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Modulation of the host cell cycle has emerged as a common theme among the pathways regulated by bacterial pathogens, arguably to promote host cell colonization. However, in most cases the exact benefit ensuing from such interference to the infection process remains unclear. Previously, we have shown that  Salmonella  actively induces G 2 /M arrest of host cells, and that infection is severely inhibited in cells arrested in G 1 . In this study, we demonstrate that  Salmonella  vacuolar replication is inhibited in host cells blocked in G 1 , whereas the cytosolic replication of the closely related pathogen  Shigella  is not affected. Mechanistically, we show that cells arrested in G 1 , but not cells arrested in G 2 , present dysregulated endolysosomal trafficking, displaying an abnormal accumulation of vesicles positive for late endosomal and lysosomal markers. In addition, the macroautophagic/autophagic flux and degradative lysosomal function are strongly impaired. This endolysosomal trafficking dysregulation results in sustained activation of the SPI-1 type III secretion system and lack of vacuole repair by the autophagy pathway, ultimately compromising the maturation and integrity of the  Salmonella- containing vacuole. As such,  Salmonella  is released in the host cytosol. Collectively, our findings demonstrate that the modulation of the host cell cycle occurring during  Salmonella  infection is related to a disparity in the permissivity of cells arrested in G 1  and G 2 /M, due to their intrinsic characteristics. Abbreviations:  CDK4: cyclin dependent kinase 4; CDK6: cyclin dependent kinase 6; CDK4-CDK6i: CDK4-CDK6 inhibitor IV; cfu: colony-forming units; CHQ: chloroquine; DMSO: dimethyl sulfoxide; EEA1: early endosome antigen 1; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; hpi: hours post-infection; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MOI: multiplicity of infection; RAB7: RAB7, member RAS oncogene family; SCV:  Salmonella- containing vacuole; SPI-1:  Salmonella  pathogenicity island-1; SPI-2:  Salmonella  pathogenicity island-2; TFEB: transcription factor EB; T3SS: type III secretion system

Dysregulated endolysosomal trafficking in cells arrested in the G 1 phase of the host cell cycle impairs Salmonella vacuolar replication