Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

PLoS Pathogens

Paul O'Brien¹  Gilla Kaplan²  Liana Tsenova³  Mi-Sun Koo³  Guibin Yang³  Blas Peixoto³  Dorothy Fallows³  Selvakumar Subbian³  Veronique Dartois³  George Muller⁴ 

[1] Biological Sciences Department, New York City College of Technology, Brooklyn, New York, United States of America;Celgene Corporation, Summit, New Jersey, United States of America;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;Novartis Institute for Tropical Diseases, Singapore

关键词: Mycobacterium tuberculosis;    Rabbits;    Gene expression;    Immune response;    Macrophages;    Respiratory infections;    Tuberculosis;    Granulomas;   

DOI  :  10.1371/journal.ppat.1002262

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY