التفاصيل البيبلوغرافية
| العنوان: |
Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity. |
| المؤلفون: |
Aprigio-Santos, Nailma S., Estevez-Castro, Carlos F., Macedo, Juan P., Chame, Daniela F., Castro-Gomes, Thiago, Santos-Cardoso, Mariana, Burle-Caldas, Gabriela A., Covington, Courtney N., Steel, Patrick G., Smith, Terry K., Denny, Paul W., Teixeira, Santuza M. R. |
| المصدر: |
PLoS Neglected Tropical Diseases; 9/20/2023, Vol. 17 Issue 9, p1-26, 26p |
| مصطلحات موضوعية: |
TRYPANOSOMA cruzi, INOSITOL, LIFE cycles (Biology), CHAGAS' disease, CELL membranes, BACTERIAL cell surfaces, GENE targeting |
| مستخلص: |
Sphingolipids (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. Author summary: Trypanosoma cruzi is a vector-borne parasite that causes Chagas disease (CD), an illness that affects 6–8 million people worldwide and results in approximately 50,000 deaths per year. Transmitted by more than 100 species of triatomine insects, T. cruzi has a complex life cycle that includes parasite forms that proliferate in the gut of the insect vector (epimastigotes) and in the cytoplasm of infected mammalian cells (amastigotes). To be transmitted to mammals, epimastigotes must differentiate into metacyclic trypomastigotes, and to infect new mammalian cells, amastigotes must differentiate into bloodstream trypomastigotes. Sphingolipids (SLs) are essential components of all eukaryotic cellular membranes and are present in all forms of T. cruzi as part of various cell surface molecules involved in host-parasite interactions. Different from mammals, in which sphingomyelin is the main SL, T. cruzi synthesizes inositol phosphorylceramide (IPC) and, because of that, enzymes of the SL biosynthetic pathway have been considered potential targets for the development of new treatments for CD. By disrupting the gene encoding the T. cruzi IPC synthase, we showed that parasite differentiation from epimastigotes into metacyclic trypomastigotes and from amastigotes to bloodstream forms are affected and, as a consequence, these knockout cell lines are unable to establish an infection in animals. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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