Fig. 1

Mechanisms of gram-negative bacteria penetration to the central nervous system. ① The gram-negative bacteria-derived exotoxins provoke detachment of endothelial cells, and the gram-negative bacteria-induced inflammatory cytokines induce disruption of the tight junction at the blood-brain barrier (BBB). These impairments of BBB allow the gram-negative bacteria to pass through the brain in the paracellular pathway. ② The gram-negative bacteria-derived exotoxins directly influence endothelial necrosis. ③ The gram-negative bacteria are transported to the brain via vesicular transport of macromolecules, such as outer membrane protein A (OmPA), invasion of the brain endothelium protein A (IbeA), endothelial receptors beta-form of the heat-shock gp96 (Ecgp96), and contactin-associated protein 1 (CaspR1). ④ The cranial nerve can be a pathway for gram-negative bacteria to enter the brain without penetrating the BBB. CNS: Central nervous system; iNOS: Inducible nitric oxide synthase; PNS: peripheral nervous system