03159nas a2200793   4500000000100000000000100001008004100002260001500043653002400058653001000082653000900092653003600101653001200137653001400149653001900163653001300182653002500195653001100220653002900231653002100260653002300281653002000304653001100324653001100335653002900346653000900375653001600384653002400400653001500424653001400439653001400453653003100467653002200498653001300520653002700533653003100560653001500591653001800606653001500624653001800639653002200657653001400679100001700693700002100710700002000731700002100751700002300772700001700795700001800812700001900830700001900849700001800868700002100886700002000907700001900927700002200946700002300968700002100991700002401012700002601036700002201062700001701084700002501101245009001126300001201216490000601228520111701234022001402351       2021                            d  c2021-12-2210aAcute Kidney Injury10aAdult10aAged10aAngiotensin-Converting Enzyme 210aAnimals10aApoptosis10aBowman Capsule10aCOVID-1910aChlorocebus aethiops10aFemale10aGene Knockout Techniques10aGenetic diseases10aHospital Mortality10aHospitalization10aHumans10akidney10aKidney Tubules, Proximal10aMale10aMiddle Aged10aMolecular pathology10aNephrology10aorganoids10aPodocytes10aPolycystic Kidney Diseases10aProtein Kinase D210aProteome10aReceptors, Coronavirus10aReproducibility of Results10aSARS-CoV-210aTranscriptome10aVero Cells10aViral Tropism10aVirus Replication10aiPS cells1 aLouisa Helms1 aSilvia Marchiano1 aIan B. Stanaway1 aTien-Ying Hsiang1 aBenjamin A. Juliar1 aShally Saini1 aYan Ting Zhao1 aAkshita Khanna1 aRajasree Menon1 aFadhl Alakwaa1 aCarmen Mikacenic1 aEric D. Morrell1 aMark M. Wurfel1 aMatthias Kretzler1 aJennifer L. Harder1 aCharles E. Murry1 aJonathan Himmelfarb1 aHannele Ruohola-Baker1 aPavan K. Bhatraju1 aMichael Gale1 aBenjamin S. Freedman00aCross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations  ae1548820 v63 aKidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.  a2379-3708