Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

• CC-11050 is an anti-inflammatory molecule targeting host phosphodiesterase-4.
• CC-11050 plus isoniazid therapy significantly reduced bacillary load and pathology in a rabbit model pulmonary tuberculosis.
• CC-11050 can be a promising candidate for adjunctive host directed therapy of patients with active pulmonary tuberculosis.In 2013, tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) killed 1.5 million people worldwide. Current antibiotic therapy for tuberculosis is ineffective in eliminating the infecting bacilli and/or disease pathology such as lung fibrosis. Therefore, alternate approaches are urgently needed to control the TB epidemic. In this study, using a rabbit model of pulmonary TB, which closely mimics the human disease, we tested the hypothesis that reducing the host inflammatory response during Mtb infection would improve the outcome of antibiotic treatment; we show that adjunctive phosphodiesterase-4 inhibition therapy with isoniazid improves bacterial clearance and lung pathology.

ObjectivesAdjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection.MethodsA rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed.ResultsSignificant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits.ConclusionsAdjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment.