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Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.

TitlePhosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.
Publication TypeJournal Article
Year of Publication2011
AuthorsKoo M-S, Manca C, Yang G, O'Brien P, Sung N, Tsenova L, Subbian S, Fallows D, Muller G, Ehrt S, Kaplan G
JournalPLoS One
Volume6
Issue2
Paginatione17091
Date Published2011 Feb 25
ISSN1932-6203
KeywordsAnimals, Antibiotics, Antitubercular, Bacterial Load, Cyclic Nucleotide Phosphodiesterases, Type 4, Disease Models, Animal, Down-Regulation, Drug Evaluation, Preclinical, Drug Interactions, Immunity, Innate, Isoniazid, Lung, Metabolic Clearance Rate, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Mycobacterium tuberculosis, Phosphodiesterase 4 Inhibitors, Thalidomide, Tuberculosis
Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome.

DOI10.1371/journal.pone.0017091
Alternate JournalPLoS One
PubMed ID21364878
PubMed Central IDPMC3045423
Grant ListR01 AI054338 / AI / NIAID NIH HHS / United States

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