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

Koo MS, Manca C, Yang G, O'Brien P, Sung N, Tsenova L, Subbian S, Fallows D, Muller G, Ehrt S, Kaplan G - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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Effect of CC-3052 on M. tuberculosis bacillary load in lungs during INH treatment.B6D2F1 mice were infected by low dose aerosol (100–200 cfu) with M. tuberculosis clinical isolates CDC1551 (A and C) or HN878 (B) [28]. CC-3052 treatment was initiated on day 1 (A and B) or day 14 (C) (arrow) after infection, and INH treatment was initiated at 14 days (A and B) or day 28 (C) post-infection (dotted line). Results are the mean CFU±SD of 2–6 independent experiments for CDC1551 (A); 2 experiments for HN878 (B) and 2 experiments for CDC1551 (C) (3–4 mice/group/experiment). Treatment groups: Untreated (open square); CC-3052 treated (filled square); INH treated (open triangle); CC-3052+INH treated (filled triangle). * Represents a statistical significant difference (P<0.05) between INH and CC-3052+INH treated mice.
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pone-0017091-g001: Effect of CC-3052 on M. tuberculosis bacillary load in lungs during INH treatment.B6D2F1 mice were infected by low dose aerosol (100–200 cfu) with M. tuberculosis clinical isolates CDC1551 (A and C) or HN878 (B) [28]. CC-3052 treatment was initiated on day 1 (A and B) or day 14 (C) (arrow) after infection, and INH treatment was initiated at 14 days (A and B) or day 28 (C) post-infection (dotted line). Results are the mean CFU±SD of 2–6 independent experiments for CDC1551 (A); 2 experiments for HN878 (B) and 2 experiments for CDC1551 (C) (3–4 mice/group/experiment). Treatment groups: Untreated (open square); CC-3052 treated (filled square); INH treated (open triangle); CC-3052+INH treated (filled triangle). * Represents a statistical significant difference (P<0.05) between INH and CC-3052+INH treated mice.

Mentions: For these studies, we selected two clinical strains of Mtb that differ in their abilities to induce an immune response in mice and in human monocytes [28]. Although the growth curves do not differ substantially in mice, CDC1551 promotes a strong, early Th1 response and is less virulent in mice, while HN878 is less immunogenic and highly virulent, causing earlier death of infected mice. Mice were infected by low dose aerosol infection with Mtb strain CDC1551 or HN878 and treated with CC-3052 from day 1 post-infection; bacillary growth, measured as colony forming units (CFU) in the lungs, was evaluated over time (Figure 1). The numbers of bacilli in the lungs of CDC1551-infected mice treated with CC-3052 were similar to those observed in untreated control infected mice, both of which stabilized by about 28 days post-infection (Figure 1A). Throughout the experiment (84 days), there were no significant differences in bacterial loads between CC-3052-treated and untreated mice (P = 0.882), suggesting that CC-3052 treatment of the mice did not accelerate the growth of Mtb in the lungs. INH treatment, initiated on day 14 post-infection, initially reduced the CFU efficiently in both experimental groups, but by 63 days post-infection, the bacterial loads in the lungs of mice treated with INH alone stabilized at about 2 log10. These results resemble the characteristic bi-phasic killing curve that was seen in early studies of INH killing in the mouse [29], [30]. In contrast, the CFU in the lungs of mice co-treated with INH plus CC-3052 continued to be cleared and at 84 days were significantly lower in numbers than those in mice treated with INH alone (P = 0.016). Plating of lung homogenates from all experimental groups on INH-containing solid medium yielded no colonies, indicating that the residual bacilli in the lungs resulted from antibiotic tolerance rather than acquired resistance to INH. CC-3052 treatment alone had no impact on the kinetics of Mtb growth in broth culture (not shown), demonstrating that the drug has no direct bactericidal/static effect. Mtb-infected mice treated with CC-3052 showed no significant reduction in body weight during the course of the experiment, as compared to untreated control mice (not shown). A similar pattern of bacillary clearance was observed in mice infected with Mtb strain HN878, indicating that the effects of CC-3052 are not Mtb strain-specific (Figure 1B). Shifting the timing of treatment also did not alter the ability of CC-3052 to impact bacillary clearance in the lungs. When CDC1551-infected mice were treated with CC-3052 and INH beginning on day 14 and day 28 post-infection, respectively, Mtb killing by INH alone did not slow until 84 days post-infection; the CFU numbers continued to decline in co-treated mice up until day 112 (Figure 1C).


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

Koo MS, Manca C, Yang G, O'Brien P, Sung N, Tsenova L, Subbian S, Fallows D, Muller G, Ehrt S, Kaplan G - PLoS ONE (2011)

Effect of CC-3052 on M. tuberculosis bacillary load in lungs during INH treatment.B6D2F1 mice were infected by low dose aerosol (100–200 cfu) with M. tuberculosis clinical isolates CDC1551 (A and C) or HN878 (B) [28]. CC-3052 treatment was initiated on day 1 (A and B) or day 14 (C) (arrow) after infection, and INH treatment was initiated at 14 days (A and B) or day 28 (C) post-infection (dotted line). Results are the mean CFU±SD of 2–6 independent experiments for CDC1551 (A); 2 experiments for HN878 (B) and 2 experiments for CDC1551 (C) (3–4 mice/group/experiment). Treatment groups: Untreated (open square); CC-3052 treated (filled square); INH treated (open triangle); CC-3052+INH treated (filled triangle). * Represents a statistical significant difference (P<0.05) between INH and CC-3052+INH treated mice.
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Related In: Results  -  Collection

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pone-0017091-g001: Effect of CC-3052 on M. tuberculosis bacillary load in lungs during INH treatment.B6D2F1 mice were infected by low dose aerosol (100–200 cfu) with M. tuberculosis clinical isolates CDC1551 (A and C) or HN878 (B) [28]. CC-3052 treatment was initiated on day 1 (A and B) or day 14 (C) (arrow) after infection, and INH treatment was initiated at 14 days (A and B) or day 28 (C) post-infection (dotted line). Results are the mean CFU±SD of 2–6 independent experiments for CDC1551 (A); 2 experiments for HN878 (B) and 2 experiments for CDC1551 (C) (3–4 mice/group/experiment). Treatment groups: Untreated (open square); CC-3052 treated (filled square); INH treated (open triangle); CC-3052+INH treated (filled triangle). * Represents a statistical significant difference (P<0.05) between INH and CC-3052+INH treated mice.
Mentions: For these studies, we selected two clinical strains of Mtb that differ in their abilities to induce an immune response in mice and in human monocytes [28]. Although the growth curves do not differ substantially in mice, CDC1551 promotes a strong, early Th1 response and is less virulent in mice, while HN878 is less immunogenic and highly virulent, causing earlier death of infected mice. Mice were infected by low dose aerosol infection with Mtb strain CDC1551 or HN878 and treated with CC-3052 from day 1 post-infection; bacillary growth, measured as colony forming units (CFU) in the lungs, was evaluated over time (Figure 1). The numbers of bacilli in the lungs of CDC1551-infected mice treated with CC-3052 were similar to those observed in untreated control infected mice, both of which stabilized by about 28 days post-infection (Figure 1A). Throughout the experiment (84 days), there were no significant differences in bacterial loads between CC-3052-treated and untreated mice (P = 0.882), suggesting that CC-3052 treatment of the mice did not accelerate the growth of Mtb in the lungs. INH treatment, initiated on day 14 post-infection, initially reduced the CFU efficiently in both experimental groups, but by 63 days post-infection, the bacterial loads in the lungs of mice treated with INH alone stabilized at about 2 log10. These results resemble the characteristic bi-phasic killing curve that was seen in early studies of INH killing in the mouse [29], [30]. In contrast, the CFU in the lungs of mice co-treated with INH plus CC-3052 continued to be cleared and at 84 days were significantly lower in numbers than those in mice treated with INH alone (P = 0.016). Plating of lung homogenates from all experimental groups on INH-containing solid medium yielded no colonies, indicating that the residual bacilli in the lungs resulted from antibiotic tolerance rather than acquired resistance to INH. CC-3052 treatment alone had no impact on the kinetics of Mtb growth in broth culture (not shown), demonstrating that the drug has no direct bactericidal/static effect. Mtb-infected mice treated with CC-3052 showed no significant reduction in body weight during the course of the experiment, as compared to untreated control mice (not shown). A similar pattern of bacillary clearance was observed in mice infected with Mtb strain HN878, indicating that the effects of CC-3052 are not Mtb strain-specific (Figure 1B). Shifting the timing of treatment also did not alter the ability of CC-3052 to impact bacillary clearance in the lungs. When CDC1551-infected mice were treated with CC-3052 and INH beginning on day 14 and day 28 post-infection, respectively, Mtb killing by INH alone did not slow until 84 days post-infection; the CFU numbers continued to decline in co-treated mice up until day 112 (Figure 1C).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus