Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.
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 ther...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-02-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3045423?pdf=render |
| _version_ | 1819074570717495296 |
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| author | Mi-Sun Koo Claudia Manca Guibin Yang Paul O'Brien Nackmoon Sung Liana Tsenova Selvakumar Subbian Dorothy Fallows George Muller Sabine Ehrt Gilla Kaplan |
| author_facet | Mi-Sun Koo Claudia Manca Guibin Yang Paul O'Brien Nackmoon Sung Liana Tsenova Selvakumar Subbian Dorothy Fallows George Muller Sabine Ehrt Gilla Kaplan |
| author_sort | Mi-Sun Koo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T18:11:37Z |
| format | Article |
| id | doaj.art-49017a7a8e43430887beb0a442abe81d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T18:11:37Z |
| publishDate | 2011-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-49017a7a8e43430887beb0a442abe81d2022-12-21T18:54:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-02-0162e1709110.1371/journal.pone.0017091Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice.Mi-Sun KooClaudia MancaGuibin YangPaul O'BrienNackmoon SungLiana TsenovaSelvakumar SubbianDorothy FallowsGeorge MullerSabine EhrtGilla KaplanTuberculosis (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.http://europepmc.org/articles/PMC3045423?pdf=render |
| spellingShingle | Mi-Sun Koo Claudia Manca Guibin Yang Paul O'Brien Nackmoon Sung Liana Tsenova Selvakumar Subbian Dorothy Fallows George Muller Sabine Ehrt Gilla Kaplan Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. PLoS ONE |
| title | Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. |
| title_full | Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. |
| title_fullStr | Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. |
| title_full_unstemmed | Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. |
| title_short | Phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of Mycobacterium tuberculosis in the lungs of infected mice. |
| title_sort | phosphodiesterase 4 inhibition reduces innate immunity and improves isoniazid clearance of mycobacterium tuberculosis in the lungs of infected mice |
| url | http://europepmc.org/articles/PMC3045423?pdf=render |
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