Abstract
ABSTRACTThe recent emergence and spread of zoonotic viruses highlights that animal-sourced viruses are the biggest threat to global public health. Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an HKU2-related bat coronavirus that was spilled over from Rhinolophus bats to swine, causing large-scale outbreaks of severe diarrhea disease in piglets in China. Unlike other porcine coronaviruses, SADS-CoV possesses broad species tissue tropism, including primary human cells, implying a significant risk of cross-species spillover. To explore host dependency factors for SADS-CoV as therapeutic targets, we employed genome-wide CRISPR knockout library screening in HeLa cells. Consistent with two independent screens, we identified the zinc finger DHHC-type palmitoyltransferase 17 (ZDHHC17 or ZD17) as an important host factor for SADS-CoV infection. Through truncation mutagenesis, we demonstrated that the DHHC domain of ZD17 that is involved in palmitoylation is important for SADS-CoV infection. Mechanistic studies revealed that ZD17 is required for SADS-CoV genomic RNA replication. Treatment of infected cells with the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly suppressed SADS-CoV infection. Our findings provide insight on SADS-CoV-host interactions and a potential therapeutic application.
Highlights
The recent emergence and spread of zoonotic viruses highlights that animal-sourced viruses are the biggest threat to global public health
Unlike other CoVs, SADS-CoV species tropism was not restricted to swine but was able to infect cells derived from multiple mammalian species, including primary human cells [11, 12]
SADS-CoV host dependency factors identified in CRISPR-Cas9 knockout library screen
Summary
The recent emergence and spread of zoonotic viruses highlights that animal-sourced viruses are the biggest threat to global public health. Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an HKU2-related bat coronavirus that was spilled over from Rhinolophus bats to swine, causing large-scale outbreaks of severe diarrhea disease in piglets in China. SADS-CoV, another coronavirus of bat origin, was only known to cause fatal diarrhea disease in piglets, the ability to infect cells derived from multiple species, including human, highlights the potential risk of animal-to-human spillover. Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses that can infect humans and a wide range of animals with various disease severities, including respiratory, enteric, and neurological pathologies [1]. Prior to 2016, at least three different types of porcine CoVs, including transmissible gastroenteritis virus, porcine epidemic diarrhea virus, and porcine deltacoronavirus, have caused severe enteric tract diseases in piglets and were regarded as major threats to swine industry [5]. No vaccine or antiviral drug against SADS-CoV is available [5]
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