Below are 15 mechanisms or biological pathways for each organism, emphasizing cells, signaling, vascular effects, and consequences for brain function. They are sometimes successive steps in the same pathway rather than 15 independent processes.
Evidence Labels:
- Human: Demonstrated in human disease; some findings come from individual cases.
- Experimental: Demonstrated in cells, tissue preparations, or animals.
- Proposed: Biologically plausible, but the specific causal mechanism in human brain disease remains unconfirmed.
- Indirect: Brain dysfunction resulting from infection elsewhere in the body.
For Borrelia, the discussion concerns Lyme-associated B. burgdorferi sensu lato, rather than all relapsing-fever Borrelia. Reference codes correspond to the full bibliography at the end.
Borrelia: 15 Ways It Can Affect the Brain and Its Supporting Cells
Crossing the Brain Vascular Endothelial Barrier
B. burgdorferi traverses cultured human brain microvascular endothelial layers, providing an experimental route from blood into CNS compartments. The exact route and its relative importance in human infection remain incompletely resolved.
Experimental. [L1] PubMed (opens in new tab)
Using Host Proteases to Facilitate Tissue Penetration
Spirochete-associated plasmin and host matrix metalloproteinase activity can facilitate traversal of experimental endothelial barriers. This connects bacterial dissemination to degradation or remodeling of extracellular structures surrounding brain vessels.
Experimental. [L1] PMC (opens in new tab)
Triggering Endothelial Calcium Signaling During Barrier Traversal
In human brain endothelial models, intracellular calcium signaling participates in Borrelia passage; interference with this signaling reduces traversal. Entry therefore involves host-cell responses as well as bacterial motility.
Experimental. [L2] PubMed (opens in new tab)
Activating Microglial TLR2 Signaling
Microglia recognize borrelial components through innate immune receptors, with TLR2 playing a prominent role. TLR2 inhibition reduces Borrelia-induced IL-6, CXCL8, CCL2, and TNF production in primary rhesus microglia.
Experimental. [L3] PubMed (opens in new tab)
Amplifying Inflammatory Transcription in Microglia
Exposure activates inflammatory programs involving NF-κB and other pathways. Transcriptomic experiments also identified changes involving TREM1, a potential amplifier of myeloid inflammation. These are cellular findings, not established patient-specific biomarkers.
Experimental. [L4] PLoS Pathogens (opens in new tab)
Making Microglia Release Inflammatory Cytokines
Borrelia-exposed microglia release IL-6 and other inflammatory mediators. This changes the extracellular environment experienced by nearby neurons and glia, even when those neighboring cells are not themselves infected.
Experimental. [L3, L4] PubMed (opens in new tab)
Recruiting Additional Inflammatory Cells Through Chemokines
Microglial production of CCL2, CCL3, CCL4, CCL5, and CXCL8 provides signals capable of attracting and organizing inflammatory-cell responses. This can amplify inflammation beyond the initial site of organism contact.
Experimental. [L4] PLoS Pathogens (opens in new tab)
Activating Astrocytes
In rhesus brain tissue and experimental inoculation models, astrocytes produce IL-6 after Borrelia exposure. Astrocytes therefore participate in the inflammatory response alongside microglia. Direct proof of consequent human synaptic or metabolic dysfunction is more limited.
Experimental. [L5] American Journal of Pathology (opens in new tab)
Producing Neuronal Injury Through a Microglial Bystander Effect
In a coculture model, Borrelia alone did not induce substantial apoptosis in SH-SY5Y neuronal cells; combining Borrelia with microglia did. The experiment supports injury mediated by the inflammatory environment rather than requiring direct bacterial killing of neurons.
Experimental. [L4] PLoS Pathogens (opens in new tab)
Inducing Oligodendrocyte Apoptosis
Borrelia exposure produced apoptosis of oligodendrocytes—the CNS cells responsible for myelin—in brain tissue preparations and experimental primate models. This establishes potential injury to myelin-supporting cells; it does not establish widespread demyelination in every patient with neuroborreliosis.
Experimental. [L5] PMC (opens in new tab)
Driving CXCL13-Mediated B-Cell Recruitment
Borrelia-associated CNS inflammation includes production of CXCL13, which recruits CXCR5-expressing B cells. This helps explain the prominent B-cell component of the neuroborreliosis inflammatory response.
Human and experimental evidence. [L6] PubMed (opens in new tab)
Supporting Local Antibody Production Within CNS Compartments
B-cell and plasma-cell recruitment supports intrathecal immunoglobulin production. This is an immune response to infection; detecting intrathecal antibody does not by itself establish antibody-mediated neuronal injury or continuing viable infection.
Human and experimental evidence. [L6] PubMed (opens in new tab)
Amplifying Inflammation Through Substance P–NK1 Receptor Signaling
In experimental neuroborreliosis preparations, an NK1 receptor antagonist reduced inflammatory mediator production and apoptosis. This implicates neuropeptide signaling as an amplifier of injury. It does not establish clinical efficacy of NK1 blockade.
Experimental. [L7] Springer (opens in new tab)
Inflaming Meninges and Perivascular Tissues
Experimental primate infection produces leptomeningitis and inflammatory infiltrates around CNS vessels. These inflammatory compartments can affect neurologic function without requiring diffuse infection of neurons throughout the brain.
Experimental pathology, consistent with clinical neuroborreliosis. [L8] PubMed (opens in new tab)
Producing Vascular and Focal Parenchymal Inflammation
Primate experiments demonstrate CNS vasculitis and focal inflammation. Vessel inflammation provides a mechanism for impaired local perfusion, while focal parenchymal inflammation can damage nearby neural tissue. The frequency and distribution in humans differ from experimentally inoculated animals.
Experimental. [L8] PMC (opens in new tab)
Bartonella: 15 Cellular and Vascular Pathways Relevant to the Brain
The strongest mechanistic work concerns B. henselae. Several endothelial mechanisms were established in nonbrain endothelial cultures; their application to human cerebral vessels requires further confirmation.
Invading Endothelial Cells
Bartonella can manipulate the endothelial actin cytoskeleton and enter cells through aggregate-associated structures called invasomes. Endothelial tropism provides a potential route to injury of the vascular compartment supplying the brain.
Experimental; cerebral application partly proposed. [T1] PubMed (opens in new tab)
Activating Endothelial NF-κB
B. henselae activates NF-κB-dependent inflammatory responses in endothelial cultures, changing the cells from relatively quiescent vessel lining to an inflammatory interface.
Experimental; not specifically established throughout human brain vasculature. [T1] PubMed (opens in new tab)
Increasing Endothelial Adhesion Molecules and Chemokine Secretion
These responses facilitate leukocyte attachment and inflammatory recruitment. They provide a plausible link between endothelial infection and perivascular inflammation.
Experimental; brain-specific consequences proposed. [T1] PubMed (opens in new tab)
Suppressing Apoptosis of Infected Endothelial Cells
The secreted effector BepA increases intracellular cAMP and protects endothelial cells from apoptosis. This may help preserve an infected cellular niche and prolong abnormal endothelial signaling rather than immediately destroying the infected cell.
Experimental. [T2] PubMed (opens in new tab)
Directly Invading Human Brain Vascular Pericytes
B. henselae enters cultured human brain vascular pericytes. These cells sit adjacent to capillary endothelial cells and help maintain the neurovascular unit.
Experimental in human-derived cells. [T3] PubMed (opens in new tab)
Reducing Proliferation of Infected Brain Pericytes
The same experiments found decreased pericyte proliferation. Impaired renewal could compromise vascular support, although actual pericyte loss and barrier failure in infected human brains were not demonstrated by this study.
Experimental; downstream consequence proposed. [T3] Duke Scholars (opens in new tab)
Increasing VEGF Production by Brain Pericytes
Infected human brain pericytes produced more VEGF. This demonstrates altered signaling between cells of the neurovascular unit. Whether the resulting effect is reparative, angiogenic, or permeability-promoting depends on context and remains unresolved in human neurobartonellosis.
Experimental. [T3] PubMed (opens in new tab)
Directly Stimulating VEGF-Receptor Signaling Through BafA
Bartonella’s angiogenic factor BafA activates the host VEGF pathway and promotes endothelial proliferation. This establishes a bacterial mechanism for vascular remodeling; its contribution to cerebral symptoms is not yet established.
Experimental. [T4] Nature Communications (opens in new tab)
Infecting Microglial Cells
B. henselae infects fetal feline brain cultures, including microglia-enriched cultures, with viable intracellular organisms recovered after infection. This supports possible glial involvement but does not establish the same infection pattern in adult human microglia.
Experimental, feline cells. [T5] PubMed (opens in new tab)
Avoiding Normal Intracellular Degradative Trafficking
Bartonella-containing vacuoles in macrophages and endothelial cells initially fail to acidify or fuse normally with lysosomes. This supports intracellular survival. Infected-cell transport into the brain is a hypothesis rather than a demonstrated human route.
Experimental mechanism; CNS transport proposed. [T6] PubMed (opens in new tab)
Being Associated With Cerebral Vasculitis
Human cases describe cerebral vessel-wall abnormalities and vasculitic presentations associated with B. henselae infection. The relative roles of direct vessel infection and immune-mediated injury remain uncertain.
Human case evidence. [T7] Neurology (opens in new tab)
Being Associated With Cerebral Infarction and Tissue Necrosis
A pediatric case documented brain pathology consistent with vasculitis, secondary infarction, and necrosis, alongside evidence of persistent B. henselae infection. It supports a vascular injury pathway, although one case cannot establish its general frequency or complete causality.
Human case evidence. [T8] PMC (opens in new tab)
Causing Embolic Stroke Through Infective Endocarditis
Bartonella-associated valvular infection can generate emboli that obstruct cerebral arteries. This is a cardiac-to-brain mechanism and does not require primary neuronal infection.
Human case evidence. [T9] PubMed (opens in new tab)
Causing Infectious Cerebral Aneurysms and Hemorrhage
Bartonella endocarditis has been associated with cerebral infectious aneurysms and intracranial hemorrhage. Infection-related arterial-wall weakening creates a mechanism distinct from simple embolic obstruction.
Human case evidence. [T10] PMC (opens in new tab)
Producing Encephalopathy Through Incompletely Defined Inflammatory Mechanisms
Cat-scratch disease can be followed by encephalopathy, seizures, and altered consciousness. An immune-mediated or systemic inflammatory mechanism is proposed in some cases; direct CNS infection and vascular mechanisms cannot always be separated.
Human syndrome; exact mechanism unresolved. [T11] PubMed (opens in new tab)
Babesia: 15 Pathways by Which Infection Can Impair the Brain
There are not 15 established direct neuronal or glial mechanisms for human babesiosis. The evidence supports several indirect routes, proposed inflammatory mechanisms, and species-specific vascular mechanisms demonstrated in cattle.
In a cohort of 163 hospitalized adults, 59.5% had at least one neurologic symptom or complication. This demonstrates a substantial neurologic burden in hospitalized disease, while leaving the underlying mechanisms unresolved. [B1] PMC (opens in new tab)
Hemolytic Anemia Reducing Cerebral Oxygen Delivery
Destruction and clearance of erythrocytes lower hemoglobin. Severe anemia can reduce oxygen delivery to the brain, particularly when respiratory or circulatory compensation is inadequate.
Human systemic complication; indirect brain mechanism. [B2] PubMed (opens in new tab)
Postinfectious Autoimmune Hemolysis Prolonging the Oxygen-Delivery Problem
Warm autoimmune hemolytic anemia can develop after parasitemia clears, especially in asplenic patients. Continuing anemia can sustain physiologic stress independently of current parasite burden. The study established hemolysis, not a specific cerebral lesion.
Human; indirect inference. [B3] PubMed (opens in new tab)
Respiratory Failure Producing Cerebral Hypoxemia
Severe babesiosis can cause acute respiratory failure or ARDS. Reduced arterial oxygenation can impair neuronal function and contribute to delirium or depressed consciousness.
Human systemic complication; indirect mechanism. [B2] PubMed (opens in new tab)
Shock Reducing Cerebral Perfusion
Severe infection may produce hypotension and shock. If cerebral perfusion falls below compensatory capacity, global brain dysfunction or ischemic injury can follow.
Human complication; indirect mechanism. [B4] PMC (opens in new tab)
Cardiac Dysfunction Compromising Cerebral Blood Flow
Heart failure, arrhythmias, and cardiac ischemia occur during babesiosis. When these compromise cardiac output or oxygenation, they can impair brain perfusion. Cardiac complications themselves are documented; cerebral consequences were not individually established in the cohort.
Human; indirect inference. [B5] PubMed (opens in new tab)
Renal Failure Contributing to Toxic-Metabolic Encephalopathy
Neurologic complications are associated with renal impairment in hospitalized babesiosis. Uremia and associated metabolic abnormalities provide plausible explanations, but association does not prove that renal failure caused each patient’s neurologic symptoms.
Human association; indirect mechanism. [B1] CDC (opens in new tab)
Severe Hepatic Dysfunction Contributing to Encephalopathy
A reported B. microti case involved acute liver failure and worsening encephalopathy. Impaired hepatic detoxification provides a route to brain dysfunction; direct parasite invasion of neurons was not demonstrated.
Human case; indirect mechanism. [B6] Karger Publishers (opens in new tab)
Acid–Base Disturbances Impairing Neural Function
Severe babesiosis with shock and renal failure can produce metabolic acidosis. Major changes in pH and the accompanying metabolic disturbances can contribute to altered consciousness.
Human systemic finding; indirect physiologic inference. [B4] PMC (opens in new tab)
DIC Potentially Impairing Cerebral Microcirculation Through Microthrombi
Disseminated intravascular coagulation occurs in severe babesiosis. Microvascular thrombosis provides a plausible ischemic mechanism, although cerebral microthrombi have not been established as a routine explanation for human babesiosis-associated encephalopathy.
Human DIC; cerebral mechanism proposed. [B2] PubMed (opens in new tab)
Coagulopathy Causing Intracranial Bleeding
A fatal B. microti case developed DIC, cerebellar hemorrhage, and coma. Here, structural brain injury provides a documented explanation for neurologic deterioration.
Human case evidence. [B7] Springer (opens in new tab)
Systemic Inflammatory Signaling Contributing to Encephalopathy
Excessive proinflammatory signaling is a proposed explanation for neurologic dysfunction, including cases without demonstrable cerebral parasite sequestration. The relevant cytokines and causal sequence have not been conclusively mapped in human brains.
Proposed. [B1, B7] CDC (opens in new tab)
Fever Increasing Metabolic Demand and Contributing to Delirium
Fever increases physiologic demand and can aggravate brain dysfunction when combined with anemia, hypoxemia, dehydration, or organ failure. This is a general infection-related pathway; its independent contribution in babesiosis has not been quantified.
Indirect physiologic inference. [B1, B2] PMC (opens in new tab)
Cytoadherence of Infected Erythrocytes to Cerebral Endothelial Cells
B. bovis-infected bovine erythrocytes adhere to bovine brain capillary endothelial cells through parasite-induced surface structures. This is a demonstrated cellular mechanism in bovine babesiosis, not an established equivalent in human B. microti infection.
Experimental, species-specific. [B8] Infection and Immunity (opens in new tab)
Sequestration of Infected Erythrocytes in Cerebral Capillaries
In cerebral B. bovis disease, retained infected erythrocytes can compromise microvascular circulation. Human B. microti pathology has also documented severe disease without sequestration; the bovine mechanism cannot be generalized across Babesia species.
Animal mechanism; human applicability unresolved. [B7, B8] Springer (opens in new tab)
Increasing Erythrocyte Rigidity and Impairing Passage Through Small Vessels
B. bovis infection makes bovine erythrocytes more rigid and adhesive under flow. However, a mouse B. microti study found no significant change in membrane deformability. This is an important species distinction when proposing cerebral perfusion mechanisms.
Experimental, species-specific. [B9, B10] PubMed (opens in new tab)
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
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.1460-0691.2009.02869.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 (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. doi:10.1136/bcr-2018-224647 (opens in new tab). Indexed author record (opens in new tab).
B5. Cardiac complications of human babesiosis. Clinical Infectious Diseases. 2023;76(3):e1385–e1391. doi:10.1093/cid/ciac525 (opens in new tab). Indexed author record (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).