Microglial Mitochondrial Dysregulation from Borrelia/Bartonella Infection

1 Myers 2009 — Microglia Mediate Borrelia-Induced Neuronal Apoptosis

Full Citation:: Myers TA, Kaushal D, Philipp MT. Microglia are mediators of Borrelia burgdorferi-induced apoptosis in SH-SY5Y neuronal cells. PLoS Pathogens. 2009;5(11):e1000659. (Myers, Kaushal, and Philipp 2009) DOI:: 10.1371/journal.ppat.1000659 PMID:: 19911057 Study Design:: In vitro co-culture (primary rhesus microglia + SH-SY5Y neuroblastoma + live Bb) Key Findings::

- Bb alone does not induce neuronal apoptosis; microglia + Bb produces robust inflammatory cytokine/chemokine expression
- Neurons + microglia + Bb → neuronal apoptosis via caspase-3
- Microglial conditioned medium sufficient (soluble mediators: TNF-α, IL-1β)

Conclusion:: Microglia are necessary intermediaries for Bb-induced neuronal injury. Limitations:: In vitro; rhesus not human microglia; cell line neurons; no mitochondrial readouts.

2 Kuhlow 2005 — Microglia as Phagocytes for Borrelia

Full Citation:: Kuhlow CJ, Garcia-Monco JC, Coleman JL, Benach JL. Murine microglia are effective phagocytes for Borrelia burgdorferi. Journal of Neuroimmunology. 2005;168(1-2):183-187. (Kuhlow et al. 2005) DOI:: 10.1016/j.jneuroim.2005.06.030 PMID:: 16125249 Study Design:: In vitro murine microglial phagocytosis assay Key Findings::

- Microglia rapidly phagocytose live Bb → proinflammatory cytokine release
- Microglial clearance may explain spirochete scarcity in CNS

Conclusion:: Microglia are first-line CNS defenders against Bb; immediate activation upon exposure. Limitations:: Murine cells; no human confirmation; no mitochondrial assays.

3 Parthasarathy 2015 — Multi-Receptor Microglial Activation by Borrelia

Full Citation:: Parthasarathy G, Philipp MT. Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways. Journal of Neuroinflammation. 2015;12:60. (Parthasarathy and Philipp 2015) DOI:: 10.1186/s12974-015-0274-z PMID:: 25889406 Study Design:: In vitro rhesus microglia + live Bb; TLR blocking; signaling inhibitors Key Findings::

- Bb activates microglia via TLR1/TLR2/TLR5 → MyD88/TRIF → NF-κB/MAPK
- TNF-α, IL-6, IL-12, CCL2, CXCL10 all upregulated
- Multiple receptor redundancy — single-target blockade only partially effective

Conclusion:: Microglial inflammatory response to Bb is multi-receptor, multi-pathway. Limitations:: In vitro; rhesus cells; no mitochondrial readouts.

4 Cassiani-Ingoni 2006 — TLR1/TLR2 in Human Microglia

Full Citation:: Cassiani-Ingoni R, et al. Borrelia burgdorferi induces TLR1 and TLR2 in human microglia and peripheral blood monocytes but differentially regulates HLA-class II expression. Journal of Neuropathology and Experimental Neurology. 2006;65(6):540-548. (Cassiani-Ingoni et al. 2006) DOI:: 10.1097/00005072-200606000-00002 PMID:: 16783164 Study Design:: In vitro human fetal microglia, astrocytes, neurons + Bb; oligoarray gene expression Key Findings::

- Bb upregulates TLR1/TLR2 in primary human microglia (critical species translation)
- Broad transcriptional response encompassing 30+ immune genes
- Differential HLA class II regulation: microglia upregulate, PBMCs downregulate

Conclusion:: Human microglia recognize Bb through TLR1/TLR2 with a distinct transcriptional program. Limitations:: Fetal tissue; in vitro; no mitochondrial gene expression data.

5 Parthasarathy 2023 — FGF/FGFR System in Borrelia-Induced Neuroinflammation

Full Citation:: Parthasarathy G, Pattison MB, Midkiff CC. The FGF/FGFR system in the microglial neuroinflammation with Borrelia burgdorferi: likely intersectionality with other neurological conditions. Journal of Neuroinflammation. 2023;20(1):10. (Parthasarathy, Pattison, and Midkiff 2023) DOI:: 10.1186/s12974-022-02681-x PMID:: 36650549 Study Design:: In vitro rhesus microglia + Bb; RNA-seq; FGFR pathway analysis Key Findings::

- Bb upregulates FGF2 and FGFR1 in microglia
- FGFR signaling contributes to inflammatory mediator production
- Links neuroborreliosis to Alzheimer's/MS — shared neuroinflammatory pathways

Conclusion:: FGF/FGFR system is a common mechanism linking neuroborreliosis to neurodegenerative diseases. Limitations:: In vitro; rhesus; no mitochondrial analysis.

6 Xu 2023 — BmpA Protein Alone Stimulates Microglia

Full Citation:: Xu X, et al. A key protein from Borrelia burgdorferi could stimulate cytokines in human microglial cells and inhibitory effects of Cucurbitacin IIa. IBRO Neuroscience Reports. 2023;15:376-385. (Xu et al. 2023) DOI:: 10.1016/j.ibneur.2023.11.004 PMID:: 38046885 Study Design:: In vitro HMC3 human microglia + recombinant BmpA; cytokine chip + qPCR Key Findings::

- Recombinant BmpA (Bb membrane protein) alone induces IL-6, IL-8, MCP-1, GRO from microglia
- Intact spirochete not required — single protein sufficient for inflammatory response
- Cucurbitacin IIa (plant compound) inhibits cytokine production

Conclusion:: Individual Bb components can trigger microglial inflammatory response. Limitations:: HMC3 immortalized cell line; recombinant protein only; no mitochondrial data.

7 Akinlusi 2025 — Borrelia Shifts Microglia to M1 Polarization

Full Citation:: Akinlusi I, et al. Human microglia polarization following infection with the Lyme disease spirochete. Journal of Investigative Medicine. 2025;73(1):172-178. (Akinlusi et al. 2025) DOI:: 10.1177/10815589241290206 PMID:: 39324305 Study Design:: In vitro HMC3 human microglia + Bb; M1/M2 polarization markers Key Findings::

- Bb shifts microglia toward M1 (proinflammatory): iNOS, TNF-α, IL-1β upregulated
- M2 markers decreased: Arg-1, CD206
- M1 polarization would imply metabolic shift to aerobic glycolysis (not measured)

Conclusion:: Neuroborreliosis drives microglial M1 polarization, consistent with chronic neuroinflammation. Limitations:: HMC3 cell line; limited polarization markers; no metabolic/mitochondrial assays.

8 Muñana 2001 — Bartonella henselae Infects Microglia

Full Citation:: Munana KR, Vitek SM, Hegarty BC, Kordick DL, Breitschwerdt EB. Infection of fetal feline brain cells in culture with Bartonella henselae. Infection and Immunity. 2001;69(1):564-569. (Munana et al. 2001) DOI:: 10.1128/IAI.69.1.564-569.2001 PMID:: 11119554 Study Design:: In vitro feline fetal microglial- and astrocyte-enriched cultures + B. henselae Key Findings::

- B. henselae infects and survives in feline microglia and astrocytes
- Non-cytolytic persistence — bacteria survive intracellularly without immediate cell death
- Establishes Bartonella can directly invade CNS glial cells

Conclusion:: Bartonella henselae can directly infect microglia — a mechanism for CNS involvement in cat-scratch disease. Limitations:: Feline cells, not human; single study; no follow-up in human microglia; no mitochondrial or cytokine data.

9 Coughlin 2018 — In Vivo Glial Activation in PTLDS (PET Imaging)

Full Citation:: Coughlin JM, et al. Imaging glial activation in patients with post-treatment Lyme disease symptoms: a pilot study using [11C]DPA-713 PET. Journal of Neuroinflammation. 2018;15(1):346. (Coughlin et al. 2018) DOI:: 10.1186/s12974-018-1381-4 PMID:: 30567544 Study Design:: Human PET imaging; [11C]DPA-713 TSPO ligand; PTLDS vs healthy controls Sample Size:: 12 PTLDS, 19 controls Key Findings::

- Increased TSPO binding in PTLDS brains — evidence of glial activation
- Binding correlates with cognitive complaints, pain, fatigue
- Activation persists years after antibiotic treatment

Conclusion:: Glial activation is present in PTLDS patients and may drive persistent symptoms — first in vivo human evidence. Limitations:: Small n (12); TSPO cannot distinguish microglia from astrocytes; no pre-treatment baseline.

10 Parthasarathy 2022 — Non-Viable Borrelia Remnants Sustain Microglial Activation

Full Citation:: Parthasarathy G, Gadila SKG. Neuropathogenicity of non-viable Borrelia burgdorferi ex vivo. Scientific Reports. 2022;12(1):688. (Parthasarathy and Gadila 2022) DOI:: 10.1038/s41598-021-03837-0 PMID:: 35027599 Study Design:: Ex vivo comparison of viable vs antibiotic-killed Bb effects on microglia Key Findings::

- Non-viable Bb remnants still activate microglia and induce neuroinflammation
- Antibiotic treatment does not eliminate the inflammatory stimulus
- Explains persistent symptoms in PTLDS after antibiotic treatment

Conclusion:: Microbial debris suffices for sustained microglial activation — important for PTLDS/ME/CFS overlap. Limitations:: Ex vivo; mechanisms of debris recognition not fully characterized; no mitochondrial analysis.

11 Peacock 2015 — Oxidative Stress in Lyme Disease

Full Citation:: Peacock BN, et al. New insights into Lyme disease. Redox Biology. 2015;5:66-70. (Peacock et al. 2015) DOI:: 10.1016/j.redox.2015.03.002 PMID:: 25838067 Study Design:: Review + original oxidative stress data in Bb-infected cells Key Findings::

- Bb infection induces oxidative stress in multiple cell types
- Lipid peroxidation and protein carbonylation detected
- Mitochondria are primary targets of Bb-induced oxidative damage (inferred)

Conclusion:: Oxidative stress is a core pathological mechanism in Lyme disease; mitochondrial involvement likely. Limitations:: Predominantly review; limited original mitochondrial data; not microglia-specific.

12 Wawrzeniak 2020 — Borrelia Outer Membrane Vesicles Induce ROS

Full Citation:: Wawrzeniak K, et al. Effect of Borrelia burgdorferi outer membrane vesicles on host oxidative stress response. Antibiotics. 2020;9(5):275. (Wawrzeniak et al. 2020) DOI:: 10.3390/antibiotics9050275 PMID:: 32466166 Study Design:: In vitro BE2C neuroblastoma + Bb outer membrane vesicles Key Findings::

- Bb OMVs induce oxidative stress in neuronal cells (ROS production)
- OMV lipoproteins, DNA, RNA sufficient to trigger host stress responses
- Antioxidant gene expression altered

Conclusion:: Bb-derived OMVs are vehicles for host cell oxidative damage with mitochondrial implications. Limitations:: Neuroblastoma cell line, not microglia; no direct mitochondrial function assays.

13 Tsilioni 2022 — ME/CFS Exosomal mtDNA Activates Microglia

Full Citation:: Tsilioni I, Natelson B, Theoharides TC. Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1β. European Journal of Neuroscience. 2022;56(10):5784-5794. (Tsilioni, Natelson, and Theoharides 2022) DOI:: 10.1111/ejn.15828 PMID:: 36153118 Study Design:: In vitro HMC3 microglia + serum exosomes from ME/CFS patients; mtDNA quantification Key Findings::

- ME/CFS serum exosomes contain elevated mtDNA (post-exercise) vs healthy controls
- ME/CFS exosomes activate HMC3 microglia to release IL-1β
- DNase treatment blocks activation → mtDNA is the active moiety

Conclusion:: Exercise-induced exosomal mtDNA release in ME/CFS directly activates microglia — bridges mitochondrial dysfunction to neuroinflammation. Limitations:: HMC3 cell line; small n (~20 ME/CFS, ~10 controls); post-exercise only; no subtyping.

14 Chaves-Filho 2019 — Shared Microglial Mechanisms in CFS and Depression

Full Citation:: Chaves-Filho AJM, Macedo DS, de Lucena DF, Maes M. Shared microglial mechanisms underpinning depression and chronic fatigue syndrome and their comorbidities. Behavioural Brain Research. 2019;372:111975. (Chaves-Filho et al. 2019) DOI:: 10.1016/j.bbr.2019.111975 PMID:: 31136774 Study Design:: Narrative review Key Findings::

- Activated microglia contribute to both depression and CFS through shared cytokine pathways
- M1 polarization drives neuroinflammation
- Kynurenine pathway activation links inflammation to glutamate dysregulation

Conclusion:: Microglial activation is a transdiagnostic mechanism for neuroinflammatory symptoms. Limitations:: Review; no original data; broad CFS/ME focus.

15 Hirsch 2025 — GWAS Overlap Between PTLDS and ME/CFS

Full Citation:: Hirsch AG, et al. A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis — chronic fatigue syndrome. BMC Infectious Diseases. 2025;25(1):265. (Hirsch et al. 2025) DOI:: 10.1186/s12879-024-10238-x PMID:: 39994562 Study Design:: GWAS comparing PTLDS, FM, and ME/CFS Key Findings::

- No genome-wide significant loci for PTLDS (underpowered, ~200 cases)
- Suggestive genetic overlap between PTLDS, FM, and ME/CFS
- Shared pathways include immune function and neuroinflammation

Conclusion:: Tentative genetic evidence linking PTLDS to ME/CFS — supports shared neuroinflammatory susceptibility. Limitations:: Underpowered for PTLDS; no microglia-specific or mitochondrial genes at genome-wide significance.

References

Akinlusi, Idris, Brian Kan, Ted Shi, Jose Barragan, Carlos Bouchot, and Jorge Cervantes. 2025. “Human Microglia Polarization Following Infection with the Lyme Disease Spirochete.” Journal of Investigative Medicine 73 (1): 172–78. https://doi.org/10.1177/10815589241290206.

Cassiani-Ingoni, Riccardo, Erik S Cabral, Jan D Lünemann, Zoila Garza, Tim Magnus, Harald Gelderblom, Peter J Munson, Adriana Marques, and Roland Martin. 2006. “Borrelia burgdorferi Induces TLR1 and TLR2 in Human Microglia and Peripheral Blood Monocytes but Differentially Regulates HLA-Class II Expression.” Journal of Neuropathology and Experimental Neurology 65 (6): 540–48. https://doi.org/10.1097/00005072-200606000-00002.

Chaves-Filho, Adriano José Maia, Danielle S Macedo, David Freitas de Lucena, and Michael Maes. 2019. “Shared Microglial Mechanisms Underpinning Depression and Chronic Fatigue Syndrome and Their Comorbidities.” Behavioural Brain Research 372: 111975. https://doi.org/10.1016/j.bbr.2019.111975.

Coughlin, Jennifer M, Ting Yang, Alison W Rebman, Kathleen T Bechtold, Yong Du, William B Mathews, Wojciech G Lesniak, et al. 2018. “Imaging Glial Activation in Patients with Post-Treatment Lyme Disease Symptoms: A Pilot Study Using [11C]DPA-713 PET.” Journal of Neuroinflammation 15 (1): 346. https://doi.org/10.1186/s12974-018-1381-4.

Hirsch, Annemarie G, Anne E Justice, Amy Poissant, Cara M Nordberg, Navya S Josyula, John Aucott, Alison W Rebman, and Brian S Schwartz. 2025. “A Comparison of Genome-Wide Association Analyses of Persistent Symptoms After Lyme Disease, Fibromyalgia, and Myalgic Encephalomyelitis – Chronic Fatigue Syndrome.” BMC Infectious Diseases 25 (1): 265. https://doi.org/10.1186/s12879-024-10238-x.

Kuhlow, Christopher J, Juan C Garcia-Monco, James L Coleman, and Jorge L Benach. 2005. “Murine Microglia Are Effective Phagocytes for Borrelia burgdorferi.” Journal of Neuroimmunology 168 (1-2): 183–87. https://doi.org/10.1016/j.jneuroim.2005.06.030.

Munana, K R, S M Vitek, B C Hegarty, D L Kordick, and E B Breitschwerdt. 2001. “Infection of Fetal Feline Brain Cells in Culture with Bartonella henselae.” Infection and Immunity 69 (1): 564–69. https://doi.org/10.1128/IAI.69.1.564-569.2001.

Myers, Tereance A, Deepak Kaushal, and Mario T Philipp. 2009. “Microglia Are Mediators of Borrelia burgdorferi-Induced Apoptosis in SH-SY5Y Neuronal Cells.” PLoS Pathogens 5 (11): e1000659. https://doi.org/10.1371/journal.ppat.1000659.

Parthasarathy, Geetha, and Shiva Kumar Goud Gadila. 2022. “Neuropathogenicity of Non-Viable Borrelia burgdorferi Ex Vivo.” Scientific Reports 12 (1): 688. https://doi.org/10.1038/s41598-021-03837-0.

Parthasarathy, Geetha, Melissa B Pattison, and Cecily C Midkiff. 2023. “The FGF/FGFR System in the Microglial Neuroinflammation with Borrelia burgdorferi: Likely Intersectionality with Other Neurological Conditions.” Journal of Neuroinflammation 20 (1): 10. https://doi.org/10.1186/s12974-022-02681-x.

Parthasarathy, Geetha, and Mario T Philipp. 2015. “Inflammatory Mediator Release from Primary Rhesus Microglia in Response to Borrelia burgdorferi Results from the Activation of Several Receptors and Pathways.” Journal of Neuroinflammation 12: 60. https://doi.org/10.1186/s12974-015-0274-z.

Peacock, Brandon N, Teshome B Gherezghiher, Jennifer D Hilario, and Gottfried H Kellermann. 2015. “New Insights into Lyme Disease.” Redox Biology 5: 66–70. https://doi.org/10.1016/j.redox.2015.03.002.

Tsilioni, Irene, Benjamin Natelson, and Theoharis C. Theoharides. 2022. “Exosome-Associated Mitochondrial DNA from Patients with ME/CFS Stimulates Human Microglia to Release IL-1\(\beta\).” European Journal of Neuroscience 56 (10): 5784–94. https://doi.org/10.1111/ejn.15828.

Wawrzeniak, Keith, Gauri Gaur, Eva Sapi, and Alireza G Senejani. 2020. “Effect of Borrelia burgdorferi Outer Membrane Vesicles on Host Oxidative Stress Response.” Antibiotics 9 (5): 275. https://doi.org/10.3390/antibiotics9050275.

Xu, Xin, Shiyuan Wen, Yu Zhang, Wenjing Cao, Peng Yue, Jing Kong, Meixiao Liu, Yuxin Fan, Jingjing Chen, and Zhenhua Ji. 2023. “A Key Protein from Borrelia burgdorferi Could Stimulate Cytokines in Human Microglial Cells and Inhibitory Effects of Cucurbitacin IIa.” IBRO Neuroscience Reports 15: 376–85. https://doi.org/10.1016/j.ibneur.2023.11.004.