GraphPad Prism 5 statistical software was used to determine statistical significance. One or two-way ANOVA with Bonferroni’s multiple comparison post-tests were performed. Where appropriate, statistical significance was determined by an unpaired t-test using GraphPad software. For all statistical analyses p<0.05 was considered significant. Values are expressed as mean±SEM. The authors thank Kay Samuel, New Royal Infirmary Edinburgh, UK, for FACS analysis and Dr Dominic Campopiano, School of Chemistry, University of Edinburgh, UK for helpful discussion. This work was supported by the MRC and grants from EPSRC (J.R.D.), ARC (M.G.) and D.J.D. is a Wellcome Trust
Research Career Development Fellow (Fellowship MI-503 concentration ♯ 078265). Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They PF-01367338 mw are made available as submitted by the authors. “
“Faculdade de Ciências Farmacêuticas, Universidade Federal do Amazonas, Manaus, AM, Brazil Commonwealth Scientific and Industrial Research Organisation–Ecosystem Sciences, Canberra, Australia Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8+ T cells that may contribute to tissue damage and
hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery. Upon hantavirus infection of various human and primate cell lines, we observed transactivation of promoters controlling classical HLA molecules. Hantavirus-induced
HLA-I upregulation required proteasomal activity and was associated with increased TAP expression. Intriguingly, human DCs acquired the capacity to cross-present antigen upon hantavirus infection. Furthermore, knockdown of TIR domain containing adaptor inducing IFN-β or retinoic acid inducible gene I abolished hantavirus-driven HLA-I induction. In contrast, MyD88-dependent viral sensors were not involved in HLA-I induction. Our results show that hantaviruses strongly boost the HLA-I antigen presentation machinery by mechanisms that are dependent on both retinoic Tacrolimus (FK506) acid inducible gene I and TIR domain containing adaptor inducing IFN-β. Rapidly changing ecosystems and climate facilitate the emergence of human infections with hantaviruses [1-3]. In Germany, increasing numbers of hantavirus-associated disease cases have been observed . The enhanced health hazard emanating from pathogenic hantavirus species has been recognized by the German National Health Institute, which has recently reprioritized infectious pathogens and placed hantaviruses in the highest priority group . Hantaviruses belong to the family Bunyaviridae and have segmented genomes .