biostudies-literatureDemoulins TNIAID NIH HHSNational Institutes of HealthSeattle Children's Research Institute77-86https://www.ebi.ac.uk/biostudies/studies/S-EPMC12924682biostudies-literatureUnknown567Type-I interferon (IFN-I) signals exert a critical role in disease progression during viral infections. However, the immunomodulatory mechanisms by which IFN-I dictates disease outcomes remain to be fully defined. Here we report that IFN-I signals mediate thymic atrophy in viral infections, with more severe and prolonged loss of thymic output and unique kinetics and subtypes of IFN-α/β expression in chronic infection compared to acute infection. Loss of thymic output was linked to inhibition of early stages of thymopoiesis (DN1-DN2 transition, and DN3 proliferation) and pronounced apoptosis during the late DP stage. Notably, infection-associated thymic defects were largely abrogated upon ablation of IFNαβR and partially mitigated in the absence of CD8 T cells, thus implicating direct as well as indirect effects of IFN-I on thymocytes. These findings provide mechanistic underpinnings for immunotherapeutic strategies targeting IFN-1 signals to manipulate disease outcomes during chronic infections and cancers.VirologyInduction of thymic atrophy and loss of thymic output by type-I interferons during chronic viral infection.PMC129246825P30CA015704AI103748R21 AI154363R01 AI132819AI154363AI132819R03 AI103748Reed SJLamarre AKettaf NSarkar SDemoulins TKalinke UKalia VCharpentier TSekaly RPGauchat DAhmed RBaron MLfalseInduction of thymic atrophy and loss of thymic output by type-I interferons during chronic viral infection.Type-I interferon (IFN-I) signals exert a critical role in disease progression during viral infections. However, the immunomodulatory mechanisms by which IFN-I dictates disease outcomes remain to be fully defined. Here we report that IFN-I signals mediate thymic atrophy in viral infections, with more severe and prolonged loss of thymic output and unique kinetics and subtypes of IFN-α/β expression in chronic infection compared to acute infection. Loss of thymic output was linked to inhibition of early stages of thymopoiesis (DN1-DN2 transition, and DN3 proliferation) and pronounced apoptosis during the late DP stage. Notably, infection-associated thymic defects were largely abrogated upon ablation of IFNαβR and partially mitigated in the absence of CD8 T cells, thus implicating direct as well as indirect effects of IFN-I on thymocytes. These findings provide mechanistic underpinnings for immunotherapeutic strategies targeting IFN-1 signals to manipulate disease outcomes during chronic infections and cancers.2022-01-01T00:00:00Z2022 Feb2026-07-09T11:48:38.793Z2026-07-09T11:01:59.987ZS-EPMC129246823503286610.1016/j.virol.2021.12.007