The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the ...central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.
One of the promising strategies for neural repair therapies is the transplantation of olfactory ensheathing cells (OECs) which are the glial cells of the olfactory system. We evaluated the effects of ...curcumin on the behaviour of mouse OECs to determine if it could be of use to further enhance the therapeutic potential of OECs. Curcumin, a natural polyphenol compound found in the spice turmeric, is known for its anti-cancer properties at doses over 10 µM, and often at 50 µM, and it exerts its effects on cancer cells in part by activation of MAP kinases. In contrast, we found that low-dose curcumin (0.5 µM) applied to OECs strikingly modulated the dynamic morphology, increased the rate of migration by up to 4-fold, and promoted significant proliferation of the OECs. Most dramatically, low-dose curcumin stimulated a 10-fold increase in the phagocytic activity of OECs. All of these potently stimulated behavioural characteristics of OECs are favourable for neural repair therapies. Importantly, low-dose curcumin gave a transient activation of p38 kinases, which is in contrast to the high dose curcumin effects on cancer cells in which these MAP kinases tend to undergo prolonged activation. Low-dose curcumin mediated effects on OECs demonstrate cell-type specific stimulation of p38 and ERK kinases. These results constitute the first evidence that low-dose curcumin can modulate the behaviour of olfactory glia into a phenotype potentially more favourable for neural repair and thereby improve the therapeutic use of OECs for neural repair therapies.
Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising ...therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4-naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.
Transplantation of peripheral nervous system glia is being explored for treating neural injuries, in particular central nervous system injuries. These glia, olfactory ensheathing cells (OECs) and ...Schwann cells (SCs), are thought to aid regeneration by clearing necrotic cells, (necrotic bodies, NBs), as well as myelin debris. The mechanism by which the glia phagocytose and traffic NBs are not understood. Here, we show that OECs and SCs recognize phosphatidylserine on NBs, followed by engulfment and trafficking to endosomes and lysosomes. We also showed that both glia can phagocytose and process myelin debris. We compared the time-course of glial phagocytosis (of both NBs and myelin) to that of macrophages. Internalization and trafficking were considerably slower in glia than in macrophages, and OECs were more efficient phagocytes than SCs. The two glial types also differed regarding their cytokine responses after NB challenge. SCs produced low amounts of the pro-inflammatory cytokine TNF-α while OECs did not produce detectable TNF-α. Thus, OECs have a higher capacity than SCs for phagocytosis and trafficking, whilst producing lower amounts of pro-inflammatory cytokines. These findings suggest that OEC transplantation into the injured nervous system may lead to better outcomes than SC transplantation.
► Mouse olfactory ensheathing cells and Schwann cells phagocytose E. coli. ► Human OECs phagocytose E. coli. ► Peripheral glia show little capacity to phagocytose Burkholderia thailandensis. ► The ...results have implications for using glial cells in neural repair therapies.
Opportunistic bacterial infections of the nasal cavity could potentially lead to infection of the brain if the olfactory or trigeminal nerves are colonised. The olfactory nerve may be a more susceptible route because primary olfactory neurons are in direct contact with the external environment. Peripheral glia are known to be able to phagocytose some species of bacteria and may therefore provide a defence mechanism against bacterial infection. As the nasal cavity is frequently exposed to bacterial infections, we hypothesised that the olfactory and trigeminal nerves within the nasal cavity could be subjected to bacterial colonisation and that the olfactory ensheathing cells and Schwann cells may be involved in responding to the bacterial invasion. We have examined the ability of mouse OECs and Schwann cells from the trigeminal nerve and dorsal root ganglia to phagocytose Escherichia coli and Burkholderia thailandensis in vitro. We found that all three sources of glia were equally able to phagocytose E. coli with 75–85% of glia having phagocytosed bacteria within 24h. We also show that human OECs phagocytosed E. coli. In contrast, the mouse OECs and Schwann cells had little capacity to phagocytose B. thailandensis. Thus subtypes of peripheral glia have similar capacities for phagocytosis of bacteria but show selective capacity for the two different species of bacteria that were examined. These results have implications for the understanding of the mechanisms of bacterial infections as well as for the use of glia for neural repair therapies.
Olfactory ensheathing cell (OEC) transplantation is emerging as a promising therapy for spinal cord injuries. However, outcomes are inconsistent, and the method needs improvement. Currently, cells ...are injected into the injury site as a suspension, and often fail to form a three-dimensional (3D) network crucial for both survival of the transplanted cells, and for regeneration of severed axons. 3D culture systems are therefore likely to improve the method. Of the many 3D culture systems available, the spheroid-producing naked liquid marble (NLM) technique is particularly advantageous compared to other platforms as it rapidly generates cell spheroids which can easily be extracted for further handling. To improve production of the spheroids, we designed and tested a device which allows fine control over vibrational stimuli to liquid marble cell cultures. We applied vibrational frequencies of 20, 60, and 80 Hz with consistent amplitude to NLM containing OECs and assessed the size and number of the 3D cell spheroids generated as well as the migratory capacity of cells cultured in the vibrated spheroids.
Vibrating the NLMs led to fewer and dramatically larger spheroids in comparison to non-vibrated NLMs. Of the frequencies tested, 60 Hz caused over 70-fold increase in spheroid volume. When transferred to a culture plate, the larger spheroids retained their structure after 72 h in culture, and cells that migrated out of the spheroids covered a significantly larger area compared to cells migrating out of spheroids formed at all the other frequencies tested.
We have shown that vibration can be used to regulate the formation of cell spheroids in NLM cultures. The ability to modulate the size of spheroids is useful for a range of 3D cell culture models and for preparing cells for in vivo transplantation.
•Intra-cranial schwannomas are rare slow growing nerve sheath tumours.•We report a case of a large schwannoma originating from the olfactory groove region.•Distinguishing olfactory tumours is ...difficult due to the lack of specific markers.
Intracranial schwannomas not originating from cranial nerves are rare. In this paper, we report a case of a 50-year-old male who presented with worsening headaches, diplopia and nausea over two years. Radiological imaging revealed a large tumour arising from the olfactory groove region with a preoperative diagnosis of olfactory groove meningioma (OGM). Intraoperatively, the tumour originated from the region of the attachment of the falx to the crista galli. The patient recovered without complication and histopathology reported an unexpected diagnosis of WHO Grade 1 schwannoma. However, as olfactory groove schwannomas (OGSs) cannot be distinguished from olfactory ensheathing cell tumours (OECTs), it is possible that the tumour could have been either an OGS or an OECT. Distinguishing between OGSs, OECTs and OGMs preoperatively is difficult. OGMs exhibit distinct histopathological features from OGSs/OECTs, however, OGSs and OECTs currently cannot be distinguished from each other. Here, we review the literature to discuss the differentiating features and cellular origins of these three tumours.
Melioidosis, caused by the bacterium Burkholderia pseudomallei, is an often severe infection that regularly involves respiratory disease following inhalation exposure. Intranasal (i.n.) inoculation ...of mice represents an experimental approach used to study the contributions of bacterial capsular polysaccharide I (CPS I) to virulence during acute disease. We used aerosol delivery of B. pseudomallei to establish respiratory infection in mice and studied CPS I in the context of innate immune responses. CPS I improved B. pseudomallei survival in vivo and triggered multiple cytokine responses, neutrophil infiltration, and acute inflammatory histopathology in the spleen, liver, nasal-associated lymphoid tissue, and olfactory mucosa (OM). To further explore the role of the OM response to B. pseudomallei infection, we infected human olfactory ensheathing cells (OECs) in vitro and measured bacterial invasion and the cytokine responses induced following infection. Human OECs killed >90% of the B. pseudomallei in a CPS I-independent manner and exhibited an antibacterial cytokine response comprising granulocyte colony-stimulating factor, tumor necrosis factor alpha, and several regulatory cytokines. In-depth genome-wide transcriptomic profiling of the OEC response by RNA-Seq revealed a network of signaling pathways activated in OECs following infection involving a novel group of 378 genes that encode biological pathways controlling cellular movement, inflammation, immunological disease, and molecular transport. This represents the first antimicrobial program to be described in human OECs and establishes the extensive transcriptional defense network accessible in these cells. Collectively, these findings show a role for CPS I in B. pseudomallei survival in vivo following inhalation infection and the antibacterial signaling network that exists in human OM and OECs.
causes neonatal meningitis and can also infect the adult central nervous system (CNS).
can cross the blood-brain barrier but may also reach the CNS
other paths. Several species of bacteria can ...directly invade the CNS
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
infection and with nasogastric tube feeding. The tubes, also used in adults, can cause nasal injuries and may be contaminated with bacteria, including
. We here investigated whether
could invade the CNS after intranasal inoculation in mice.
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.
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
was used to understand the role of capsule on glial cells interaction. Interestingly, we found that the
capsule significantly altered cytokine and chemokine responses and affected intracellular survival in trigeminal glia. In summary, this study shows that
can infect the CNS
the nose-to-brain path with increased load after epithelial injury, and that the bacteria can survive in glia.
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