S Transcriptome Study of Borrelia burgdorferi Infection in Murine Heart and Brain Tissues
Juni 2017
Author: Maureen A Carey and Eric S. Ho
Institution: Departement of Microbiology; Immunology, and Cancer Biology, University of Virginia,
doi:10.22186/jyi.33.1.28-41
DISCUSSION
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Blood-Brain Barrier Disruption in Response to Borrelia Infection in Brain Tissue
Only three consensus pathways were perturbed in the brain tissue by our dual-method pipeline. Moreover, these pathways had fewer differentially expressed genes compared to the heart tissue results (Table 1). This is expected: because B. burgdorferi does not actively infect murine brain tissue (Radolf et al., 2012), a less cohesive response occurs upon host infection as a variety of cell types are responding to inflammation, not generating an inflammatory response. We observed perturbations in calcium signaling, gap junction, and melanogenesis. Calcium signaling has been shown to influence bacterial infection (Soderblom et al., 2005; TranVan Nhieu et al., 2004). We propose that this phenomenon is exploited by B. burgdorferi to cross the blood-brain barrier (Coureuil et al., 2013; Grab et al. 2005; Halperin, 2015), even if these bacteria fail to establish infection (Radolf et al., 2012) once across the barrier. This perturbation of the blood-brain barrier could be used to study human neuroborreliosis. Previous studies indicate that neurological symptoms exhibited by Borrelia infection in humans may be attributed to the success of Borrelia in crossing the blood-brain barrier and attacking the CNS (Grab et al., 2009). Our results are consistent with these findings, suggesting that the bacterium may also disrupt the blood-brain barrier in mice by dysregulated calcium signaling and gap junctions. This suggests the potential of targeting bacterial crossing of blood-brain barrier for therapeutic use.
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They found over 30 genes to be significantly upregulated, including Cxcl9, H2-Eb1, Ccl8, H2-Aa, Zbp1 and Igtp. We observed these genes to be also upregulated in Lyme heart infection. However, no genes were found in both the T. gondii study and on our list of DEGs in the brain. [color=#0000FF]This suggests more work needs to be done to understand the molecular basis of neuroborreliosis.[/color]
In conclusion, we present a dual-method pipeline to analyze the host transcriptome Borrelia infection using RNA-seq. Many immune response-related genes were differentially expressed in heart tissue and far fewer were identified in the brain. We propose that Borrelia may disrupt the blood-brain barrier in mice and induces a peripheral inflammatory cascade.
First, although infection was not established in the brain, the tissue is affected as many genes are differentially expressed and we found that neuronal gap junctions and calcium signaling are disrupted. This is a hallmark of loss of integrity of the blood-brain barrier. Thus, the damage is occurring irrespective of direct brain infection. Moreover, this suggests that in human infection, the crossing of the blood-brain barrier and infection of the central nervous system are two events. It may be possible to study Borrelia’s effect on the blood-brain barrier in mice, even though the central nervous system is not infected in a mouse
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Challenges facing diagnosis and treatment of Lyme are significant.
Prolonged symptoms after antibiotic treatment are still afflicting a small percentage of patients, making the topic of “chronic Lyme disease” interesting but understudied. Although the mouse is not a perfect model of human Lyme disease, we show that the mouse can be used to examine unique features of Borrelia infection and the crossing of the blood-brain barrier. A thorough molecular study to explore these pathways over time is needed to elucidate the etiology of lingering Lyme symptoms in the host in order to improve patient outcome.
