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.
Using a rabbit model of tuberculous meningitis, we evaluated the protective efficacy of vaccination with the recombinant polyprotein Mtb72F, which is formulated in two alternative adjuvants, AS02A and AS01B, and compared this to vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) alone or as a BCG prime/Mtb72F-boost regimen. Vaccination with Mtb72F formulated in AS02A (Mtb72F؉AS02A) or Mtb72F formulated in AS01B (Mtb72F؉AS01B) was protective against central nervous system (CNS) challenge with Mycobacterium tuberculosis H37Rv to an extent comparable to that of vaccination with BCG. Similar accelerated clearances of bacilli from the cerebrospinal fluid, reduced leukocytosis, and less pathology of the brain and lungs were noted. Weight loss of infected rabbits was less extensive for Mtb72F؉AS02A-vaccinated rabbits. In addition, protection against M. tuberculosis H37Rv CNS infection afforded by BCG/Mtb72F in a prime-boost strategy was similar to that by BCG alone. Interestingly, Mtb72F؉AS01B induced better protection against leukocytosis and weight loss, suggesting that the polyprotein in this adjuvant may boost immunity without exacerbating inflammation in previously BCG-vaccinated individuals.The development of improved tuberculosis (TB) vaccines has been recognized as a major public health priority by the World Health Organization. At present, the attenuated strain of Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only vaccine that is widely used against TB (7, 17). The BCG vaccine is relatively effective against the progression of infection to disseminated TB and tuberculous meningitis (TBM) in children (38). It has limited efficacy, however, against pulmonary TB in adults (16,35,48). An improved vaccine that protects both children against TBM and adults against pulmonary TB disease would be very useful in combating TB. Consequently, a number of research groups are engaged in developing more effective anti-TB vaccines by utilizing either new attenuated live vaccines (4,12,20,22,39,40,47,49) or subunit protein vaccines (3,6,11,26,34,37,41). While attenuated live vaccines provide prolonged exposure of the host immune system to newly synthesized antigens, the advantage of subunit vaccines is the possibility that their efficacy may not be compromised by exposure to environmental mycobacteria (5) or by prior BCG vaccination (8).To adequately predict the efficacy of any new anti-TB vaccine in humans, it is imperative to develop assays for measuring the level of protection that the vaccines provide. Animal models of infection are useful tools for this purpose. In our previous studies, we established and characterized a rabbit model of TBM which mirrors human central nervous system (CNS) disease (45). In this model, mycobacteria are inoculated directly into the cisterna magna of rabbits and the course of infection and the host response are monitored. We are using this animal model of CNS infection to evaluate the efficacy of new candidate vaccines for protecting the host against both infection...
Using a rabbit model of tuberculous meningitis (TBM), we compared the protective efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination against central nervous system infection with the virulent M. tuberculosis clinical isolate HN878 and the laboratory strain H37Rv. Although BCG clearly provided protection against infection with either challenge strain, protection against disease manifestations was significantly poorer in rabbits infected with HN878. BCG was less efficient in protecting against HN878 dissemination to the liver and spleen and against HN878-induced inflammation, loss of body weight, lung and brain pathology, and signs of disease. We suggest that the efficacy of newly developed vaccines should be tested in animal models not only against challenge with M. tuberculosis H37Rv but also with different clinical isolates including the highly virulent strains of the W-Beijing family.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.