A neurotoxin that specifically targets Anopheles mosquitoes

Abstract

Clostridial neurotoxins, including tetanus and botulinum neurotoxins, generally target vertebrates. We show here that this family of toxins has a much broader host spectrum, by identifying PMP1, a clostridial-like neurotoxin that selectively targets anopheline mosquitoes. Isolation of PMP1 from Paraclostridium bifermentans strains collected in anopheline endemic areas on two continents indicates it is widely distributed. The toxin likely evolved from an ancestral form that targets the nervous system of similar organisms, using a common mechanism that disrupts SNARE-mediated exocytosis. It cleaves the mosquito syntaxin and employs a unique receptor recognition strategy. Our research has an important impact on the study of the evolution of clostridial neurotoxins and provides the basis for the use of P. bifermentans strains and PMP1 as innovative, environmentally friendly approaches to reduce malaria through anopheline control.

Tables of Toxicity of Botulinum and Tetanus Neurotoxins

“…The extremely high potency of clostridial neurotoxins is due to the unique combination of two factors: (a) the very rapid binding to neurons, whose integrity is essential for survival, and (b) their enzymatic activity highly specific for the three SNARE proteins, whose cleavage is sufficient to block neurotransmitter release with ensuing neuroparalysis [2,3]. This is evident for vertebrates, but it is also true for invertebrates-particularly for flying insects, as shown by the very recent discovery of a BoNT-like neurotoxin specific for Anopheles mosquitos [92].…”

Looking for the X Factor in Bacterial Pathogenesis: Association of orfX-p47 Gene Clusters with Toxin Genes in Clostridial and Non-Clostridial Bacterial Species

“…Although the mode of action of OrfX proteins is unknown, recent work in Paraclostridium bifermentans subsp. malaysia showed that the co-expression of OrfX proteins may increase the oral toxicity of the mosquitocidal toxin PMP1 [23]. The relatively high degree of conservation among OrfX and P47 (Figure 3 and Tables S1-S5) as opposed to the diversity of associated toxins (in terms of size, structure, mode of action) suggests that the OrfX and P47 proteins indirectly assist in toxin production, release, or trafficking.…”

“…This subcomplex is involved in the formation of tripartite ABC toxin of P. luminescens which is a well-studied example of RHS-repeat containing polymorphic toxin targeting insect larvae [52,53]. Recent studies showed that BoNT-like proteins can exhibit insecticidal potential [23], therefore the presence of bna next to the genes putatively encoding anti-insect toxin components did not appear coincidental. Accordingly, we discuss below whether incorporation of BNA into an ABC toxin complex can be rationalized.…”

Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

“…Recent studies of clinical isolates also revealed a new mosaic toxin known as BoNT/H or BoNT/FA, with an LC most similar to a subtype of BoNT/F (BoNT/F5) and an H C similar to BoNT/A1-H C [11][12][13]. Most recently, a few BoNT-like toxins have been reported and characterized, including BoNT/X in a Clostridium botulinum strain [14], BoNT/En in an Enterococcus faecium strain [15], and Paraclostridial Mosquitocidal Protein 1 (PMP1) in Paraclostridium bifermentans strains [16].…”