Dataset Information

Cathepsin F of Teladorsagia circumcincta is a recently evolved cysteine protease.

ABSTRACT: Parasitic cysteine proteases are involved in parasite stage transition, invasion of host tissues, nutrient uptake, and immune evasion. The cysteine protease cathepsin F is the most abundant protein produced by fourth-stage larvae (L4) of the nematode Teladorsagia circumcincta, while its transcript is only detectable in L4 and adults. T. circumcincta cathepsin F is a recently evolved cysteine protease that does not fall clearly into either of the cathepsin L or F subfamilies. This protein exhibits characteristics of both cathepsins F and L, and its phylogenetic relationship to its closest homologs is distant, including proteins of closely related nematodes of the same subfamily.

SUBMITTER: Sloan S

PROVIDER: S-EPMC7549167 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cathepsin F of Teladorsagia circumcincta is a recently evolved cysteine protease.

Sloan Sarah S Jenvey Caitlin C Cairns Callum C Stear Michael M

Evolutionary bioinformatics online 20201010

Parasitic cysteine proteases are involved in parasite stage transition, invasion of host tissues, nutrient uptake, and immune evasion. The cysteine protease cathepsin F is the most abundant protein produced by fourth-stage larvae (L4) of the nematode Teladorsagia circumcincta, while its transcript is only detectable in L4 and adults. T. circumcincta cathepsin F is a recently evolved cysteine protease that does not fall clearly into either of the cathepsin L or F subfamilies. This p ...[more]

PMID: 33100828

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Project description:Monepantel (MPTL) is one of two new anthelmintic compounds introduced onto the sheep market to control gastro-intestinal nematodes. Resistance to this compound is rare but has been reported. In order to preserve the efficacy of this and other anthelmintics, it is essential to understand both (a) the mechanisms involved in the selection of resistance and (b) how the parasites evolve to deal with these compounds. To address these questions three MPTL-resistant Teladorsagia circumcincta isolates (MTci2-11, MTci5-13 and MTci7-12) have been artificially selected in vivo from phenotypically characterised parent isolates (MTci2, MTci5, MTci7 respectively). The selection process involved collecting and culturing eggs from surviving worms from sheep administered sub-optimal dosages of MPTL (Zolvix®) to provide infective larvae to infect further sheep until resistant isolates were generated (between 9 and 13 rounds of selection). A controlled efficacy test was conducted using the original parental isolates and the newly generated MPTL resistant isolates (n = 5 per group). Selected isolates were assessed both under anthelmintic stress (Zolvix®, 2.5 mg/kg bodyweight; MTci-MPTL) and at rest (untreated, MTci-CON). A number of life-history traits were assessed, namely, worm establishment rates, time to patency, faecal egg output, body length of adults and eggs in utero. The estimated resistance status of the selected isolates was confirmed with 48%, 28% and 9% reductions in worm burden at 7-days post Zolvix® administration for MTci2-11-MPTL, MTci5-13-MPTL and MTci7-12-MPTL, respectively, compared with untreated controls. One of the selected isolates MTci7-12-CON showed significantly greater total worm burden (p = 0.025), greater establishment rate (p = 0.033), decreased time to patency (p = 0.048), higher cumulative egg outputs (p = 0.002) compared with its parental derivative MTci7. The trial results suggest that anthelmintic selection in T. circumcincta, albeit under experimental conditions, can select for more prolific/fecund and quicker maturing populations. These data provide an insight into how parasites evolve in response to anthelmintic pressure.

Project description:BACKGROUND:The multifaceted interactions between gastrointestinal (GI) helminth parasites, host gut microbiota and immune system are emerging as a key area of research within the field of host-parasite relationships. In spite of the plethora of data available on the impact that GI helminths exert on the composition of the gut microflora, whether alterations of microbial profiles are caused by direct parasite-bacteria interactions or, indirectly, by alterations of the GI environment (e.g. mucosal immunity) remains to be determined. Furthermore, no data is thus far available on the downstream roles that qualitative and quantitative changes in gut microbial composition play in the overall pathophysiology of parasite infection and disease. RESULTS:In this study, we investigated the fluctuations in microbiota composition and local immune microenvironment of sheep vaccinated against, and experimentally infected with, the 'brown stomach worm' Teladorsagia circumcincta, a parasite of worldwide socio-economic significance. We compared the faecal microbial profiles of vaccinated and subsequently infected sheep with those obtained from groups of unvaccinated/infected and unvaccinated/uninfected animals. We show that alterations of gut microbial composition are associated mainly with parasite infection, and that this involves the expansion of populations of bacteria with known pro-inflammatory properties that may contribute to the immunopathology of helminth disease. Using novel quantitative approaches for the analysis of confocal microscopy-derived images, we also show that gastric tissue infiltration of T cells is driven by parasitic infection rather than anti-helminth vaccination. CONCLUSIONS:Teladorsagia circumcincta infection leads to an expansion of potentially pro-inflammatory gut microbial species and abomasal T cells. This data paves the way for future experiments aimed to determine the contribution of the gut flora to the pathophysiology of parasitic disease, with the ultimate aim to design and develop novel treatment/control strategies focused on preventing and/or restricting bacterial-mediated inflammation upon infection by GI helminths. Video Abstract.

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Dataset Information

Cathepsin F of Teladorsagia circumcincta is a recently evolved cysteine protease.

Publications

Cathepsin F of <i>Teladorsagia circumcincta</i> is a recently evolved cysteine protease.

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