morbidity and can involve the central nervous system (CNS). We have previously discovered that B. pseudomallei can infect the CNS via the olfactory and trigeminal nerves in mice. We have shown that the nerve path is dependent on mouse strain, with outbred mice showing resistance to olfactory nerve infection. Damage to the nasal epithelium by environmental factors is common, and we hypothesised that injury to the olfactory epithelium may increase the vulnerability of the olfactory nerve to microbial insult. We therefore investigated this, using outbred mice that were intranasally inoculated with B. pseudomallei, with or without methimazole-induced injury to the olfactory neuroepithelium. Methimazole-mediated injury resulted in increased B. pseudomallei invasion of the olfactory epithelium, and only in pre-injured animals were bacteria found in the olfactory nerve and bulb. In vitro assays demonstrated that B. pseudomallei readily infected glial cells isolated from the olfactory and trigeminal nerves (olfactory ensheathing cells and trigeminal Schwann cells, respectively). Bacteria were degraded by some cells but persisted in other cells, which led to the formation of multinucleated giant cells (MNGCs), with olfactory ensheathing cells less likely to form MNGCs than Schwann cells. Double Cap mutant bacteria, lacking the protein BimA, did not form MNGCs. These data suggest that injuries to the olfactory epithelium expose the primary olfactory nervous system to bacterial invasion, which can then result in CNS infection with potential pathogenic consequences for the glial cells.

Chlamydia muridarum Can Invade the Central Nervous System via the Olfactory and Trigeminal Nerves and Infect Peripheral Nerve Glial Cells.

Chlamydia pneumoniae can infect the brain and has been linked to late-onset dementia. Chlamydia muridarum, which infects mice, is often used to model human chlamydial infections. While it has been suggested to be also important for modelling brain infection, nervous system infection by C. muridarum has not been reported in the literature. C. pneumoniae has been shown to infect the olfactory bulb in mice after intranasal inoculation, and has therefore been suggested to invade the brain via the olfactory nerve; however, nerve infection has not been shown to date. Another path by which certain bacteria can reach the brain is via the trigeminal nerve, but it remains unknown whether Chlamydia species can infect this nerve. Other bacteria that can invade the brain via the olfactory and/or trigeminal nerve can do so rapidly, however, whether Chlamydia spp. can reach the brain earlier than one-week post inoculation remains unknown. In the current study, we showed that C. muridarum can within 48 h invade the brain via the olfactory nerve, in addition to infecting the trigeminal nerve. We also cultured the glial cells of the olfactory and trigeminal nerves and showed that C. muridarum readily infected the cells, constituting a possible cellular mechanism explaining how the bacteria can invade the nerves without being eliminated by glial immune functions. Further, we demonstrated that olfactory and trigeminal glia differed in their responses to C. muridarum, with olfactory glia showing less infection and stronger immune response than trigeminal glia.

Why are olfactory ensheathing cell tumors so rare?

The glial cells of the primary olfactory nervous system, olfactory ensheathing cells (OECs), are unusual in that they rarely form tumors. Only 11 cases, all of which were benign, have been reported to date. In fact, the existence of OEC tumors has been debated as the tumors closely resemble schwannomas (Schwann cell tumors), and there is no definite method for distinguishing the two tumor types. OEC transplantation is a promising therapeutic approach for nervous system injuries, and the fact that OECs are not prone to tumorigenesis is therefore vital. However, why OECs are so resistant to neoplastic transformation remains unknown. The primary olfactory nervous system is a highly dynamic region which continuously undergoes regeneration and neurogenesis throughout life. OECs have key roles in this process, providing structural and neurotrophic support as well as phagocytosing the axonal debris resulting from turnover of neurons. The olfactory mucosa and underlying tissue is also frequently exposed to infectious agents, and OECs have key innate immune roles preventing microbes from invading the central nervous system. It is possible that the unique biological functions of OECs, as well as the dynamic nature of the primary olfactory nervous system, relate to the low incidence of OEC tumors. Here, we summarize the known case reports of OEC tumors, discuss the difficulties of correctly diagnosing them, and examine the possible reasons for their rare incidence. Understanding why OECs rarely form tumors may open avenues for new strategies to combat tumorigenesis in other regions of the nervous system.