title: Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic glycolipid produced by the bacilli.
abstract: Infection with Mycobacterium tuberculosis in humans results in active disease in approximately 10% of immune-competent individuals, with the most-severe clinical manifestations observed when the bacilli infect the central nervous system (CNS). Here, we use a rabbit model of tuberculous meningitis to evaluate the severity of disease caused by the M. tuberculosis clinical isolates CDC1551, a highly immunogenic strain, and HN878 or W4, 2 members of the W/Beijing family of strains. Compared with infection with CDC1551, CNS infection with HN878 or W4 resulted in higher bacillary loads in the cerebrospinal fluid and brain, increased dissemination of bacilli to other organs, persistent levels of tumor necrosis factor-alpha , higher leukocytosis, and more-severe clinical manifestations. This pathogenic process is associated with the production by HN878 of a polyketide synthase-derived phenolic glycolipid (PGL), as demonstrated by reduced virulence in rabbits infected with an HN878 mutant disrupted in the pks1-15 gene, which is required for PGL synthesis.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute, Newark, New Jersey 07103, USA.
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Evette
authors.initials: E
authors.lastname: Ellison
authors.forename: Ryhor
authors.initials: R
authors.lastname: Harbacheuski
authors.forename: Andre L
authors.initials: AL
authors.lastname: Moreira
authors.forename: Natalia
authors.initials: N
authors.lastname: Kurepina
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reed
authors.forename: Barun
authors.initials: B
authors.lastname: Mathema
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000382:microbiology; D005838:Genotype; D006017:Glycolipids / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D011817:Rabbits; D013997:Time Factors; D014390:Tuberculosis, Meningeal / Q000382:microbiology* / Q000473:pathology; D014774:Virulence / Q000235:genetics
chemical_list: D006017:Glycolipids