Phosphodiesterase 4 Inhibition Reduces Innate Immunity and Improves Isoniazid Clearance of Mycobacterium tuberculosis in the Lungs of Infected Mice

Ahidjo

Antimicrob Agents Chemother

et al. 2015

cWith phosphodiesterase inhibitors (PDE-Is) showing significant promise in shortening tuberculosis treatment, we assessed the effect of roflumilast, an FDA-approved type 4 PDE-I, in both acute and chronic murine models of tuberculosis. Alone, roflumilast had no effect on lung bacillary burden and mortality. However, when roflumilast was used in combination with isoniazid, a reduction in lung bacillary burden was observed. These data suggest that roflumilast may be a good candidate for tuberculosis host-directed therapy (HDT). The treatment of tuberculosis (TB) still takes at least 6 months of multidrug therapy, and adjunctive host-directed therapies (HDTs) have the potential to shorten its duration and prevent drug resistance (1). We have previously shown that type 3 and 5 phosphodiesterase inhibitors (PDE-Is) (cilostazol and sildenafil, respectively) are beneficial in shortening TB first-line standard treatment (2). While type 4 PDE-I (PDE4-I) therapies have been hampered by adverse-effect profiles, two have been approved by the Food and Drug Administration (FDA) since 2011 and others are in development (3). PDE4-Is have recently been studied as adjunctive therapies for TB (1,4). Although the synergism of the PDE4-I CC-3052 with isoniazid (INH) has been reported (5), our group found that, when used as part of a complete tuberculosis multidrug regimen, the PDE4-I rolipram was detrimental to bacterial clearance (6). Since PDE4 has four subtypes (PDE4A to -D), with at least 25 splice variants (7), these contradictory observations may be due to action on different PDE isoforms and the different isoform tissue distributions (7). Additionally, off-target effects or effects on the pharmacokinetics of anti-TB drugs cannot be ruled out.At the start of this study, the only PDE4-I approved by the FDA was roflumilast (trade names, Daxas and Daliresp) (8). Roflumilast is indicated for the management of severe chronic obstructive pulmonary disease (COPD). This agent induces accumulation of host cyclic AMP (cAMP) in lung cells, blocks neutrophil recruitment, and reduces inflammatory cytokines such as tumor necrosis factor alpha (TNF-␣), all of which delay the progression of lung pathology in COPD. To determine whether these anti-inflammatory, tissue-protective effects of roflumilast might also be useful in the management of TB, we assessed the effect of roflumilast as an adjunctive, host-directed therapy on (i) the survival of Mycobacterium tuberculosis-infected mice, (ii) lung cytokine levels during infection, and (iii) bacillary burden during monotherapy and combination therapy with isoniazid.Six-week-old female BALB/c mice were aerosol infected with a high dose of M. tuberculosis H37Rv (4.06 Ϯ 0.20 log 10 CFU). Daily oral gavage (5 days per week) of each group of 20 mice was started the day following infection with roflumilast at the anti-inflammatory dose of 5 mg/kg of body weight/day (9) or isoniazid at 25 mg/kg/day (10) or sham treatment (water). As expected, isoniazid significantly prolonged mouse survival time (P Ͻ 0....

supporting

confidence: 92%

mentioning

confidence: 99%

Roflumilast, a Type 4 Phosphodiesterase Inhibitor, Shows Promising Adjunctive, Host-Directed Therapeutic Activity in a Mouse Model of Tuberculosis

Ahidjo

Antimicrob Agents Chemother

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

“…Histologic sections were stained with H&E or Ziehl-Neelsen (ZN) acid-fast stain for evaluation of pathology and mycobacterial load, respectively, as previously described (80). Briefly, photographs of the H&E-and ZN-stained sections were taken and analyzed using Nikon FX-35DX.…”

Section: Methodsmentioning

confidence: 99%

Macrophage migration inhibitory factor (MIF) is a critical mediator of the innate immune response to Mycobacterium tuberculosis

Das

Koo²,

Kim

et al. 2013

Self Cite

109

112

Significance Failure of the host immune system to control infection with Mycobacterium tuberculosis is a major determinant of tuberculosis (TB) disease. In this work, we examined the role of macrophage migration inhibitory factor (MIF), a cytokine that is encoded in a functionally polymorphic locus in humans, in TB. We found genetic low expressers of MIF to be enriched in a population of patients with HIV and disseminated TB. From our work in cellular and mouse models, we propose a key mechanism by which MIF regulates bacterial recognition as the first step in triggering inflammatory pathways to enable mycobacterial control.

The American Journal of Pathology

“…The dose of CC-3052 used was previously established in mice and is comparable to the half maximal inhibitory concentration in this animal model. 26 Treatment with CC-3052 started at 4 weeks after infection and continued until 12 weeks after infection.…”

Section: Rabbit Treatment Regimensmentioning

confidence: 99%

Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

Subbian¹,

Tsenova

O'Brien

et al. 2011

Self Cite

Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-␣ and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading infectious disease causes of morbidity and mortality worldwide. Although current multidrug regimens are generally effective, treatment is lengthy, requiring a minimum of 6 months and sometimes more than 1 year, for patients with drug-resistant TB or other clinical complications.1 Even after successful microbiological cure, pulmonary TB patients are often left with residual lung damage.2-5 Pulmonary impairment after TB treatment has been observed as changes in the structure and function of bronchial parenchymal tissue and the persistence of fibrocavitary lung damage.6,7 The risk and the extent of chronic respiratory dysfunction in individuals after curative therapy have been shown to increase with the number of previous TB episodes. 8 Most importantly, one recent study in South Africa found a fourfold higher risk of TB due to reinfection in previously treated patients compared with incidence rates among new TB cases.