title: Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs.
abstract: Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, the Public Health Research Institute (PHRI) at the University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, New Jersey, United States of America.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Subbian
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.forename: Guibin
authors.initials: G
authors.lastname: Yang
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Koo
authors.forename: Blas
authors.initials: B
authors.lastname: Peixoto
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fallows
authors.forename: Veronique
authors.initials: V
authors.lastname: Dartois
authors.forename: George
authors.initials: G
authors.lastname: Muller
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use; D058491:Bacterial Load; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D005260:Female; D005786:Gene Expression Regulation; D007538:Isoniazid / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D011817:Rabbits; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000995:Antitubercular Agents; C115112:CC 3052; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007538:Isoniazid