Arthropod saliva in vector-borne disease transmission: Functional analysis of novel domains in salivary secretions

National Institute Of Allergy And Infectious Diseases

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Abstract

The main accomplishments of the Molecular Entomology Section is: 1. Identification of a novel anti-hemostatic activities isolated from the “river blindness” vector, Simulium guianense. Black flies, known also as “buffalo gnats”, are very small, robust flies that are annoying biting pests of humans and wildlife, and can also transmit parasites and viruses to their vertebrate hosts. Simulium guianense is the primary vector of Onchocerca volvulus in the Latin American endemic region on the border of Brazil and Venezuela. The salivary functions from this species remain largely understudied. We isolated a secreted molecule from female salivary gland of S. guianense, which we have named Guianensin. Guianensin belongs to the Kunitz inhibitor family and displays a broad anti-hemostatic and anti-inflammatory properties both in vitro and in vivo. We showed that Guianensin is a salivary anticoagulant that targets coagulation factor Xa (FXa). The lack of binding of Guianensin to FX and the catalytic-blocked FXa indicated that this inhibitor binds directly to the catalytic site of the protease. Guianensin was also active against other serine proteases involved in blood clotting and inflammatory immune responses, including neutrophil elastase, cathepsin G, and proteinase 3, α-chymotrypsin, β-tryptase, and trypsin. These proteases can trigger inflammatory responses in the vertebrate host, inducing the expression of chemokines, cytokines, cell surface receptors, and adhesion molecules. We also found that Guianensin has a strong anticomplement activity, directly inhibiting the lectin pathway (LP), by targeting MASP-2, a crucial enzyme for the LP activation. No inhibitory activity against other proteases in the complement pathways was found. These pro-inflammatory and procoagulant processes can be detrimental to the acquisition of a blood meal by S. guianense. Consequently, the presence of Guianensin in the saliva of this species represents an evolutionary adaptation for blood feeding. Guianensin emerges as a novel compound with possible therapeutic application.