Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood–brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood–brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood–brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial–host interactions that are involved in microbial traversal of the blood–brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.

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Although Escherichia coli strains possessing the Kl capsule are predominant among isolates from neonatal E. coli meningitis and most of these Kl isolates are associated with a limited number of 0 lipopolysaccharide (LPS) types, the basis of this association of Kl and certain 0 antigens with neonatal E. coli meningitis is not clear. The present study examined in experimental E. coli bacteremia and meningitis in newborn and adult rats whether or not the Kl capsule and/or 0-LPS antigen are critical determinants in the development of meningitis. Rats received subcutaneously a Kl E. coli strain (018+K1+) or mutants lacking either the Kl capsule (018+K1-) or 0 side-chain (018-K1+). 12-24 h later, blood and cerebrospinal fluid (CSF) specimens were obtained for quantitative cultures. The isolation of E. coli from CSF was observed in both newborn and adult rats infected with K1+ strains regardless of LPS phenotype (018+ or 18-) who also developed a high degree of bacteremia (e.g., > 104 CFU/ml of blood). In contrast, none of the newborn and adult rats infected with 018+K1-and developing bacteremia of > 10' were found to have positive CSF cultures.These findings indicate that the presence of the Kl capsule and a high degree ofbacteremia are key determinants in the development of E. coli meningitis, suggesting that there may be specific binding sites present in the brain which have an affinity for the Kl capsule and thus may be responsible for the entry of Kl-encapsulated E. coli into the meninges. (J. Clin. Invest. 1992. 90:897-905.)

Infectious meningitis and encephalitis is caused by invasion of circulating pathogens into the brain. It is unknown how the circulating pathogens dynamically interact with brain endothelium under shear stress, leading to invasion into the brain. Here, using intravital microscopy, we have shown that Cryptococcus neoformans, a yeast pathogen that causes meningoencephalitis, stops suddenly in mouse brain capillaries of a similar or smaller diameter than the organism, in the same manner and with the same kinetics as polystyrene microspheres, without rolling and tethering to the endothelial surface. Trapping of the yeast pathogen in the mouse brain was not affected by viability or known virulence factors. After stopping in the brain, C. neoformans was seen to cross the capillary wall in real time. In contrast to trapping, viability, but not replication, was essential for the organism to cross the brain microvasculature. Using a knockout strain of C. neoformans, we demonstrated that transmigration into the mouse brain is urease dependent. To determine whether this could be amenable to therapy, we used the urease inhibitor flurofamide. Flurofamide ameliorated infection of the mouse brain by reducing transmigration into the brain. Together, these results suggest that C. neoformans is mechanically trapped in the brain capillary, which may not be amenable to pharmacotherapy, but actively transmigrates to the brain parenchyma with contributions from urease, suggesting that a therapeutic strategy aimed at inhibiting this enzyme could help prevent meningitis and encephalitis caused by C. neoformans infection.

In determining the mechanism of neutrophil elastase (NE)-mediated killing of Escherichia coli, we found that NE degraded outer membrane protein A (OmpA), localized on the surface of Gram-negative bacteria. NE killed wild-type, but not OmpA-deficient, E. coli. Also, whereas NE-deficient mice had impaired survival in response to E. coli sepsis, as compared to wild-type mice, the presence or absence of NE had no influence on survival in response to sepsis that had been induced with OmpA-deficient E. coli. These findings define a mechanism of nonoxidative bacterial killing by NE and point to OmpA as a bacterial target in host defense.

The relative frequency of complicated disease in hospitalized children with pneumococcal pneumonia is increasing. Patients with complicated pneumococcal disease were older and significantly more likely to be of white race compared with those patients with uncomplicated disease. Pneumococcal serotype 1 caused significantly more disease in patients with complicated versus uncomplicated pneumonia. Patients with complicated disease were not more likely to be infected with an antibiotic-resistant isolate.