Trojan horse strategy and TfR/ LDLR-Mediated transcytosis determine the dissemination of mycobacteria in tuberculous meningoencephalitis

Abstract

Tuberculous meningoencephalitis (TBM), caused by the Mycobacterium tuberculosis complex, stands as one of the most lethal infections affecting the central nervous system (CNS). The understanding of the mechanisms underlying the neuroinvasion of Mycobacterium bovis (M. bovis) remains limited. Our findings reveal that M. bovis could exploit host transferrin receptor (TfR)- and low-density lipoprotein receptor (LDLR)-mediated transcytosis, while simultaneously utilizing infected macrophages as vectors to traverse the blood-brain barrier (BBB). Infected macrophages accelerate the M. bovis’ neuroinvasion and promote its proliferation and dissemination to various organs. Persistent infection disrupts BBB integrity by degrading tight junction proteins and upregulating intercellular cell adhesion molecule-1 (iCAM-1), facilitating macrophage adhesion and migration, which contribute to the pathogen’s entry into the brain. This study established a murine TBM model by administering M. bovis through carotid artery injection, accurately mimicking the interactions between the pathogen and the BBB. These findings offer insights into the mechanisms of TBM and serve as a foundation for developing targeted therapeutic strategies.