Vascular and Leukocyte-Mediated Access in Bacterial Neurological Disease: A Lesion-Topology Framework for Phenotypic Divergence

Abstract

Abstract Background Rickettsia rickettsii/conorii is an endotheliotropic bacterium with a demonstrated capacity to activate human vascular endothelium via NF-κB-dependent pathways, a mechanism also reported, with more limited evidence, in Treponema pallidum [1-4]; Ehrlichia chaffeensis and Anaplasma phagocytophilum instead gain access to the central nervous system predominantly through leukocyte-mediated transendothelial migration of infected monocytes or neutrophils [5]. All four have published cases of central-nervous-system involvement, but their predominant clinical phenotypes, and their status as autoimmune-cycle candidates versus structural/infectious mimics, diverge sharply: acute vasculitic encephalopathy without a demonstrated autoimmune cycle in rickettsiosis; an ischemic-occlusive picture with direct structural damage and no autoimmune cycle in meningovascular neurosyphilis; and meningoencephalitis of variable severity in ehrlichiosis, rarer and more heterogeneous in anaplasmosis, where part of the reported neurological burden may reflect coinfection with tick-borne encephalitis virus rather than a bacterium-specific effect [6-7]. Bartonella henselae and Borrelia burgdorferi — the two endotheliotropic pathogens of this series with the most extensively documented diagnostic overlap with demyelinating disease — are each the subject of a dedicated case note [8-9] and are referenced here only as founding antecedents of this framework (Section 1), not re-derived. Hypothesis We propose that the anatomical and pathophysiological pattern of the vascular lesion —not merely its existence— biases, in a partially falsifiable way, which tissue antigen pools become accessible for uptake and presentation, and in which territory, tilting the resulting neurological phenotype. We further propose that this same lesion-topology axis separates pathogens for which vascular access plausibly initiates an autoimmune or post-infectious cycle from pathogens for which it produces direct structural damage without such a cycle, a distinction made explicit within the taxonomy itself rather than inferred afterward (Section 3.5). Five candidate archetypes are distinguished: occlusive/chronic ischemic, diffuse/acute small-vessel, focal/perineural-radicular, mixed/indeterminate, and leukocyte-mediated transendothelial —useful categories that are not mutually orthogonal, since each combines, unevenly, underlying dimensions such as hemodynamics, barrier integrity, distribution, caliber, territory, temporal course, and dominant mechanism (Section 3). This document does not replace the compartmental-access framework already established in [10]; it specializes that framework for endotheliotropic and leukocyte-trafficking infections in which vascular injury, vascular activation, or infected-leukocyte transmigration may shape neurological compartmental access, adding lesion topology, and its autoimmune-cycle-candidate status, as second-order causal variables. Conclusions The framework places four clinically and mechanistically relevant pathogens without an independent case note elsewhere in this series —Rickettsia, Treponema, Ehrlichia, and Anaplasma— within a single comparative structure, and proposes six prediction blocks, including an incremental-value falsification criterion that delimits when the framework should be considered refuted, distinguishing it from the anecdotal observation that "different bacteria produce different syndromes." As an exploratory extension, the framework also assesses which pathogens should be more or less permissive for the aluminum-laden CCR2+ monocyte second hit already proposed for Bartonella henselae [8], independent of the framework's vascular core (Section 5). Treponema pallidum is retained throughout as an explicit structural/infectious-mimic control: it shares the occlusive vascular-access route with autoimmune-cycle candidates elsewhere in this series, yet produces no demonstrated autoimmune cycle, illustrating that vascular access is not sufficient for autoimmune triggering.