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.
Highlights
Despite effective chemotherapy available for over 50 years, and development of a control strategy of directly observed therapy shortcourse (DOTS), tuberculosis (TB) remains the leading cause of adult mortality attributable to a single infectious disease [1]
In this study, using a rabbit model of pulmonary TB, we show that immune modulation of Mycobacterium tuberculosis (Mtb) infected animals with CC-3052, a phosphodiesterase-4 (PDE4) inhibitor that reduces tumor necrosis factor alpha (TNF-a) production by increasing intracellular cyclic AMP (cAMP) levels, resulted in the down-regulation of host genes involved in the innate immune response
Similar to results reported in several studies, after 4 weeks of INH treatment, we observed significant increases in the mRNA levels of the Mtb genes, katG, ahpC, inhA, kasA, iniB and efpA (Figure 8). [55,57,68]
Summary
Despite effective chemotherapy available for over 50 years, and development of a control strategy of directly observed therapy shortcourse (DOTS), tuberculosis (TB) remains the leading cause of adult mortality attributable to a single infectious disease [1]. M. tuberculosis (Mtb), the causative agent of TB, is an intracellular pathogen that is well adapted to survive in host phagocytes within lung granulomas in humans and experimentally infected animals [2,3,4]. The outcome of Mtb infection is largely determined by a delicate balance between the host immune response and bacterial evasion and/or subversion of this response, resulting in successful control of the infection or manifestations of active disease of different severity [5,6]. During growth arrest, not all the infecting bacilli are necessarily killed. Rather, they can adapt to survive in a viable latent state, serving as a reservoir for potential reactivation
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