Bacterial meningitis is still a common disease worldwide. Despite the introduction of antibiotics, the morbidity and mortality rates have not improved in more than 30 years. We will examine two specific aspects of the pathogenesis and pathophysiology of bacterial meningitis by in vitro and experimental rat meningitis in vivo techniques in an attempt to improve the results of treatment and prevention. Both areas of investigation are discrete and intimately related to the interaction of meningeal pathogens and the blood-brain barrier (BBB). The precise effect(s) of meningitis on the morphology and transport characteristics of the BBB are unknown. We will quantitate the morphologic alterations of isolated rat cerebral capillaries (a major site of the BBB) induced after incubation with meningeal pathogens (E. coli, H influenzae, S. pneumoniae, S. agalactiae) in vitro. We will determine the influence of E. coli and H. influenzae capsule and lipopolysaccharide (LPS) on the morphology of cerebral capillaries in vitro and correlate these results with changes in BBB permeability in rats with experimental meningitis by quantitative autoradiography. We will examine the effect of E. coli icubation on the transport of glucose and penicillin across the BBB in isolated cerebral microvessles and cannulated single cerebral arterioles in vitro. The route of invasion of the cerebrospinal fluid (CSF), and the reasons for neutropism of only a small group of bacterial species during bacteremia are unknown. We will examine bacterial affinity fo the central nervous system by studing adhesion of E. coli and H. influenzae to a major site of the BBB, infant and adult rat cerebral capillary endothelial cells in tissue culture. The E. coli and H. influenzae strains examined for adhesion to the endothelial cells will be identical to those used to study the influence of meningitis in BBB morphology and transport properties above. These strains wil be chosen from clinical isolates, mutants, and laboratory DNA tansformants of well-characterized phenotype to precisely define the role of encapsulation, amount of capsular polyribosephoshate expressed, and cell-surface lipopolysaccharide on adhesion to, and alterations produced in, the BBB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI017904-01A4
Application #
3127524
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1985-09-30
Project End
1988-08-31
Budget Start
1985-09-30
Budget End
1986-08-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Townsend, G C; Scheld, W M (1994) Platelet-activating factor augments meningeal inflammation elicited by Haemophilus influenzae lipooligosaccharide in an animal model of meningitis. Infect Immun 62:3739-44
Townsend, G C; Scheld, W M (1993) Adjunctive therapy for bacterial meningitis: rationale for use, current status, and prospects for the future. Clin Infect Dis 17 Suppl 2:S537-49
Tunkel, A R; Fisch, M J; Schlein, A et al. (1992) Enterobacter endocarditis. Scand J Infect Dis 24:233-40
Sable, C A; Scheld, W M (1992) Theoretical and practical considerations of antibiotic therapy for bacterial meningitis. Antibiot Chemother 45:96-117
Bryan, J P; Scheld, W M (1992) Therapy of experimental meningitis due to Salmonella enteritidis. Antimicrob Agents Chemother 36:949-54
Tunkel, A R; Wispelwey, B; Quagliarello, V J et al. (1992) Pathophysiology of blood-brain barrier alterations during experimental Haemophilus influenzae meningitis. J Infect Dis 165 Suppl 1:S119-20
Quagliarello, V J; Wispelwey, B; Long Jr, W J et al. (1991) Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor. J Clin Invest 87:1360-6
Tunkel, A R; Rosser, S W; Hansen, E J et al. (1991) Blood-brain barrier alterations in bacterial meningitis: development of an in vitro model and observations on the effects of lipopolysaccharide. In Vitro Cell Dev Biol 27A:113-20
Tunkel, A R; Scheld, W M (1991) Ofloxacin. Infect Control Hosp Epidemiol 12:549-57
Bryan, J P; de Silva, H R; Tavares, A et al. (1990) Etiology and mortality of bacterial meningitis in northeastern Brazil. Rev Infect Dis 12:128-35

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