Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy.
Proc Natl Acad Sci U S A
; 118(39)2021 09 28.
Article
in English
| MEDLINE | ID: covidwho-1428995
ABSTRACT
Bats are responsible for the zoonotic transmission of several major viral diseases, including those leading to the 2003 SARS outbreak and likely the ongoing COVID-19 pandemic. While comparative genomics studies have revealed characteristic adaptations of the bat innate immune system, functional genomic studies are urgently needed to provide a foundation for the molecular dissection of the viral tolerance in bats. Here we report the establishment of genome-wide RNA interference (RNAi) and CRISPR libraries for the screening of the model megabat, Pteropus alecto. We used the complementary RNAi and CRISPR libraries to interrogate P. alecto cells for infection with two different viruses mumps virus and influenza A virus, respectively. Independent screening results converged on the endocytosis pathway and the protein secretory pathway as required for both viral infections. Additionally, we revealed a general dependence of the C1-tetrahydrofolate synthase gene, MTHFD1, for viral replication in bat cells and human cells. The MTHFD1 inhibitor, carolacton, potently blocked replication of several RNA viruses, including SARS-CoV-2. We also discovered that bats have lower expression levels of MTHFD1 than humans. Our studies provide a resource for systematic inquiry into the genetic underpinnings of bat biology and a potential target for developing broad-spectrum antiviral therapy.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Pandemics
/
Formate-Tetrahydrofolate Ligase
/
COVID-19
/
Aminohydrolases
/
Methylenetetrahydrofolate Dehydrogenase (NADP)
/
Multienzyme Complexes
Type of study:
Systematic review/Meta Analysis
Limits:
Animals
/
Humans
Language:
English
Year:
2021
Document Type:
Article
Affiliation country:
Pnas.2104759118
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