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People with vector-borne infections often report a variety of symptoms that originate in the central nervous system. How can all of these different pathogens have so many symptoms that overlap?
As Galaxy Diagnostics president and CEO Amanda Elam wrote in her 10-year reflection, “our bodies are complex biological systems with only a few ways to express disorder and disease, leaving our doctors with the challenging task of figuring out which of a long list of potential causal and complicating factors could be involved.”
The answer once again is the host response. It turns out that many symptoms of infection in the central nervous system come from the host response and not from the pathogen itself. The host response that causes these symptoms can even originate in other areas of the body.
The central nervous system used to be thought of as fairly cut off from the rest of the body, regulating the body on a kind of a one-way street of nerve pathways. Within the last five years, however, research has turned that thinking around.
How can the immune system affect the central nervous system (CNS)?
The CNS is the nerve tissue that makes up the brain and spinal column. The brain itself is made up of several parts, each of which can develop different symptoms when it becomes disrupted.
The brain was once thought to be completely cut off from the rest of the body through the blood-brain barrier. This blood-brain barrier is an exchange system in which blood itself does not enter brain tissue. Rather, nutrients and waste are exchanged into cerebrospinal fluid through a selective membrane. This protects the brain from pathogens and toxins and also prevents some medications from reaching brain tissue, for better and worse.
However, in 2017, researchers discovered lymph vessels in the brain. Dr. Walter J. Koroshetz, director of the NIH National Institute of Neurological Disorders and Stroke (NINDS) said of the discovery, “These results could fundamentally change the way we think about how the brain and immune system interrelate.” As discussed in a previous post, the lymph vascular system is crucial in mounting an immune response to pathogens.
Also in 2017, researchers started looking deeper into pediatric autoimmune neuropsychiatric disorders associated with Streptococcal infections (PANDAS), a disorder first described in 2005 by Dr. Susan Swedo, Chief of the Pediatrics & Developmental Neuroscience Branch of the US National Institute of Mental Health. Building on criteria and guidelines first developed in 2012, an expert panel developed a guideline for recommended treatment. As “PANS”, this disorder has been expanded to include other pathogenic causes, including bacteria transmitted by fleas.
Bartonella and PANS
As researchers looked for other pathogens that have profound neuropsychiatric effects, Bartonella species presented as targets. In 2019, Galaxy Diagnostics co-founders Dr. Edward B. Breitschwerdt, Dr. Ricardo G. Maggi and other researchers published a case study of a 14-year-old boy with PANS caused by Bartonella henselae infection. The complete case study is free to read here. The child had been treated with immune-suppressing medications in addition to psychiatric medications, but had not improved. Only after antibiotic treatment did his symptoms resolve.
Testing in this case was crucial. The child was not seropositive (see our previous blog post about serology testing). The Galaxy Diagnostics ePCR Triple Draw (find out more) test was used and blood was tested before and after culturing in the patented growth medium used at Galaxy Diagnostics. Only one of the three blood samples tested positive before culturing and only two tested positive after culturing. A single blood draw might have missed confirming a diagnosis of bartonellosis.
But what, exactly, caused the child’s symptoms? In the case study, researchers discuss other cases in which autoimmune disease markers where found in people and animals with bartonellosis. It is possible an autoimmune reaction was harming the central nervous system. At this point, however, the exact causation is unknown.
Tick-borne infections negatively impact the CNS, but how? The question of how the immune system and the infection interact to generate symptoms is only just beginning to be understood. In June 2018, researchers exposed the brains of rhesus monkeys to Borrelia burgdorferi, the pathogen that causes Lyme disease, in a laboratory. In the monkey brains, more than 2,000 genetic expressions were altered within six hours of exposure to B. burgdorferi. While this is not a Bartonella species, insights into how it affects the brain may give an idea what is happening with Bartonella.
However, the pathogen doesn’t even have to reach the brain to have an effect. In 2019, researchers found that chronic inflammation affects dopamine levels to reduce motivation. The researchers theorized that this conserves energy for future necessary activities. In recent research, inflammation has been associated with other conditions including schizophrenia.
Also in 2019, researchers investigated the relationship between immune response to tick-borne encephalitis with symptoms of the condition. They found that certain markers of immune response were associated with symptoms. In other words, a more intense immune response results in more intense symptoms. This was especially true when the pathogen and the immune response markers were found in cerebrospinal fluid.
Research on how systemic inflammation affects the brain is only just beginning.
Conclusion
The central nervous system effects of the host response and consequently of any infection (including tick-borne infection) are only just beginning to be understood. Some of the most consequential research on the topic has only been published within the last 24 months. What is known is that even without crossing the blood-brain barrier or entering the central nervous system, pathogens can have a profound effect on the CNS via the host response.
References
National Institutes of Health. (2017). Brain cleaning system uses lymphatic vessels. NIH Research Matters. Available at: https://www.nih.gov/news-events/nih-research-matters/brain-cleaning-system-uses-lymphatic-vessels
National Institute of Mental Health. (2017). Guidelines published for treating PANS/PANDAS. Available at: https://www.nimh.nih.gov/news/science-news/2017/guidelines-published-for-treating-pans-pandas.shtml
Breitschwerdt, E. B. et al. (2019). Bartonella henselae bloodstream infection in a boy with pediatric acute-onset neuropsychiatric syndrome [online version]. Journal of Central Nervous System Disease, 11. Available at: https://journals.sagepub.com/doi/10.1177/1179573519832014
Ding, Z. et al. (2019). Rhesus brain transcriptomic landscape in an ex vivo model of the interaction of live Borrelia burgdorferi with frontal cortex tissue explants. Frontiers in Neuroscience, 13, 651. doi:10.3389/fnins.2019.00651 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610209/
Bogović, P. et al. (2019). Inflammatory immune responses in the pathogenesis of tick-borne encephalitis. Journal of Clinical Medicine, 8(5), 731. https://doi.org/10.3390/jcm8050731 https://www.mdpi.com/2077-0383/8/5/731
Treadway, M. T. et al. (2019). Can’t or won’t? Immunometabolic constraints on dopaminergic drive. Trends in Cognitive Sciences, 23(5), 435-448. https://doi.org/10.1016/j.tics.2019.03.003 https://www.cell.com/trends/cognitive-sciences/fulltext/S1364-6613(19)30066-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS136466131930066X%3Fshowall%3Dtrue
Müller, N. (2018). Inflammation in schizophrenia: Pathogenetic aspects and therapeutic considerations. Schizophrenia Bulletin, 44(5), 973-982. doi:10.1093/schbul/sby024 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101562/
