A conserved coccidian gene is involved in Toxoplasma sensitivity to the anti-apicomplexan compound, tartrolon E

Gregory D. Bowden, Patricia M. Reis, Maxwell B. Rogers, Rachel M. Bone Relat, Kelly A. Brayton, Sarah K. Wilson, Bruno Martorelli Di Genova, Laura J. Knoll, Felix J. Nepveux V, Albert K. Tai, Timothy R. Ramadhar, Jon Clardy, Roberta M. O'Connor

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

New treatments for the diseases caused by apicomplexans are needed. Recently, we determined that tartrolon E (trtE), a secondary metabolite derived from a shipworm symbiotic bacterium, has broad-spectrum anti-apicomplexan parasite activity. TrtE inhibits apicomplexans at nM concentrations in vitro, including Cryptosporidium parvum, Toxoplasma gondii, Sarcocystis neurona, Plasmodium falciparum, Babesia spp. and Theileria equi. To investigate the mechanism of action of trtE against apicomplexan parasites, we examined changes in the transcriptome of trtE-treated T. gondii parasites. RNA-Seq data revealed that the gene, TGGT1_272370, which is broadly conserved in the coccidia, is significantly upregulated within 4 h of treatment. Using bioinformatics and proteome data available on ToxoDB, we determined that the protein product of this tartrolon E responsive gene (trg) has multiple transmembrane domains, a phosphorylation site, and localizes to the plasma membrane. Deletion of trg in a luciferase-expressing T. gondii strain by CRISPR/Cas9 resulted in a 68% increase in parasite resistance to trtE treatment, supporting a role for the trg protein product in the response of T. gondii to trtE treatment. Trg is conserved in the coccidia, but not in more distantly related apicomplexans, indicating that this response to trtE may be unique to the coccidians, and other mechanisms may be operating in other trtE-sensitive apicomplexans. Uncovering the mechanisms by which trtE inhibits apicomplexans may identify shared pathways critical to apicomplexan parasite survival and advance the search for new treatments.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume14
DOIs
StatePublished - Dec 2020
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Center for Complimentary and Integrative Health, National Institutes of Health (grant number R21 AT009174 ) to RMO and support from the Department of Veterinary Microbiology and Pathology, Washington State University , College of Veterinary Medicine . GDB is a recipient of a Poncin Scholarship for Medical Research awarded by the Cora May Poncin Trust.

Funding Information:
This work was supported by the National Center for Complimentary and Integrative Health, National Institutes of Health (grant number R21 AT009174) to RMO and support from the Department of Veterinary Microbiology and Pathology, Washington State University, College of Veterinary Medicine. GDB is a recipient of a Poncin Scholarship for Medical Research awarded by the Cora May Poncin Trust.

Publisher Copyright:
© 2020

Keywords

  • Anti-apicomplexan
  • CRISPR/Cas9
  • Drug discovery
  • Natural products
  • Tartrolon E
  • Toxoplasma

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'A conserved coccidian gene is involved in Toxoplasma sensitivity to the anti-apicomplexan compound, tartrolon E'. Together they form a unique fingerprint.

Cite this