title: Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910.
abstract: The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. lenaerts@colostate.edu
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Donald
authors.initials: D
authors.lastname: Hoff
authors.forename: Sahar
authors.initials: S
authors.lastname: Aly
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehlers
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Luis
authors.initials: L
authors.lastname: Cantarero
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D005260:Female; D006099:Granuloma / Q000473:pathology; D006168:Guinea Pigs; D000860:Hypoxia / Q000473:pathology; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use; D008168:Lung / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles; D011718:Pyrazinamide / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents; D012293:Rifampin / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D064687:Diarylquinolines; D009593:Nitroimidazoles; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D011718:Pyrazinamide; C033815:pimonidazole; C493870:bedaquiline; D007538:Isoniazid; D012293:Rifampin