Proteases in Blood-Feeding Nematodes and Their Potential as Vaccine Candidates

Abstract

Parasitic nematodes express and secrete a variety of proteases which they use for many purposes including the penetration of host tissues, digestion of host protein for nutrients, evasion of host immune responses and for internal processes such as tissue catabolism and apoptosis. For these broad reasons they have been examined as possible parasite control targets. Blood-feeding nematodes such as the barber-pole worm Haemonchus contortus that infect sheep and goats and the hookworms, Ancylostoma spp. and Necator americanus, affecting man, use an array of endo- and exopeptidases to digest the blood meal. Haemoglobin digestion occurs by an ordered and partly conserved proteolytic cascade. These proteases are accessible to host immune responses which can block enzyme function and lead to parasite expulsion and/or death. Thus they are receiving attention as components of vaccines against several parasitic nematodes of social and economic importance.

The genome and developmental transcriptome of the strongylid nematode Haemonchus contortus

“…Most notable were 318 peptidases, including 98 metallopeptidases and 68 cysteine, 67 aspartic, 19 serine peptidases (predominantly clans MA, CA, AA, and SA, respectively) and 66 peptidase inhibitors (including fibronectin type III), 90 lectins (including C-type and concanavalin A-like), 65 sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) proteins, 38 transthyretin-like (TTL) proteins, and 27 kinases. Many secreted peptidases (comprising the 'degradome') and their respective inhibitors have known roles in the penetration of tissue barriers and feeding for a range of parasitic worms, including H. contortus [2,6,18]. Some of these ES proteins are involved in host interactions and/or inducing or modulating host immune responses against parasitic worms, which are often Th2-biased [19].…”

“…There has been a major emphasis on the development of vaccines to fight against haemonchosis [6]. Most effort has been directed at inducing immunity in sheep against proteins expressed in or excreted/secreted from the gut of H. contortus , with the aim of disrupting or inhibiting the parasite's digestion of host blood.…”

“…It is thus highly desirable to search for new drug targets encoded in the H. contortus genome. Although vaccines using some native parasite antigens (called H11 or H-gal-GP) can partially prevent haemonchosis in experimental sheep, homologous recombinant molecules have failed to achieve protection [6]. Therefore, current treatment relies predominantly on the use of nematocidal drugs (anthelmintics).…”

Proteases secreted by Gnathostoma binucleatum degrade fibronectin and antibodies from mammals

“…Likewise, the fact that proteolytic activity was observed at a slightly alkaline pH indicates that these proteases could be used by the parasite to cross such host tissues as skeletal muscle tissue, as suggested by the clinical manifestations caused by the migration of the parasite (Martínez et al, 1989;Ollague et al, 1984;Tudor & Blair, 1971). The bands with protease activity at 80 and 56 kDa are able to hydrolyze proteins from the extracellular matrix, suggesting that they could be involved in penetrating or migrating through tissues, as has been described for other helminthes (Berasain et al, 1997;Knox, 2011). The infective larvae of the nematode Ancylostoma caninum secrete proteases involved in migration through host tissues (Williamson et al, 2011); moreover, proteolytic activity by a protease against collagen and fibrinogen has been reported in the ESP of third-stage larvae of the nematode Lagochilascaris minor (Barbosa et al, 2006).…”

Cracking the nodule worm code advances knowledge of parasite biology and biotechnology to tackle major diseases of livestock

“…In addition, transcription of genes encoding 75 peptidase inhibitors (primarily aprotinin- and Bombyx subtilisin-like molecules) was assessed. Many secreted peptidases likely to represent the ‘degradome’ and respective inhibitors are known to enable parasitic worms to invade, penetrate tissue barriers and feed (Knox, 2011; McKerrow et al, 2006; Nikolaou and Gasser, 2006; Tang et al, 2014); some of them (e.g., ES-62 in Acanthocheilonema viteae ) have been reported to induce or modulate the host’s immune response against the parasite (Hewitson et al, 2008). …”