Show simple item record

Files in this item

Thumbnail

Item metadata

dc.contributor.authorDos Santos, Nailma S.A.
dc.contributor.authorEstevez-Castro, Carlos F.
dc.contributor.authorMacedo, Juan P.
dc.contributor.authorChame, Daniela F.
dc.contributor.authorCastro-Gomes, Thiago
dc.contributor.authorSantos-Cardoso, Mariana
dc.contributor.authorBurle-Caldas, Gabriela A.
dc.contributor.authorCovington, Courtney N.
dc.contributor.authorSteel, Patrick G.
dc.contributor.authorSmith, Terry K.
dc.contributor.authorDenny, Paul W.
dc.contributor.authorTeixeira, Santuza M.R.
dc.date.accessioned2024-02-16T16:30:01Z
dc.date.available2024-02-16T16:30:01Z
dc.date.issued2023-09-20
dc.identifier297582448
dc.identifiera4f60450-f08e-48d0-8ee5-41df16add7b5
dc.identifier85173589534
dc.identifier37729272
dc.identifier.citationDos Santos , N S A , Estevez-Castro , C F , Macedo , J P , Chame , D F , Castro-Gomes , T , Santos-Cardoso , M , Burle-Caldas , G A , Covington , C N , Steel , P G , Smith , T K , Denny , P W & Teixeira , S M R 2023 , ' Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity ' , PLoS Neglected Tropical Diseases , vol. 17 , no. 9 , e0011646 . https://doi.org/10.1371/journal.pntd.0011646en
dc.identifier.issn1935-2727
dc.identifier.urihttps://hdl.handle.net/10023/29280
dc.description.abstractSphingolipids (SLs) are essential components of all eukaryotic cellular membranes. In fungi, plants and many protozoa, the primary SL is inositol-phosphorylceramide (IPC). Trypanosoma cruzi is a protozoan parasite that causes Chagas disease (CD), a chronic illness for which no vaccines or effective treatments are available. IPC synthase (IPCS) has been considered an ideal target enzyme for drug development because phosphoinositol-containing SL is absent in mammalian cells and the enzyme activity has been described in all parasite forms of T. cruzi. Furthermore, IPCS is an integral membrane protein conserved amongst other kinetoplastids, including Leishmania major, for which specific inhibitors have been identified. Using a CRISPR-Cas9 protocol, we generated T. cruzi knockout (KO) mutants in which both alleles of the IPCS gene were disrupted. We demonstrated that the lack of IPCS activity does not affect epimastigote proliferation or its susceptibility to compounds that have been identified as inhibitors of the L. major IPCS. However, disruption of the T. cruzi IPCS gene negatively affected epimastigote differentiation into metacyclic trypomastigotes as well as proliferation of intracellular amastigotes and differentiation of amastigotes into tissue culture-derived trypomastigotes. In accordance with previous studies suggesting that IPC is a membrane component essential for parasite survival in the mammalian host, we showed that T. cruzi IPCS null mutants are unable to establish an infection in vivo, even in immune deficient mice.
dc.format.extent26
dc.format.extent2654985
dc.language.isoeng
dc.relation.ispartofPLoS Neglected Tropical Diseasesen
dc.subjectPublic Health, Environmental and Occupational Healthen
dc.subjectInfectious Diseasesen
dc.subjectDASen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.titleDisruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacityen
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.contributor.institutionUniversity of St Andrews. Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.identifier.doi10.1371/journal.pntd.0011646
dc.description.statusPeer revieweden
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85173589534&partnerID=8YFLogxKen


This item appears in the following Collection(s)

Show simple item record