Glycolytic Reprogramming in the Host Response to Tick-Borne Pathogens

Context: These papers address whether Borrelia, Bartonella, and Babesia drive glycolytic reprogramming in host cells analogous to the viral glial reprogramming mechanism. The evidence is overwhelmingly in vitro or animal-based; direct ME/CFS-specific evidence is absent. The mechanistic parallels are strong, particularly for Bartonella (HIF-1α activation via Kempf2005) and Borrelia (trained immunity with glycolytic switch via Barriales2021).

1 Dong 2026 — Glycolytic Reprogramming in Host Response to B. burgdorferi

Full Citation:: Dong Y, Chen Y, Luo Y, Liu M, Song C, Chen X, Yang F, Luo Q, Zhou G. Glycolytic reprogramming in host response to Borrelia burgdorferi. Experimental and Therapeutic Medicine. 2026;32(1):187. (Dong et al. 2026) DOI:: 10.3892/etm.2026.13182 PMID:: 42199349 Study Design:: Bioinformatics + in vitro validation (THP-1 human monocytic cell line) Key Findings::

- 63 differentially expressed glycolysis-related genes in Borrelia burgdorferi infection
- LDHA and TXN identified as key diagnostic genes via LASSO and SVM-RFE
- RT-qPCR confirmed LDHA and TXN upregulation in Bb-infected THP-1 cells
- Reduced extracellular glucose and increased lactate accumulation
- Immune infiltration: LDHA/TXN linked to Tregs, γδ T cells, CD4 memory resting T cells, monocytes

Conclusion:: Borrelia burgdorferi drives a Warburg-like glycolytic shift in human monocytes (↑LDHA → ↑lactate), contributing to LD immunopathology. Limitations:: Single cell line (THP-1); bioinformatics-heavy with limited functional validation; single timepoint; no primary human cells; no ME/CFS context.

2 Barriales 2021 — B. burgdorferi Induces Long-Term Macrophage Memory with Glycolytic Reprogramming

Full Citation:: Barriales D, Martín-Ruiz I, Carreras-González A, et al. Borrelia burgdorferi infection induces long-term memory-like responses in macrophages with tissue-wide consequences in the heart. PLoS Biology. 2021;19(1):e3001062. (Barriales et al. 2021) DOI:: 10.1371/journal.pbio.3001062 PMID:: 33395408 Study Design:: In vitro + in vivo mouse model (transcriptomics, proteomics, metabolomics) Key Findings::

- Broad transcriptomic/proteomic changes in heart: profound downregulation of mitochondrial components
- Bb-exposed macrophages: augmented glycolytic output, increased spirochetal binding, reduced inflammatory responses
- Glycolysis inhibition in vitro: reduces TNF production by memory macrophages
- In vivo glycolysis inhibition: reverses memory phenotype, recovers mitochondrial components, decreases inflammation and spirochetal burdens

Conclusion:: Bb induces long-term trained immunity with glycolytic reprogramming that is reversible by metabolic intervention — directly analogous to the viral glial reprogramming paradigm. Limitations:: Mouse model; cardiac focus may not generalize to other tissues; in vivo glycolysis inhibition used broad-spectrum inhibitor (2-DG) with pleiotropic effects.

3 Kerstholt 2022 — B. burgdorferi Alters Monocyte Glucose Metabolism and Lactate

Full Citation:: Kerstholt M, van de Schoor FR, Oosting M, et al. Identifying platelet-derived factors as amplifiers of B. burgdorferi-induced cytokine production. Clinical and Experimental Immunology. 2022;210(1):53-67. (Kerstholt et al. 2022) DOI:: 10.1093/cei/uxac073 PMID:: 36001729 Study Design:: Human in vitro (primary monocytes) + GWAS Key Findings::

- Bb exposure decreases baseline glycolysis (lactate production) in human monocytes
- MFAP3L identified via GWAS: influences lactate and cytokine production after Bb
- MFAP3L mediates effects via ERK2 activation and platelet degranulation
- CXCL7 and CCL5 elevated in circulation of LB patients vs healthy

Conclusion:: Bb modulates monocyte lactate production via the novel MFAP3L→ERK2→platelet axis. Bidirectional metabolic effects suggest complex, context-dependent host glycolytic response. Limitations:: Decreased lactate finding contrasts with Dong2026 (increased lactate); in vitro only for mechanistic experiments; GWAS requires replication in larger cohorts.

4 Oosting 2016 — Functional Genomics of Borrelia-Induced Cytokine Responses

Full Citation:: Oosting M, Kerstholt M, Ter Horst R, et al. Functional and genomic architecture of Borrelia burgdorferi-induced cytokine responses in humans. Cell Host & Microbe. 2016;20(6):822-833. (Oosting et al. 2016) DOI:: 10.1016/j.chom.2016.10.006 PMID:: 27818078 Study Design:: Human in vitro (primary monocytes, two healthy cohorts, n=~500) Key Findings::

- Non-genetic and genetic host factors influence Borrelia-induced cytokine production
- Age strongly impairs IL-22 responses
- Genetic variants in immune genes identified
- Monocyte glucose metabolism is altered by Borrelia (framework for Kerstholt 2022)

Conclusion:: Host genetic variation shapes Borrelia-induced immune responses, providing the framework for subsequent immunometabolic studies. Limitations:: In vitro stimulation only; healthy donors not Lyme patients; pre-dates detailed metabolic characterization.

5 Bernard 2020 — Borrelia Induces Cell-Type-Specific Trained Immunity

Full Citation:: Bernard Q, Hu LT. Innate immune memory to repeated Borrelia burgdorferi exposure. Journal of Immunology. 2020;205(12):3383-3389. (Bernard and Hu 2020) DOI:: 10.4049/jimmunol.2000686 PMID:: 33168577 Study Design:: In vitro + ex vivo mouse model Key Findings::

- Murine fibroblast-like synoviocytes display trained immunity upon Bb exposure
- Trained phenotype correlates with Lyme arthritis susceptibility (C3H > C57BL/6)
- Skin fibroblasts do NOT exhibit trained immunity (tissue specificity)
- Host genetic background affects trained phenotype

Conclusion:: Borrelia induces trained immunity in a cell-type-specific manner, influenced by host genetics. Limitations:: Short report format; mouse only; limited mechanistic depth; no direct glycolytic measurements.

6 Lynch 2023 — Borrelia burgdorferi Is Obligately Glycolytic; LDH as Drug Target

Full Citation:: Lynch A, Pearson P, Savinov SN, Li AY, Rich SM. Lactate dehydrogenase inhibitors suppress Borrelia burgdorferi growth in vitro. Pathogens. 2023;12(7):962. (Lynch et al. 2023) DOI:: 10.3390/pathogens12070962 PMID:: 37513809 Study Design:: In vitro axenic culture Key Findings::

- Bb has highly reduced genome, relies heavily on glycolysis for carbon metabolism
- LDH inhibitors (gossypol, oxamate, galloflavin, stiripentol) suppress Bb growth dose-dependently

Conclusion:: Bb’s obligate glycolytic metabolism means a host glycolytic environment may favor spirochetal persistence — potential mechanism for ongoing immune activation in PTLDS. Limitations:: In vitro only; no host cells; single species; therapeutic concentrations may not be achievable in vivo.

7 Kempf 2005 — Bartonella henselae Activates HIF-1α in Host Cells

Full Citation:: Kempf VAJ, Lebiedziejewski M, Alitalo K, et al. Activation of hypoxia-inducible factor-1 in bacillary angiomatosis: evidence for a role of hypoxia-inducible factor-1 in bacterial infections. Circulation. 2005;111(8):1054-1062. (Kempf et al. 2005) DOI:: 10.1161/01.CIR.0000155608.07691.B7 PMID:: 15723970 Study Design:: In vitro + human tissue immunohistochemistry Key Findings::

- B. henselae activates HIF-1α in infected host cells (immunofluorescence, Western blot, EMSA, reporter gene, microarray)
- HIF-1α essential for B. henselae-induced VEGF expression (siRNA inhibition)
- Infection increases oxygen consumption, causes cellular hypoxia, decreases ATP
- Pilus-negative variant does not activate HIF-1α or VEGF

Conclusion:: Bartonella stabilizes HIF-1α → VEGF → cellular hypoxia → decreased ATP. First demonstration of HIF-1α in any bacterial infection. Directly parallels viral HIF-1α → glycolytic shift mechanism. Limitations:: 2005 publication; no direct glycolytic flux measurements; bacillary angiomatosis-specific (not typical Bartonella presentation in ME/CFS); no ME/CFS context.

8 Ohmori 2004 — Babesia-Infected Erythrocytes Show Increased Glucose Uptake

Full Citation:: Ohmori T, Adachi K, Fukuda Y, Tamahara S, Matsuki N, Ono K. Glucose uptake activity in murine red blood cells infected with Babesia microti and Babesia rodhaini. Journal of Veterinary Medical Science. 2004;66(8):945-949. (Ohmori et al. 2004) DOI:: 10.1292/jvms.66.945 PMID:: 15353845 Study Design:: Animal (mouse), radiolabeled glucose uptake assay Key Findings::

- Babesia-infected RBCs show increased glucose and L-glucose uptake vs uninfected
- De novo, non-transporter-mediated uptake systems develop
- Two distinct systems: one common to B. microti and B. rodhaini, another with higher activity in B. microti
- Sodium-independent, temperature-sensitive

Conclusion:: Babesia-infected RBCs develop novel glucose uptake pathways, effectively a glycolytic reprogramming of the erythrocyte — suggesting increased glucose consumption as part of the host-parasite metabolic interaction. Limitations:: Small n; pooled mouse blood; single assay method; no human data; older publication (2004); no protein/molecular characterization of the novel uptake system.

9 Fitzgerald 2021 — PTLDS Metabolomic Profile (Glycolysis-Null Finding)

Full Citation:: Fitzgerald BL, Graham B, Delorey MJ, et al. Metabolic response in patients with post-treatment Lyme disease symptoms/syndrome. Clinical Infectious Diseases. 2021;73(7):e2342-e2349. (Fitzgerald et al. 2021) DOI:: 10.1093/cid/ciaa1455 PMID:: 32975577 Study Design:: Untargeted LC-MS metabolomics, multi-timepoint longitudinal, two-cohort validation Sample Size:: PTLDS patients vs clinically cured non-PTLDS Lyme patients Key Findings::

- Observable metabolic differences between PTLDS and non-PTLDS at multiple time points
- Differentially abundant metabolites: glycerophospholipids, bile acids, acylcarnitines (NOT glycolytic metabolites)
- Greater metabolic variability in PTLDS patients
- 6-40 metabolites discriminate PTLDS from non-PTLDS at defined time points
- Validated in second cohort

Conclusion:: PTLDS has a distinct metabolomic signature. Non-glycolytic pathways (phospholipid, bile acid, acylcarnitine) dominate serum metabolome — consistent with upstream mitochondrial dysfunction rather than direct glycolytic shift. Host glycolytic changes may be cell-type specific and not detectable in serum. Limitations:: Serum metabolomics may miss cell-type-specific or tissue-level metabolic changes (e.g., in macrophages or synoviocytes); not ME/CFS-specific; cross-sectional at each time point.

References

Barriales, Diego, Itziar Martı́n-Ruiz, Ana Carreras-González, Marta Montesinos-Robledo, Mikel Azkargorta, Ibon Iloro, Iraide Escobés, et al. 2021. “Borrelia Burgdorferi Infection Induces Long-Term Memory-Like Responses in Macrophages with Tissue-Wide Consequences in the Heart.” PLoS Biology 19 (1): e3001062. https://doi.org/10.1371/journal.pbio.3001062.

Bernard, Quentin, and Linden T Hu. 2020. “Innate Immune Memory to Repeated Borrelia Burgdorferi Exposure.” Journal of Immunology 205 (12): 3383–89. https://doi.org/10.4049/jimmunol.2000686.

Dong, Yan, Yantong Chen, Yanshuang Luo, Meng Liu, Chao Song, Xuesong Chen, Fusong Yang, Qingyi Luo, and Guozhong Zhou. 2026. “Glycolytic Reprogramming in Host Response to Borrelia burgdorferi.” Experimental and Therapeutic Medicine 32 (1): 187. https://doi.org/10.3892/etm.2026.13182.

Fitzgerald, Bryna L, Barbara Graham, Mark J Delorey, Adoracion Pegalajar-Jurado, M Nurul Islam, Gary P Wormser, John N Aucott, et al. 2021. “Metabolic Response in Patients with Post-Treatment Lyme Disease Symptoms/Syndrome.” Clinical Infectious Diseases 73 (7): e2342–49. https://doi.org/10.1093/cid/ciaa1455.

Kempf, Volkhard A J, Maria Lebiedziejewski, Kari Alitalo, Joo-Hee Wälzlein, Urs Ehehalt, Jeannette Fiebig, Stephan Huber, et al. 2005. “Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis: Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections.” Circulation 111 (8): 1054–62. https://doi.org/10.1161/01.CIR.0000155608.07691.B7.

Kerstholt, Mariska, Freek R van de Schoor, Marije Oosting, Simone J C F M Moorlag, Yang Li, Martin Jaeger, Wouter A van der Heijden, et al. 2022. “Identifying Platelet-Derived Factors as Amplifiers of B. Burgdorferi-Induced Cytokine Production.” Clinical and Experimental Immunology 210 (1): 53–67. https://doi.org/10.1093/cei/uxac073.

Lynch, Adam, Patrick Pearson, Sergey N Savinov, Andrew Y Li, and Stephen M Rich. 2023. “Lactate Dehydrogenase Inhibitors Suppress Borrelia Burgdorferi Growth in Vitro.” Pathogens 12 (7): 962. https://doi.org/10.3390/pathogens12070962.

Ohmori, Takashi, Keishi Adachi, Yoshimitsu Fukuda, Satoshi Tamahara, Naoaki Matsuki, and Kenichiro Ono. 2004. “Glucose Uptake Activity in Murine Red Blood Cells Infected with Babesia Microti and Babesia Rodhaini.” Journal of Veterinary Medical Science 66 (8): 945–49. https://doi.org/10.1292/jvms.66.945.

Oosting, Marije, Mariska Kerstholt, Rob Ter Horst, Yang Li, Patrick Deelen, Sanne Smeekens, Martin Jaeger, et al. 2016. “Functional and Genomic Architecture of Borrelia Burgdorferi- Induced Cytokine Responses in Humans.” Cell Host and Microbe 20 (6): 822–33. https://doi.org/10.1016/j.chom.2016.10.006.