A genome-wide CRISPR screen for herpes simplex virus type-1 host factors reveals PAPS synthase as a key factor for heparan sulfate biosynthesis

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen that causes various diseases in humans, ranging from common mucocutaneous lesions to severe life-threatening encephalitis. Therefore, to identify the host factors for HSV-1 infections, we performed a human genome-wide CRISPR screen using near-haploid HAP1 cells, in which gene knockout (KO) could be efficiently achieved. Along with several already known host factors, we identified 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) as a novel factor for HSV-1 infections. The KO of PAPSS1 in HAP1 cells reduced heparan sulfate (HepS) expression, consequently diminishing the binding of HSV-1 and several other HepS-dependent viruses (such as HSV-2, hepatitis B virus, and a human seasonal coronavirus). Hence, our findings provide new insights into the host factor requirements for HSV-1 infection and HepS biosynthesis.

单纯疱疹病毒1型（Herpes simplex virus type 1，HSV-1）是一种普遍存在的人类病原体，可引发多种人类疾病，涵盖常见黏膜皮肤病变乃至危及生命的重症脑炎。为鉴定HSV-1感染的宿主因子，本研究利用可高效实现基因敲除（gene knockout，KO）的近单倍体HAP1细胞开展了全基因组CRISPR筛选。结合多种已知宿主因子，我们鉴定出3'-磷酸腺苷5'-磷酸硫酸合酶1（3'-phosphoadenosine 5'-phosphosulfate synthase 1，PAPSS1）作为HSV-1感染的新型宿主因子。在HAP1细胞中敲除PAPSS1会降低硫酸乙酰肝素（heparan sulfate，HepS）的表达水平，进而削弱HSV-1以及其他多种依赖HepS的病毒（如HSV-2、乙型肝炎病毒、人类季节性冠状病毒）的结合能力。综上，本研究结果为HSV-1感染的宿主因子需求及HepS生物合成途径提供了新的研究视角。