Abstract
Emerging coronaviruses (CoVs) pose a severe threat to human and animal health worldwide. To identify host factors required for CoV infection, we used α-CoV transmissible gastroenteritis virus (TGEV) as a model for genome-scale CRISPR knockout (KO) screening. Transmembrane protein 41B (TMEM41B) was found to be a bona fide host factor involved in infection by CoV and three additional virus families. We found that TMEM41B is critical for the internalization and early-stage replication of TGEV. Notably, our results also showed that cells lacking TMEM41B are unable to form the double-membrane vesicles necessary for TGEV replication, indicating that TMEM41B contributes to the formation of CoV replication organelles. Lastly, our data from a mouse infection model showed that the KO of this factor can strongly inhibit viral infection and delay the progression of a CoV disease. Our study revealed that targeting TMEM41B is a highly promising approach for the development of broad-spectrum anti-viral therapeutics.
Highlights
As enveloped positive-strand RNA viruses, coronaviruses (CoVs) have genetically evolved into the following four major genera: α, β, γ, and δ
We identified numerous candidate host factors for transmissible gastroenteritis virus (TGEV) infection
Considering its extremely strong effect on TGEV infection, we focused our efforts on characterizing the roles that Transmembrane protein 41B (TMEM41B) play in the virus replication cycle
Summary
As enveloped positive-strand RNA viruses, coronaviruses (CoVs) have genetically evolved into the following four major genera: α, β, γ, and δ. CoVs cause various diseases in mammals and birds, ranging from enteritis in pigs to potentially lethal human respiratory infections [1,2]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the β-CoV genera, is a causative viral pathogen that causes upper respiratory diseases, fever, and severe pneumonia in humans [3] and currently presents a global public health threat. Transmissible gastroenteritis virus (TGEV), together with several human CoVs (e.g., HCoV-NL63 and HCoV-229E), belongs to the α-CoV genera. Mouse hepatitis virus (MHV), belonging to the β-CoV genera, is a natural pathogen that infects mice. The MHV-A59 strain can produce moderate to severe hepatitis, mild to moderate acute meningoencephalitis, and chronic demyelination in C57BL/6 weanling mice [8]. MHV infection of mice is considered one of the suitable animal models for the study of CoV-host interactions [9,10,11,12]
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