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• W1816652705 abstract "Hookworms are an important group of intestinal parasites and, like many othernpathogens, are highly host-specific. Necator americanus only produces patent infectionsnin humans under natural conditions; while Ancylostoma caninum only reaches patency inncanids. However, A. caninum infective larvae (L3) readily penetrate human skin, andnalthough some parasites reach the gut, they are never sexually mature. Likewise, dogsncan be experimentally infected with A'; americanus L3, however, the vast majority do notnmature to fertility. It was therefore hypothesized that the development of L3 to thenblood-feeding adult stage may partly depend on host-specific nutritional requirements.nOther blood-feeding parasites including schistosomes and Plasmodium digest hostnhaemoglobin (Hb) using aspartic proteases. Hookworms might also utilize similarnproteolytic mechanisms to cleave host Hb, and furthermore, the complementaritynbetween hookworm haemoglobinases and their specific host Hb molecules may be ancontributing factor governing which host species a hookworm can develop and maturenin.nnnnnn n cDNAs encoding cathepsin D-like aspartic proteases from A. caninum (Ac-apr-1)nand N. americanus (Na-apr-1 and Na-apr-2) were expressed as secreted pro-peptidasesnin baculovirus and were active against a cathepsin D fluorescent substrate (Abz-Ile-Glu-nPhe-nPhe-Arg-Leu-NH2). The abilities of the recombinant enzymes to cleave Hb werenassessed by incubating each purified protease with Hb from both permissive and non permissivenhosts. The two orthologous cathepsin D proteases from A. caninum (Ac-APR-n1) and N. americanus (Na-APR-1) exhibited 80% identity over the entire protein butnwere 100% identical in their active site residues. Both recombinant zymogensnautoactivated at pH 3.6 to form proteases that cleaved Hb at a pH optimum of 5.5. Ac-nAPR-1 digested canine Hb almost twice as efficiently as human Hb. In contrast, Na-nAPR-1 cleaved human Hb almost twice as efficiently as dog Hb. Furthermore, bothnproteases were shown to degrade collagens, albumin, and fibrinogen. Both enzymesnequally degraded human fibrinogen and albumin, whereas Na-APR-1 was less efficientnat degrading dog fibrinogen and albumin than Ac-APR-1. Na-APR-1 degraded humanncollagen more efficiently than Ac-APR-1. Specific cleavage sites were mapped to theni- and b-chains of human and dog Hb. Despite some conserved cleavage sites, manyncleavage events were unique to just one protease. Ac- and Na-APR-1 accommodatednsubstrates with serine or alanine in the P3 position of i-Hb, but Na-APR-1 was unique innnits affinity for histidine at P3. Two cleavage sites (LDKF*SLASV and LDKF*FAAV)non human and canine Hb i-chains respectively, were synthesized to kinetically confirmnthe differences in substrate specificity between the two proteases. Ac-APR-1 cleaved thendog Hb peptide 6-fold more efficiently than Na-APR-1. Na-APR-1 cleaved the humannHb peptide 4-fold more efficiently than Ac-APR-1. Antisera were raised to thenrecombinant proteases and purified IgG completely inhibited the enzymatic activitiesnagainst the fluorogenic substrate but did not inhibit their activity against Hb. Antiseranpartially inhibited (20-30%) L3 migration through hamster skin in vitro. Both Ac-APR-1nand Na-APR-1 primarily localized to the gut and amphidial glands in adult worms innimmunohistochemical localization, supporting their roles as haemoglobinases.nnnnn n nA pepsinogen-like aspartic protease from N americanus (Na-apr-2) was alsoncloned, expressed, and its activity characterized. The predicted Na-APR-2 protein hadn30% identity to Na-APR-1 and 45% to pepsinogen from Haemonchus contortus.nRecombinant Na-APR-2 autoactivated at pH 3.6 to form a protease that digested humannHb almost twice as efficiently as dog Hb. Differences in the pH profiles and Hb cleavagensites of Na-APR-2 (compared to Na-APR-1) were also found, suggesting an orderednpathway for hookworm gut Hb degradation. Na-APR-2 is also expressed in infectivenlarvae and it degraded collagen, albumin, and fibrinogen. Antiserum was raised againstnrecombinant, purified Na-APR-2. Purified anti-Na-APR-2 IgG completely inhibited thenenzymatic activity against Abz-Ile-Glu-Phe-nPhe-Arg-Leu-NH2 but did not inhibit itsnactivity against Hb. Anti-Na-APR-2 IgG also partially inhibited the enzymatic activity ofnNa-APR-1 and Ac-APR-1 against the fluorogenic substrate. Anti-Na-APR-1 and anti-Ac-APR-1 IgG inhibited the enzymatic activity of Na-APR-2 against the fluorogenicnsubstrate by 40%. Anti-Na-APR-2 inhibited migration of N. americanus L3 throughnhamster skin by 50%, and A. caninum L3 migration by 30%. Na-APR-2 localizednprimarily to the gut and amphidial glands in male and female adult worms, supporting anrole as a haemoglobinase in vivo.nnnnnn n A likely mechanism that may contribute to the host specificity of hookworms, andnperhaps many other pathogens, has now been identified. In this case, complementaritynbetween Hb molecules and the parasite proteases which cleave them appears to influencenwhich hosts a given hookworm species can survive in. Incompatibility between proteasesnand target host molecules might also explain the limited host range of other blood feedingnpathogens.n" @default.
• W1816652705 created "2016-06-24" @default.
• W1816652705 creator A5060621815 @default.
• W1816652705 date "2002-01-01" @default.
• W1816652705 modified "2023-09-27" @default.
• W1816652705 title "Hookworm aspartic proteases & their contribution to host specificity" @default.
• W1816652705 hasPublicationYear "2002" @default.
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