Structure of Aedes aegypti procarboxypeptidase B1 and its binding with Dengue virus for controlling infection.

Metallocarboxypeptidases play critical roles in the development of mosquitoes and influence pathogen/parasite infection of the mosquito midgut. Here, we report the crystal structure of Aedes aegypti procarboxypeptidase B1 (PCPBAe1), characterized its substrate specificity and mechanism of binding to and inhibiting Dengue virus (DENV). We show that the activated PCPBAe1 (CPBAe1) hydrolyzes both Arg- and Lys-substrates, which is modulated by residues Asp251 and Ser239 Notably, these residues are conserved in CPBs across mosquito species, possibly required for efficient digestion of basic dietary residues that are necessary for mosquito reproduction and development. Importantly, we characterized the interaction between PCPBAe1 and DENV envelope (E) protein, virus-like particles, and infectious virions. We identified residues Asp18A, Glu19A, Glu85, Arg87, and Arg89 of PCPBAe1 are essential for interaction with DENV. PCPBAe1 maps to the dimeric interface of the E protein domains I/II (Lys64-Glu84, Val238-Val252, and Leu278-Leu287). Overall, our studies provide general insights into how the substrate-binding property of mosquito carboxypeptidases could be targeted to potentially control mosquito populations or proposes a mechanism by which PCPBAe1 binds to and inhibits DENV.

Absence of Annexin A1 impairs host adaptive immunity against Mycobacterium tuberculosis in vivo.

The role of Annexin A1 (ANXA1) in counter-regulating the activities of innate immune cells, such as the migration of neutrophils and monocytes, and the generation of pro-inflammatory mediators in various models of inflammatory and autoimmune diseases is well documented. However, while ANXA1 has been proposed as an important mediator of the adaptive immune response, its involvement in this respect has been less studied. Furthermore, while there have been numerous studies on the role of ANXA1 in inflammatory diseases, less has been reported on its influence in immunity against infection. A recent study reported a link between ANXA1 and tuberculosis, and proposed a model in which Mycobacterium tuberculosis exerts its virulence by manipulating the ANXA1-mediated host apoptotic response. This has prompted us to further investigate the role of ANXA1 in the pathogenesis of tuberculosis in vivo. Here, we show that ANXA1(-/-) mice are more susceptible to M. tuberculosis infection, as evidenced by a transient increase in the pulmonary bacterial burden, and exacerbated and disorganized granulomatous inflammation. These pathological manifestations correlated with an impaired ability of ANXA1(-/-) dendritic cells to activate naïve T cells, thereby supporting a role for ANXA1 in shaping the adaptive immunity against M. tuberculosis.