ArticlePLoS pathogens2014
Cathepsin-L can resist lysis by human serum in Trypanosoma brucei brucei.
Article in PLoS pathogens, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- Germline-targeted baboon apolipoprotein L-1 protects mice against African trypanosomes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Pathogenicity and virulence of African trypanosomes: From laboratory models to clinically relevant hosts.Virulence · 2023Review
- Targeted protein degradation might present a novel therapeutic approach in the fight against African trypanosomiasis.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2023Article
- Article
- Diversity of trypanosomes in humans and cattle in the HAT foci Mandoul and Maro, Southern Chad-A matter of concern for zoonotic potential?PLoS neglected tropical diseases · 2021Article
- Proteases as Therapeutic Targets Against the Parasitic CnidarianFrontiers in cellular and infection microbiology · 2021Article
- Forward Genetics in African Trypanosomes.Methods in molecular biology (Clifton, N.J.) · 2020Article
- Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei.Antimicrobial agents and chemotherapy · 2019Article
- Cysteine proteases in protozoan parasites.PLoS neglected tropical diseases · 2018Review
- Decoding the network of Trypanosoma brucei proteins that determines sensitivity to apolipoprotein-L1.PLoS pathogens · 2018Article
- Article
- APOLs with low pH dependence can kill all African trypanosomes.Nature microbiology · 2017Article
- Ornithine uptake and the modulation of drug sensitivity inFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei.PLoS pathogens · 2017Article
- Article
- Exploiting the Achilles' heel of membrane trafficking in trypanosomes.Current opinion in microbiology · 2016Review
- A Primate APOL1 Variant That Kills Trypanosoma brucei gambiense.PLoS neglected tropical diseases · 2016Article
- Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1.Nature communications · 2015Article
- Genome-scale RNAi screens for high-throughput phenotyping in bloodstream-form African trypanosomes.Nature protocols · 2015Article
- The molecular arms race between African trypanosomes and humans.Nature reviews. Microbiology · 2014Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Closely related African trypanosomes cause lethal diseases but display distinct host ranges. Specifically, Trypanosoma brucei brucei causes nagana in livestock but fails to infect humans, while Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause sleeping sickness in humans. T. b. brucei fails to infect humans because it is sensitive to innate immune complexes found in normal human serum known as trypanolytic factor (TLF) 1 and 2; the lytic component is apolipoprotein-L1 in both TLFs. TLF resistance mechanisms of T. b. gambiense and T. b. rhodesiense are now known to arise through either gain or loss-of-function, but our understanding of factors that render T. b. brucei susceptible to lysis by human serum remains incomplete. We conducted a genome-scale RNA interference (RNAi) library screen for reduced sensitivity to human serum. Among only four high-confidence 'hits' were all three genes previously shown to sensitize T. b. brucei to human serum, the haptoglobin-haemoglobin receptor (HpHbR), inhibitor of cysteine peptidase (ICP) and the lysosomal protein, p67, thereby demonstrating the pivotal roles these factors play. The fourth gene identified encodes a predicted protein with eleven trans-membrane domains. Using chemical and genetic approaches, we show that ICP sensitizes T. b. brucei to human serum by modulating the essential cathepsin, CATL, a lysosomal cysteine peptidase. A second cathepsin, CATB, likely to be dispensable for growth in in vitro culture, has little or no impact on human-serum sensitivity. Our findings reveal major and novel determinants of human-serum sensitivity in T. b. brucei. They also shed light on the lysosomal protein-protein interactions that render T. b. brucei exquisitely sensitive to lytic factors in human serum, and indicate that CATL, an important potential drug target, has the capacity to resist these factors.
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