01899nas a2200289   4500000000100000000000100001008004100002260001500043653001400058653001400072100001500086700002300101700001300124700002000137700002000157700002600177700001900203700002800222700001800250700001900268700001500287245007700302856005500379300000900434520115200443022001401595       2023                            d  c2023-10-1210ainfection10aPox virus1 aPengfei Li1 aSpyridon T. Pachis1 aGuige Xu1 aRick Schraauwen1 aRoberto Incitti1 aAnnemarie C. de Vries1 aMarco J. Bruno1 aMaikel P. Peppelenbosch1 aIntikhab Alam1 aKarine Raymond1 aQiuwei Pan00aMpox virus infection and drug treatment modelled in human skin organoids  uhttps://www.nature.com/articles/s41564-023-01489-6  a1-133 aMpox virus (MPXV) primarily infects human skin to cause lesions. Currently, robust models that recapitulate skin infection by MPXV are lacking. Here we demonstrate that human induced pluripotent stem cell-derived skin organoids are susceptible to MPXV infection and support infectious virus production. Keratinocytes, the predominant cell type of the skin epithelium, effectively support MPXV infection. Using transmission electron microscopy, we visualized the four stages of intracellular virus particle assembly: crescent formation, immature virions, mature virions and wrapped virions. Transcriptional analysis showed that MPXV infection rewires the host transcriptome and triggers abundant expression of viral transcripts. Early treatment with the antiviral drug tecovirimat effectively inhibits infectious virus production and prevents host transcriptome rewiring. Delayed treatment with tecovirimat also inhibits infectious MPXV particle production, albeit to a lesser extent. This study establishes human skin organoids as a robust experimental model for studying MPXV infection, mapping virus–host interactions and testing therapeutics.  a2058-5276