Rickettsia Deregulates Genes Coding for the Neurotoxic Cell Response Pathways in Cerebrocortical Neurons In Vitro, 2023, Cente et al

Hutan · May 27, 2025 at 10:35 AM

Abstract
Rickettsial infections of the central nervous system (CNS) are manifested by severe neurological symptoms and represent a serious life-threatening condition. Despite the considerable health danger, only a few studies have been conducted focusing on the pathogenesis induced by Rickettsia sp. in CNS.

To investigate the signaling pathways associated with the neurotoxic effects of rickettsiae, we employed an experimental model of cerebrocortical neurons combined with molecular profiling and comprehensive bioinformatic analysis. The cytopathic effect induced by Rickettsia akari and Rickettsia slovaca was demonstrated by decreased neuronal viability, structural changes in cell morphology, and extensive fragmentation of neurites in vitro. Targeted profiling revealed the deregulation of genes involved in the neuroinflammatory and neurotoxic cell response pathways.

Although quantitative analysis showed differences in gene expression response, functional annotation revealed that the biological processes are largely shared between both Rickettsia species. The identified enriched pathways are associated with cytokine signaling, chemotaxis of immune cells, responses to infectious agents, interactions between neurons, endothelial and glial cells, and regulation of neuronal apoptotic processes. The findings of our study provide new insight into the etiopathogenesis of CNS infection and further expand the understanding of molecular signaling associated with neuroinvasive Rickettsia species.

https://www.mdpi.com/2073-4409/12/9...ssociated neuroinflammation may,vitro [24,25].
Open access

Hutan · May 27, 2025 at 10:42 AM

I recall the old study that found a high level of rickettsia seropositivity and some evidence of active infections in cohorts of Australian women with persistent symptoms.
Markers of exposure to spotted fever rickettsiae in patients with chronic illness, including fatigue..., 2008, Unsworth et al

So, just parking this 2023 study here. Excerpts:

Although quantitative analysis showed differences in gene expression response, functional annotation revealed that the biological processes are largely shared between both Rickettsia species. The identified enriched pathways are associated with cytokine signaling, chemotaxis of immune cells, responses to infectious agents, interactions between neurons, endothelial and glial cells, and regulation of neuronal apoptotic processes. The findings of our study provide new insight into the etiopathogenesis of CNS infection and further expand the understanding of molecular signaling associated with neuroinvasive Rickettsia species.
Click to expand...

At the cell level, since rickettsiae are obligate intracellular bacteria, a recent hypothesis includes two ways of intrusion, direct or indirect neuroinvasion or immunologically mediated neuronal damage [9]. In spite of the clinical importance and neurological consequences of rickettsial brain infection, including neuroinflammation and neurotoxicity, very little research was performed in order to reveal underlying molecular mechanisms induced by rickettsiae in neurons. It was reported that massive activation of microglia after rickettsial infection results in neurotoxicity and inflammation of the CNS, leading to the death of infected mice [12]. However, in the context of the published data, we suppose that microglia migrate to the site of neuronal damage and exert neuroprotective processes, as this is their authentic function in a diseased brain [39]. The recent review summarizes the pathogenesis of Rickettsia-infected mice and presents a set of upregulated genes coding for specific cytokines and indicates affected brain cells [14].

In the present study, we confirmed that the bacteria are clearly localized inside the neuronal cell bodies and in cell neurites. As a consequence of the intraneuronal pathogenic activity of rickettsiae, we found that the identified biological processes are associated with increased migration and chemotaxis of macrophages, lymphocytes, and natural killer cells, suggesting that neuronal signaling attracts phagocytic and immune cells to sites of rickettsial neuroinfection.

The spreading of rickettsiae throughout the body leads to the infection of the vascular endothelium of the small and medium-sized blood vessels [40]. Thus, most of the clinical symptoms of rickettsial diseases are associated with the infection of endothelial cells [41]. Our analysis revealed that neuronal infection is associated with identical signaling pathways, as observed in Rickettsia-infected endothelial cells. In particular, NF-κB-mediated regulation of apoptotic pathways [42], represented by the balance between pro- (↑Bak1) and anti-apoptotic (↑Birc3) signals and prevention of caspase activation (↓Casp3) was observed. Mitochondrial role in apoptotic signaling in neurons was observed concluding the importance of this signaling as it was described in Rickettsia-infected endothelial cells [43].

Furthermore, infected neurons overexpressed a panel of pro-inflammatory chemokines, cytokines, and innate immunity-responsive genes, such as Il1b, Il6, Ccl2, Ccl3, and Ccl4 that were previously reported in Rickettsia-infected endothelium [44]. Typical host response to bacterial infection is mediated via TLR4/lipopolysaccharide signaling that triggers pro-inflammatory reactions. Mechanisms involving TLR4 and MyD88 were previously reported in dendritic cells, playing a critical role in eradication of the invading bacteria and host protection in vivo [45,46]. Immune responses via multiple TLRs and NLRs recognizing endotoxins from R. akari were also documented [47,48].

Based on the data, we conclude that rickettsial neuroinfection induces innate immunity pathways involving TLRs with its downstream signals. Furthermore, the bioinformatic analysis highlighted significant crosstalk between neuronal, glial, and endothelial cells, the main components of the blood–brain-barrier. Positive regulation of vascular endothelial growth factor production, together with the regulatory pathways of migration and proliferation of glial cells, suggests that rickettsial neuroinfection may also activate reparative mechanisms necessary for the neuronal protection, re-establishment of homeostasis and integrity of the blood–brain-barrier. These pro-survival signals at the background of observed neuronal cell death in vitro are not surprising, as the rickettsiae manipulate host cell death mechanisms using several strategies (reviewed in [48]).

The findings of our study are consistent with published observations and further expand the understanding of molecular signaling associated with neuroinvasive Rickettsia species. Nevertheless, we acknowledge several limiting aspects that need to be considered. In particular, the analysis explored two specific Rickettsia species targeting only a subset of regulatory mechanisms that may be affected after infection of neuronal cells. Recent research in non-neuronal cells has identified impairment of many other regulatory pathways involved in Rickettsia–host interactions, such as cell adhesion, autophagy, cytoskeleton, oxidative stress, or regulation by non-coding RNAs [48,49], which were not investigated in more detail in this analysis.

We are also aware that host–pathogen interactions may be cell-type and species-dependent, as the signaling mechanism may differ between the diverse hosts [43,50]. Therefore, further studies are warranted to explore the broad complexity of signaling pathways after rickettsial infection of neurons considering these aspects.
Click to expand...

Log in or Sign up

Rickettsia Deregulates Genes Coding for the Neurotoxic Cell Response Pathways in Cerebrocortical Neurons In Vitro, 2023, Cente et al

Hutan Moderator Staff Member

Hutan Moderator Staff Member

Share This Page

Log in or Sign up

Rickettsia Deregulates Genes Coding for the Neurotoxic Cell Response Pathways in Cerebrocortical Neurons In Vitro, 2023, Cente et al

Hutan Moderator Staff Member

Hutan Moderator Staff Member

Share This Page

Useful Searches