Calpain-Mediated Processing of Adenylate Cyclase Toxin Generates a Cytosolic Soluble Catalytically Active N-Terminal Domain

Bordetella pertussis, the whooping cough pathogen, secretes several virulence factors among which adenylate cyclase toxin (ACT) is essential for establishment of the disease in the respiratory tract. ACT weakens host defenses by suppressing important bactericidal activities of the phagocytic cells. Up to now, it was believed that cell intoxication by ACT was a consequence of the accumulation of abnormally high levels of cAMP, generated exclusively beneath the host plasma membrane by the toxin N-terminal catalytic adenylate cyclase (AC) domain, upon its direct translocation across the lipid bilayer. Here we show that host calpain, a calcium-dependent Cys-protease, is activated into the phagocytes by a toxin-triggered calcium rise, resulting in the proteolytic cleavage of the toxin N-terminal domain that releases a catalytically active "soluble AC''. The calpain-mediated ACT processing allows trafficking of the "soluble AC'' domain into subcellular organella. At least two strategic advantages arise from this singular toxin cleavage, enhancing the specificity of action, and simultaneously preventing an indiscriminate activation of cAMP effectors throughout the cell. The present study provides novel insights into the toxin mechanism of action, as the calpain-mediated toxin processing would confer ACT the capacity for a space- and time-coordinated production of different cAMP "pools'', which would play different roles in the cell pathophysiology.

INTERPOL's surveillance network in curbing transnational terrorism

This paper investigates the role that INTERPOL surveillance – the Mobile INTERPOL Network Database (MIND) and the Fixed INTERPOL Network Database (FIND) – played in the War on Terror since its inception in 2005. MIND/FIND surveillance allows countries to screen people and documents systematically at border crossings against INTERPOL databases on terrorists, fugitives, and stolen and lost travel documents. Such documents have been used in the past by terrorists to transit borders. By applying methods developed in the treatment-effects literature, this paper establishes that countries adopting MIND/FIND experienced fewer transnational terrorist attacks than had they not adopted MIND/FIND. Our estimates indicate that, on average, during 2008–2011, adopting and using MIND/FIND results in 1.23 fewer transnational terrorist incidents each year per 100 million people. Thus, a country like France with a population just above 64 million people in 2008 would have 0.79 fewer transnational terrorist incidents per year owing to its use of INTERPOL surveillance. For most treatment countries, this amounts to a sizeable proportional reduction of about 60 per cent.