Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment

The EU Humanitarian Border and the Securitization of Human Rights:The “Rescue-through-Interdiction/Rescue-without-Protection” Paradigm

This article looks at securitization/humanitarianization dynamics in the EU external sea borders to track and critique the substantial transformation of the role played by human rights in the Mediterranean. Mapping the evolution of maritime engagement up to the ‘refugee crisis’, it is revealed how the invocation of human rights serves paradoxically to curtail (migrants') human rights, justifying interdiction (‘to save lives’), and impeding access to safety in Europe. The result is a double reification of ‘boat migrants’ as threats to border security and as victims of smuggling/trafficking. Through a narrative of ‘rescue’, interdiction is laundered into an ethically sustainable strategy of border governance. Instead of being considered a problematic (potentially lethal) means of control, it is re-defined into a life-saving device. The ensuing ‘rescue-through-interdiction’/‘rescue-without-protection’ paradigm alters the nature of human rights, which, rather than functioning as a check on interdiction, end up co-opted as another securitization/humanitarianization tool