No abstract

Patients infected with the malaria parasite Plasmodium falciparum may develop a diffuse reversible encephalopathy, termed cerebral malaria. It is unclear how the intraerythrocytic parasite, which sequesters in the cerebral microvasculature but does not enter the brain parenchyma, induces this neurological syndrome. Adhesion of parasitized red blood cells in the brain microvasculature is mediated by specific receptors on the host endothelium, including intercellular adhesion molecule (ICAM)-1, CD36 and CD31. Leucocyte binding to cerebral endothelial cells in culture induces intracellular signalling via ICAM-1. The hypothesis that parasitized red blood cells binding to receptors on cerebral endothelial cells causes changes in the integrity of the blood-brain barrier was tested. Immunohistochemistry was used to examine the blood-brain barrier in human cerebral malaria, with antibodies to macrophage and endothelial activation markers, intercellular junction proteins, and plasma proteins. The distribution of the cell junction proteins occludin, vinculin and ZO-1 were altered in cerebral malaria cases compared to controls. While fibrinogen was the only plasma protein detected in the perivascular space, there was widespread perivascular macrophage activation, suggesting that these cells had been exposed to plasma proteins. It was concluded that functional changes to the blood-brain barrier occur in cerebral malaria, possibly as a result of the binding of parasitized red blood cells to cerebral endothelial cells. These changes require further examination in vitro.

Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A casecontrol study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n ¼ 183) and TBM (n ¼ 175), and cord blood controls (n ¼ 389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR) ¼ 2.22, 95% confidence interval (CI): 1.23À3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR ¼ 3.26, 95% CI: 1.72À6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR ¼ 5.28, 95% CI: 2.20À12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR ¼ 1.93, 95% CI: 0.54À6.92; grade II, OR ¼ 3.32, 95% CI: 0.84À13.2; and grade III, OR ¼ 5.70, 95% CI: 1.81À18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.

CM appears to involve only subtle functional changes in BBB integrity with minimal intraparenchymal inflammatory responses compared with other neurologic infections. This focuses attention on local events within and around the cerebral microvasculature in CM, rather than indicating widespread parenchymal disease.