Metacytofilin Is a Potent Therapeutic Drug Candidate for Toxoplasmosis.
Administration, Intravenous
Administration, Oral
Animals
Antiparasitic Agents
/ administration & dosage
DNA Replication
/ drug effects
DNA, Protozoan
Disease Models, Animal
Female
Infectious Disease Transmission, Vertical
/ prevention & control
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Oxazines
/ administration & dosage
Pregnancy
Survival Rate
Toxoplasma
/ drug effects
Toxoplasmosis
/ drug therapy
Treatment Outcome
Metarhizium
Toxoplasma gondii
congenital toxoplasmosis
drug
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
18 02 2020
18 02 2020
Historique:
received:
09
08
2019
accepted:
28
09
2019
pubmed:
2
10
2019
medline:
25
11
2020
entrez:
2
10
2019
Statut:
ppublish
Résumé
Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound. Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq. In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites. With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.
Sections du résumé
BACKGROUND
Toxoplasmosis, a parasitic disease caused by Toxoplasma gondii, is an important cause of miscarriage or adverse fetal effects, including neurological and ocular manifestations in humans. Current anti-Toxoplasma drugs have limited efficacy against toxoplasmosis and also have severe side effects. Therefore, novel efficacious drugs are urgently needed. Here, we identified metacytofilin (MCF) from a fungal Metarhizium species as a potential anti-Toxoplasma compound.
METHODS
Anti-Toxoplasma activities of MCF and its derivatives were evaluated in vitro and in vivo using nonpregnant and pregnant mice. To understand the mode of action of MCF, the RNA expression of host and parasite genes was investigated by RNAseq.
RESULTS
In vitro, MCF inhibited the viability of intracellular and extracellular T. gondii. Administering MCF intraperitoneally or orally to mice after infection with T. gondii tachyzoites increased mouse survival compared with the untreated animals. Remarkably, oral administration of MCF to pregnant mice prevented vertical transmission of the parasite. Interestingly, RNA sequencing of T. gondii-infected cells treated with MCF showed that MCF inhibited DNA replication and enhanced RNA degradation in the parasites.
CONCLUSIONS
With its potent anti-T. gondii activity, MCF is a strong candidate for future drug development against toxoplasmosis.
Identifiants
pubmed: 31573038
pii: 5579831
doi: 10.1093/infdis/jiz501
doi:
Substances chimiques
Antiparasitic Agents
0
DNA, Protozoan
0
Oxazines
0
metacytofilin
145398-57-8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
766-774Informations de copyright
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.