Receptor tyrosine kinases and Lyme disease bacterium Borrelia burgdorferi

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
RitaA
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Joined: Thu 1 Jul 2010 8:33

Receptor tyrosine kinases and Lyme disease bacterium Borrelia burgdorferi

Postby RitaA » Wed 28 Jun 2017 6:53

https://www.ncbi.nlm.nih.gov/pubmed/28558791

J Neuroinflammation. 2017 May 30;14(1):110. doi: 10.1186/s12974-017-0883-9.

Receptor tyrosine kinases play a significant role in human oligodendrocyte inflammation and cell death associated with the Lyme disease bacterium Borrelia burgdorferi.

Parthasarathy G1, Philipp MT2.

Author information

1 Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, 18703, Three Rivers Road, Covington, LA, 70433, USA.
2 Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, 18703, Three Rivers Road, Covington, LA, 70433, USA.

Abstract

BACKGROUND:
In previous studies, human oligodendrocytes were demonstrated to undergo apoptosis in the presence of Borrelia burgdorferi under an inflammatory milieu. Subsequently, we determined that the MEK/ERK pathway played a significant role in triggering downstream inflammation as well as apoptosis. However, the identity of receptors triggered by exposure to B. burgdorferi and initiating signaling events was unknown.

METHODS:
In this study, we explored the role of several TLR and EGFR/FGFR/PDGFR tyrosine kinase pathways in inducing inflammation in the presence of B. burgdorferi, using siRNA and/or inhibitors, in MO3.13 human oligodendrocytes. Cell death and apoptosis assays were also carried out in the presence or absence of specific receptor inhibitors along with the bacteria to determine the role of these receptors in apoptosis induction. The expression pattern of specific receptors with or without B. burgdorferi was also determined.

RESULTS:
TLRs 2 and 5 had a minimal role in inducing inflammation, particularly IL-6 production. Rather, their effect was mostly inhibitory, with TLR2 downregulation significantly upregulating CXCL8, and CXCL (1,2,3) levels, and TLR5 likely having a similar role in CXCL8, CXCL(1,2,3), and CCL5 levels. TLR4 contributed mostly towards CCL5 production. On the other hand, inhibition of all three EGF/FGF/PDGF receptors significantly downregulated all five of the inflammatory mediators tested even in the presence of B. burgdorferi. Their inhibition also downregulated overall cell death and apoptosis levels. The expression pattern of these receptors, as assessed by immunohistochemistry indicated that the PDGFRβ receptor was the most predominantly expressed receptor, followed by FGFR, although no significant differences were discernible between presence and absence of bacteria. Interestingly, inhibition of individual EGFR, FGFR, or PDGFR receptors did not indicate an individual role for any of these receptors in the overall downregulation of pathogenesis. Contrarily, suppression of FGFR signaling alone in the presence of bacteria significantly upregulated inflammatory mediator levels indicating that it might control an inhibitory pathway when triggered individually.

CONCLUSIONS:
Unlike TLRs, EGF/FGF/PDGF receptors collectively play a significant role in the inflammation and apoptosis of human oligodendrocytes as mediated by B. burgdorferi. It is likely that these three receptors need to be triggered simultaneously to achieve this effect.

KEYWORDS:
B. burgdorferi; Human oligodendrocytes; Inflammation; Lyme neuroborreliosis; Receptor tyrosine kinases

PMID: 28558791
PMCID: PMC5450372
DOI: 10.1186/s12974-017-0883-9
Free PMC Article


From the free, full text link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450372/

Background

Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi, is a morbid form of Lyme disease with complex neurological sequelae. LNB manifests in about 15% of patients with primary erythema migrans, and may be evidenced as a lymphocytic meningo-radiculitis, lymphocytic meningitis, cranial neuritis, radiculoneuritis, radiculoneuropathy, and/or, rarely, encephalitis and myelitis [1]. The pathogenesis of LNB is not clearly understood. We have established a rhesus macaque model and several in vitro and ex vivo models to help delineate mechanisms of acute LNB. Intrathecal inoculation of live B. burgdorferi in rhesus macaques elicited in these animals signs of acute LNB, including leptomeningitis, radiculitis, inflammatory lesions in dorsal root ganglia (DRG), accompanied by glial and neuronal apoptosis in the DRG [2].

[snip]

Conclusion

Unlike previous data, the overall immune response from human oligodendrocytes, upon exposure to B. burgdorferi, results from activation of primarily three receptor tyrosine kinases, with as yet unknown activation mechanisms. Such activation also contributes to cell death processes, further underscoring the observation that inflammation in the nervous system due to B. burgdorferi results in apoptosis of neuroglial cells. The key receptors that were identified in this study may lead to the uncovering of novel pathogenic mechanisms in LNB.

[snip]

Henry
Posts: 1104
Joined: Thu 10 Nov 2011 18:49

Re: Receptor tyrosine kinases and Lyme disease bacterium Borrelia burgdorferi

Postby Henry » Wed 28 Jun 2017 15:56

One must be very careful in relating the results of these in vitro studies to events that may occur during human neuroborreliosis acquired naturally. In this study, a cell line ( that may not be typical in all respects to normal human oligodendrocytes) was infected with Borrelia at a MOI of 10:1 -- an extremely high dose, representing 10 bacteria per single oligodendrocyte. That would be an example of an overwhelming infection, to say the least, considering that infections of that sort are seldom if ever observed in patients with neuroborreliosis. It would be a huge "leap of faith" to consider this to be analogous to what happens during naturally acquired human neuroborreliosis.

RitaA
Posts: 2768
Joined: Thu 1 Jul 2010 8:33

Re: Receptor tyrosine kinases and Lyme disease bacterium Borrelia burgdorferi

Postby RitaA » Wed 28 Jun 2017 16:19

Thanks for your expert input, Henry. This article is way above my level of scientific understanding, to be honest, however it does reinforce the notion that more research into all aspects of Lyme disease is more than justified.

Henry
Posts: 1104
Joined: Thu 10 Nov 2011 18:49

Re: Receptor tyrosine kinases and Lyme disease bacterium Borrelia burgdorferi

Postby Henry » Wed 28 Jun 2017 17:28

The issue is always whether the results of such in vitro studies are clinically relevant. The same can be said for the results of numerous in vitro studies on persisters.

Another major issue in the tyrosine kinase study is whether human cell lines, which really are abnormal cells, are truly representative of normal human cells. That is a major unknown.


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