Amazing Examples of How Lyme, Bartonella, and Babesia Alter Your Brain!

Introduction

Below are 15 mechanisms or biological pathways for each infection few know.

Borrelia or Lyme Bacteria: 15 Ways It Can Affect the Brain and Its Supporting Cells

1. Crossing the Brain Vascular Endothelial Barrier
2. Using Host Proteases to Facilitate Tissue Penetration
3. Triggering Endothelial Calcium Signaling During Barrier Traversal
4. Activating Microglial TLR2 Signaling
5. Amplifying Inflammatory Transcription in Microglia
6. Making Microglia Release Inflammatory Cytokines
7. Recruiting Additional Inflammatory Cells Through Chemokines
8. Activating Astrocytes
9. Producing Neuronal Injury Through a Microglial Bystander Effect
10. Inducing Oligodendrocyte Apoptosis
11. Driving CXCL13-Mediated B-Cell Recruitment
12. Supporting Local Antibody Production Within CNS Compartments
13. Amplifying Inflammation Through Substance P–NK1 Receptor Signaling
14. Inflaming Meninges and Perivascular Tissues
15. Producing Vascular and Focal Parenchymal Inflammation

Bartonella: 15 Cellular and Vascular Pathways Relevant to the Brain

1. Invading Endothelial Cells
2. Activating Endothelial NF-κB
3. Increasing Endothelial Adhesion Molecules and Chemokine Secretion
4. Suppressing Apoptosis of Infected Endothelial Cells
5. Directly Invading Human Brain Vascular Pericytes
6. Reducing Proliferation of Infected Brain Pericytes
7. Increasing VEGF Production by Brain Pericytes
8. Directly Stimulating VEGF-Receptor Signaling Through BafA
9. Infecting Microglial Cells
10. Avoiding Normal Intracellular Degradative Trafficking
11. Being Associated With Cerebral Vasculitis
12. Being Associated With Cerebral Infarction and Tissue Necrosis
13. Causing Embolic Stroke Through Infective Endocarditis
14. Causing Infectious Cerebral Aneurysms and Hemorrhage
15. Producing Encephalopathy Through Incompletely Defined Inflammatory Mechanisms

Babesia: 15 Pathways by Which Infection Can Impair the Brain

1. Hemolytic Anemia Reducing Cerebral Oxygen Delivery
2. Postinfectious Autoimmune Hemolysis Prolonging the Oxygen-Delivery Problem
3. Respiratory Failure Producing Cerebral Hypoxemia
4. Shock Reducing Cerebral Perfusion
5. Cardiac Dysfunction Compromising Cerebral Blood Flow
6. Renal Failure Contributing to Toxic-Metabolic Encephalopathy
7. Severe Hepatic Dysfunction Contributing to Encephalopathy
8. Acid–Base Disturbances Impairing Neural Function
9. DIC Potentially Impairing Cerebral Microcirculation Through Microthrombi
10. Coagulopathy Causing Intracranial Bleeding
11. Systemic Inflammatory Signaling Contributing to Encephalopathy
12. Fever Increasing Metabolic Demand and Contributing to Delirium
13. Cytoadherence of Infected Erythrocytes to Cerebral Endothelial Cells
14. Sequestration of Infected Erythrocytes in Cerebral Capillaries
15. Increasing Erythrocyte Rigidity and Impairing Passage Through Small Vessels

Full References

Author lists are abbreviated with et al. for longer papers; titles, publication details, and DOI or indexed links identify the complete references.

Borrelia (Lyme Disease)

L1. Grab DJ, Perides G, Dumler JS, et al. Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier. Infection and Immunity. 2005;73(2):1014–1022.

DOI: 10.1128/IAI.73.2.1014-1022.2005 (opens in new tab)

L2. Grab DJ, Nyarko E, Nikolskaia OV, Kim YV, Dumler JS. Human brain microvascular endothelial cell traversal by Borrelia burgdorferi requires calcium signaling. Clinical Microbiology and Infection. 2009;15(5):422–426.

DOI: 10.1111/j.1469-0691.2009.02869.x (opens in new tab)

L3. 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.

DOI: 10.1186/s12974-015-0274-z (opens in new tab)

L4. 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.

DOI: 10.1371/journal.ppat.1000659 (opens in new tab)

L5. Ramesh G, Borda JT, Dufour J, et al. Interaction of the Lyme disease spirochete Borrelia burgdorferi with brain parenchyma elicits inflammatory mediators from glial cells as well as glial and neuronal apoptosis. American Journal of Pathology. 2008;173(5):1415–1427.

DOI: 10.2353/ajpath.2008.080483 (opens in new tab)

L6. Narayan K, Dail D, Li L, Cadavid D, Amrute S, Fitzgerald-Bocarsly P, Pachner AR. The nervous system as ectopic germinal center: CXCL13 and IgG in Lyme neuroborreliosis. Annals of Neurology. 2005;57(6):813–823.

DOI: 10.1002/ana.20486 (opens in new tab)

L7. Martinez AN, Ramesh G, Jacobs MB, Philipp MT. Antagonist of the neurokinin-1 receptor curbs neuroinflammation in ex vivo and in vitro models of Lyme neuroborreliosis. Journal of Neuroinflammation. 2015;12:243.

DOI: 10.1186/s12974-015-0453-y (opens in new tab)

L8. Ramesh G, Didier PJ, England JD, Santana-Gould L, Doyle-Meyers LA, Martin DS, Jacobs MB, Philipp MT. Inflammation in the pathogenesis of Lyme neuroborreliosis. American Journal of Pathology. 2015;185(5):1344–1360.

DOI: 10.1016/j.ajpath.2015.01.024 (opens in new tab)

Bartonella

T1. Schmid MC, Schülein R, Dehio M, Denecker G, Carena I, Dehio C. The VirB type IV secretion system of Bartonella henselae mediates invasion, proinflammatory activation and antiapoptotic protection of endothelial cells. Molecular Microbiology. 2004;52(1):81–92.

DOI: 10.1111/j.1365-2958.2003.03964.x (opens in new tab)

T2. Schmid MC, Scheidegger F, Dehio M, et al. A translocated bacterial protein protects vascular endothelial cells from apoptosis. PLoS Pathogens. 2006;2(11):e115.

DOI: 10.1371/journal.ppat.0020115 (opens in new tab)

T3. Varanat M, Maggi RG, Linder KE, Breitschwerdt EB. Infection of human brain vascular pericytes (HBVPs) by Bartonella henselae. Medical Microbiology and Immunology. 2013;202:143–151.

PubMed PMID: 23184416

View on PubMed (opens in new tab)

T4. Tsukamoto K, Shinzawa N, Kawai A, et al. The Bartonella autotransporter BafA activates the host VEGF pathway to drive angiogenesis. Nature Communications. 2020;11:3571.

DOI: 10.1038/s41467-020-17391-2 (opens in new tab)

T5. Muñana 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.

DOI: 10.1128/IAI.69.1.564-569.2001 (opens in new tab)

T6. Kyme PA, Haas A, Schaller M, Peschel A, Iredell J, Kempf VAJ. Unusual trafficking pattern of Bartonella henselae-containing vacuoles in macrophages and endothelial cells. Cellular Microbiology. 2005;7(7):1019–1034.

DOI: 10.1111/j.1462-5822.2005.00531.x (opens in new tab)

T7. Poursheykhi M, Mithani F, Garg T, et al. A case of cerebral vasculitis due to neurobartonellosis. Neurology: Neuroimmunology & Neuroinflammation. 2020;7:e791.

DOI: 10.1212/NXI.0000000000000791 (opens in new tab)

T8. Balakrishnan N, Ericson M, Maggi R, Breitschwerdt EB. Vasculitis, cerebral infarction and persistent Bartonella henselae infection in a child. Parasites & Vectors. 2016;9:254.

DOI: 10.1186/s13071-016-1547-9 (opens in new tab)

T9. Charles K, Abraham A, Bassi R, Elsadek R, Cockey G. A rare case of Bartonella henselae infective endocarditis causing an embolic cerebrovascular accident. Cureus. 2023;15:e41364.

DOI: 10.7759/cureus.41364 (opens in new tab)

T10. Ogbebor O, Pawate V, Woo J, Kelly K, Cerejo R, Bhanot N. Bartonella endocarditis presenting as recurrent cerebral mycotic aneurysm. Cureus. 2021;13(11):e19969.

DOI: 10.7759/cureus.19969 (opens in new tab)

T11. Samarkos M, Antoniadou V, Vaiopoulos AG, Psichogiou M. Encephalopathy in an adult with cat-scratch disease. BMJ Case Reports. 2018;2018:bcr2017223647.

DOI: 10.1136/bcr-2017-223647 (opens in new tab)

Babesia

B1. Locke S, O’Bryan JO, Zubair AS, et al. Neurologic complications of babesiosis, United States, 2011–2021. Emerging Infectious Diseases. 2023;29(6):1109–1117.

DOI: 10.3201/eid2906.221890 (opens in new tab)

B2. Hatcher JC, Greenberg PD, Antique J, Jimenez-Lucho VE. Severe babesiosis in Long Island: review of 34 cases and their complications. Clinical Infectious Diseases. 2001;32(8):1117–1125.

DOI: 10.1086/319742 (opens in new tab)

B3. Woolley AE, Montgomery MW, Savage WJ, Achebe MO, Dunford K, Villeda S, Maguire JH, Marty FM. Post-babesiosis warm autoimmune hemolytic anemia. New England Journal of Medicine. 2017;376(10):939–946.

DOI: 10.1056/NEJMoa1612165 (opens in new tab)

B4. Severe Babesia microti infection presenting as multiorgan failure in an immunocompetent host. BMJ Case Reports. 2018;2018:bcr2018224647. Indexed author record.

DOI: 10.1136/bcr-2018-224647 (opens in new tab)

B5. Cardiac complications of human babesiosis. Clinical Infectious Diseases. 2023;76(3):e1385–e1391. Indexed author record.

DOI: 10.1093/cid/ciac525 (opens in new tab)

B6. Nassar Y, Richter S. Babesiosis presenting as acute liver failure. Case Reports in Gastroenterology. Published online December 18, 2017;11(3):769–773.

DOI: 10.1159/000485373 (opens in new tab)

B7. Clark IA, Budd AC, Hsue G, Haymore BR, Joyce AJ, Thorner R, Krause PJ. Absence of erythrocyte sequestration in a case of babesiosis in a splenectomized human patient. Malaria Journal. 2006;5:69.

DOI: 10.1186/1475-2875-5-69 (opens in new tab)

B8. O’Connor RM, Long JA, Allred DR. Cytoadherence of Babesia bovis-infected erythrocytes to bovine brain capillary endothelial cells provides an in vitro model for sequestration. Infection and Immunity. 1999;67(8):3921–3928.

DOI: 10.1128/IAI.67.8.3921-3928.1999 (opens in new tab)

B9. Hutchings CL, Li A, Fernandez KM, Fletcher T, Jackson LA, Molloy JB, Jorgensen WK, Lim CT, Cooke BM. New insights into the altered adhesive and mechanical properties of red blood cells parasitized by Babesia bovis. Molecular Microbiology. 2007;65(4):1092–1105.

DOI: 10.1111/j.1365-2958.2007.05850.x (opens in new tab)

B10. Park H, Hong SH, Kim K, Cho SH, Lee WJ, Kim Y, Lee SE, Park Y. Characterizations of individual mouse red blood cells parasitized by Babesia microti using 3-D holographic microscopy. Scientific Reports. 2015;5:10827.

DOI: 10.1038/srep10827 (opens in new tab)