Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic tick-borne bunyavirus that causes lethal infectious disease and severe fever with thrombocytopenia syndrome (SFTS) in humans.The molecular mechanisms and host cellular factors required for SFTSV infection remain uncharacterized.Using a genome-wide CRISPR-based screening strategy,we identified a host cellular protein,sorting nexin 11 (SNX11) which is involved in the intracellular endosomal trafficking pathway,as an essential cell factor for SFTSV infection.An SNXll-KO HeLa cell line was established,and SFTSV replication was significantly reduced.The glycoproteins of SFTSV were detected and remained in later endosomal compartments but were not detectable in the endoplasmic reticulum (ER) or Golgi apparatus,pH values in the endosomal compartments of the SNX11-KO cells increased compared with the pH of normal HeLa cells,and lysosomal-associated membrane protein 1 (LAMP1) expression was significantly elevated in the SNX11-KO cells.Overall,these results indicated that penetration of SFFSV from the endolysosomes into the cytoplasm of host cells was blocked in the cells lacking SNX11.Our study for the first time provides insight into the important role of the SNX11 as an essential host factor in the intracellular trafficking and penetrating process of SFTSV infection via potential regulation of viral protein sorting,membrane fusion,and other endocytic machinery.