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While some host factors are known, a comprehensive, temporally\u2010resolved understanding of the host\u2010pathogen interface has been hindered by a lack of suitable genome\u2010wide methodologies. To address this, a parallel CRISPR screening platform is developed to identify host determinants for distinct infection stages. An invasion screen captured factors for bacterial entry, while a fitness screen identified factors governing long\u2010term survival. The screens reveal a temporal switch in host dependency, from endosomal trafficking in early infection to cell cycle and DNA damage response pathways governing host cell fitness in long\u2010term infection. Notably, the approach uncovers two novel host factors with stage\u2010specific roles, SORL1 as a mediator of bacterial invasion and ZFYVE19 as a factor supporting intracellular proliferation. Genetic disruption of SORL1 or ZFYVE19 validate these roles, leading to impaired invasion or replication, respectively. Importantly, antibody\u2010mediated blockade of SORL1 effectively prevented\n                    <jats:italic>Salmonella<\/jats:italic>\n                    entry, highlighting it as a novel host\u2010directed therapeutic target. Together, the screening strategy provides a powerful framework for the temporal dissection of host\u2010pathogen interactions, revealing novel biology and promising therapeutic targets.\n                  <\/jats:p>","DOI":"10.1002\/advs.202515042","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T05:02:00Z","timestamp":1763960520000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Parallel Genome\u2010Wide CRISPR Screens Reveal SORL1 and ZFYVE19 as Sequential Host Determinants of\n                    <i>Salmonella<\/i>\n                    Infection"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4513-0471","authenticated-orcid":false,"given":"Sehee","family":"Yun","sequence":"first","affiliation":[{"name":"Department of Life Sciences School of Life Sciences and Biotechnology Korea University Seoul 02841 Republic of 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