Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation

In recent years, a class of chemical compounds (benzoxaboroles) that are active against a range of parasites has been shown to target mRNA polyadenylation by inhibiting the activity of CPSF73, the endonucleolytic core of the eukaryotic polyadenylation complex. One particular compound, termed AN3661,...

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Autores principales:	Arthur G. Hunt, Daniel K. Howe, Ashley Brown, Michelle Yeargan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a598a60240da4817b82afd5416164455
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spelling	oai:doaj.org-article:a598a60240da4817b82afd54161644552021-11-04T06:49:31ZTranscriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation1932-6203https://doaj.org/article/a598a60240da4817b82afd54161644552021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553156/?tool=EBIhttps://doaj.org/toc/1932-6203In recent years, a class of chemical compounds (benzoxaboroles) that are active against a range of parasites has been shown to target mRNA polyadenylation by inhibiting the activity of CPSF73, the endonucleolytic core of the eukaryotic polyadenylation complex. One particular compound, termed AN3661, is active against several apicomplexan parasites that cause disease in humans. In this study, we report that AN3661 is active against an apicomplexan that causes disease in horses and marine mammals (Sarcocystis neurona), with an approximate IC50 value of 14.99 nM. Consistent with the reported mode of action of AN3661 against other apicomplexans, S. neurona mutants resistant to AN3661 had an alteration in CPSF73 that was identical to a mutation previously documented in AN3661-resistant Toxoplasma gondii and Plasmodium falciparum. AN3661 had a wide-ranging effect on poly(A) site choice in S. neurona, with more than half of all expressed genes showing some alteration in mRNA 3’ ends. This was accompanied by changes in the relative expression of more than 25% of S. neurona genes and an overall 5-fold reduction of S. neurona transcripts in infected cells. In contrast, AN3661 had no discernible effect on poly(A) site choice or gene expression in the host cells. These transcriptomic studies indicate that AN3661 is exceedingly specific for the parasite CPSF73 protein, and has the potential to augment other therapies for the control of apicomplexan parasites in domestic animals.Arthur G. HuntDaniel K. HoweAshley BrownMichelle YearganPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arthur G. Hunt Daniel K. Howe Ashley Brown Michelle Yeargan Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation
description	In recent years, a class of chemical compounds (benzoxaboroles) that are active against a range of parasites has been shown to target mRNA polyadenylation by inhibiting the activity of CPSF73, the endonucleolytic core of the eukaryotic polyadenylation complex. One particular compound, termed AN3661, is active against several apicomplexan parasites that cause disease in humans. In this study, we report that AN3661 is active against an apicomplexan that causes disease in horses and marine mammals (Sarcocystis neurona), with an approximate IC50 value of 14.99 nM. Consistent with the reported mode of action of AN3661 against other apicomplexans, S. neurona mutants resistant to AN3661 had an alteration in CPSF73 that was identical to a mutation previously documented in AN3661-resistant Toxoplasma gondii and Plasmodium falciparum. AN3661 had a wide-ranging effect on poly(A) site choice in S. neurona, with more than half of all expressed genes showing some alteration in mRNA 3’ ends. This was accompanied by changes in the relative expression of more than 25% of S. neurona genes and an overall 5-fold reduction of S. neurona transcripts in infected cells. In contrast, AN3661 had no discernible effect on poly(A) site choice or gene expression in the host cells. These transcriptomic studies indicate that AN3661 is exceedingly specific for the parasite CPSF73 protein, and has the potential to augment other therapies for the control of apicomplexan parasites in domestic animals.
format	article
author	Arthur G. Hunt Daniel K. Howe Ashley Brown Michelle Yeargan
author_facet	Arthur G. Hunt Daniel K. Howe Ashley Brown Michelle Yeargan
author_sort	Arthur G. Hunt
title	Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation
title_short	Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation
title_full	Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation
title_fullStr	Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation
title_full_unstemmed	Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation
title_sort	transcriptional dynamics in the protozoan parasite sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mrna polyadenylation
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/a598a60240da4817b82afd5416164455
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Transcriptional dynamics in the protozoan parasite Sarcocystis neurona and mammalian host cells after treatment with a specific inhibitor of apicomplexan mRNA polyadenylation

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