title: Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity inMycobacterium tuberculosisInfected C3HeB/FeJ Mice.
abstract: BALB/c and Swiss mice are routinely used to validate the effectiveness of tuberculosis drug regimens, although these mouse strains fail to develop human-like pulmonary granulomas exhibiting caseous necrosis. Microenvironmental conditions within human granulomas may negatively impact drug efficacy, and this may not be reflected in non-necrotizing lesions found within conventional mouse models. The C3HeB/FeJ mouse model has been increasingly utilized as it develops hypoxic, caseous necrotic granulomas which may more closely mimic the pathophysiological conditions found within human pulmonary granulomas. Here, we examined the treatment response of BALB/c and C3HeB/FeJ mice to bedaquiline (BDQ) and pyrazinamide (PZA) administered singly and in combination. BALB/c mice consistently displayed a highly uniform treatment response to both drugs, while C3HeB/FeJ mice displayed a bimodal response composed of responsive and less-responsive mice. Plasma pharmacokinetic analysis of dissected lesions from BALB/c and C3HeB/FeJ mice revealed that PZA penetrated lesion types from both mouse strains with similar efficiency. However, the pH of the necrotic caseum of C3HeB/FeJ granulomas was determined to be 7.5, which is in the range where PZA is essentially ineffective under standard laboratory in vitro growth conditions. BDQ preferentially accumulated within the highly cellular regions in the lungs of both mouse strains, although it was present at reduced but still biologically relevant concentrations within the central caseum when dosed at 25 mg/kg. The differential treatment response which resulted from the heterogeneous pulmonary pathology in the C3HeB/FeJ mouse model revealed several factors which may impact treatment efficacy, and could be further evaluated in clinical trials.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Irwin
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey , Newark, New Jersey 07103, United States.
authors.forename: Brendan
authors.initials: B
authors.lastname: Prideaux
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Lyon
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey , Newark, New Jersey 07103, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Zimmerman
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Brooks
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Schrupp
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey , Newark, New Jersey 07103, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine , Aurora, Colorado 80045, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Reichlen
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Bryce C
authors.initials: BC
authors.lastname: Asay
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine , Aurora, Colorado 80045, United States.
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.affiliation: Department of Infectious Diseases, Janssen Pharmaceutica , 2340 Beerse, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lyons
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey , Newark, New Jersey 07103, United States.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523, United States.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
keywords: C3HeB/FeJ; bedaquiline; mouse models; pyrazinamide; tuberculosis