title: Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.
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.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute Center at the University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Koo
authors.forename: Claudia
authors.initials: C
authors.lastname: Manca
authors.forename: Guibin
authors.initials: G
authors.lastname: Yang
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.forename: Nackmoon
authors.initials: N
authors.lastname: Sung
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Subbian
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fallows
authors.forename: George
authors.initials: G
authors.lastname: Muller
authors.forename: Sabine
authors.initials: S
authors.lastname: Ehrt
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics; D058491:Bacterial Load / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D007113:Immunity, Innate / Q000187:drug effects* / Q000502:physiology; D007538:Isoniazid / Q000493:pharmacokinetics*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000276:immunology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; C115112:CC 3052; D058988:Phosphodiesterase 4 Inhibitors; D013792:Thalidomide; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007538:Isoniazid