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

Abstract

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.

Phagocytosis by Peripheral Glia: Importance for Nervous System Functions and Implications in Injury and Disease

“…Most of these pathologies are due to immune responses, in particular development of autoimmunity, for example production of antibodies targeting axons or myelin in addition to, or rather than, the infectious agent (reviewed by Neal and Gasque, 2016). However, a few pathogenic bacteria, viruses and protozoans can directly infect SCs, which can result in peripheral nerve damage (Neal and Gasque, 2016) or invasion of the CNS via cranial nerves in which SCs are found, in particular the trigeminal nerve (St John et al, 2016;Duarte et al, 2019;Nazareth et al, 2021). The intranasal branches of this nerve can serve as a direct path to CNS infection by several infectious agents, including Streptococcus pneumoniae, Burkholderia pseudomallei, Chlamydia muridarum, Herpes simplex virus, and Listeria monocytogenes (Shimeld et al, 2001;van Ginkel et al, 2003;St John et al, 2014Wei et al, 2020;Nazareth et al, 2021).…”

“…As macrophages are known to utilize both FcγRs and CR3 to phagocytose infectious agents (Fitzer-Attas et al, 2000;Campagne et al, 2007), it is likely that SCs also utilize these receptors to recognize and engulf microbes. SCs have been also reported to produce a range of cytokines, including interleukins such as IL-6, IL-8, IL-10, IL-23, IFN-β1, IFN-γ, IL-1β, and TNF-α, and chemokines, such as CCL-2,CC-17, CC-19, CXC-11, CXCL-1, MCP-1, MIP-1α, MIP-1β in response to pathogens (Ramesh et al, 2013;Masaki et al, 2014;Dhiman et al, 2019;Nazareth et al, 2021). Secretion of these cyto-and chemokines occurs in parallel with activation of NF-κB and inducible nitric oxide (iNOS) production, in response to pathogenic ligands (Lee et al, 2007).…”

“…C. muridarum, another Chlamydia species that infects mice, is often used to model C. pneumoniae infections. We recently showed that mice inoculated intranasally with C. muridarum develop CNS infection via both the olfactory and the trigeminal nerves (Nazareth et al, 2021). In vitro, trigeminal SCs were readily infected by C. muridarum, but exhibited more resistance to infection than fibroblasts (Nazareth et al, 2021).…”

“…We recently showed that mice inoculated intranasally with C. muridarum develop CNS infection via both the olfactory and the trigeminal nerves (Nazareth et al, 2021). In vitro, trigeminal SCs were readily infected by C. muridarum, but exhibited more resistance to infection than fibroblasts (Nazareth et al, 2021). Chlamydiae are obligate intracellular bacteria that live inside modified intracellular membrane compartments termed inclusions.…”

“…Thus, SCs can recognize, internalize, and produce an immune response to microbes. However, while SCs are more resistant to infection than many non-professional phagocytes (such as fibroblasts), they appear to be not as efficient phagocytes as macrophages (Nazareth et al, 2021). Intracellular pathogens, in particular, can manipulate SC plasticity and phagocytic pathways to survive within the cells.…”