How human dendritic cells respond to the vaccine vector MVA: elucidating mechanisms at the intersection of viral replication and innate immune sensing
Final Report Abstract
Modified vaccinia Ankara (MVA) is a live attenuated human smallpox vaccine and a vector for the development of new vaccines against infectious diseases and cancer. Efficient activation of the immune system by MVA relies in part on its encounter with dendritic cells (DCs). MVA infection of DCs leads to multiple outcomes including cytokine production, activation of co-stimulatory molecules for T cell stimulation, and cell death. How these diverse responses are orchestrated in human DCs has not been resolved at the single-cell level. Here, we characterize the distinct DC fates in response to MVA infection using single-cell analyses. We show that, in DCs, MVA infection is limited to early gene expression, because the restriction factor SAMHD1 prevents DNA replication. In response to the early events in the viral cycle, we find that DCs group in three distinct clusters. A cluster of infected cells senses the incoming MVA genome by the cGAS-STING-TBK1-IRF3 pathway of intracellular innate immunity and produces inflammatory cytokines. In response to these cytokines, a cluster of non-infected bystander cells upregulates co-stimulatory molecules. A separate cluster of infected cells undergoes apoptosis. Unexpectedly, induction of apoptosis remains intact following inhibition of the cGAS-STING-TBK1- IRF3 pathway. Instead, it is a response to early MVA gene expression. Thus, apoptosis induction by human DCs in response to MVA infection is distinct from previously described IRF-dependent or replication-dependent pathways. Altogether, our study identifies distinct mechanisms that underlie the complex interactions of MVA with human dendritic cells.
Publications
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(2017). "A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle." Scientific Reports 7(1): 2933
Matschulla, T., R. Berry, C. Gerke, M. Döring, J. Busch, J. Paijo, U. Kalinke, F. Momburg, H. Hengel and A. Halenius
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(2017). "Systemic Virus Infections Differentially Modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo." CellReports 19(11): 2345-2356
Hirche, C., T. Frenz, S. F. Haas, M. Döring, K. Borst, P.-K. Tegtmeyer, I. Brizic, S. Jordan, K. Keyser, C. Chhatbar, E. Pronk, S. Lin, M. Messerle, S. Jonjic, C. S. Falk, A. Trumpp, M. A. G. Essers and U. Kalinke
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(2018). "Human monocyte-derived macrophages inhibit HCMV spread independent of classical antiviral cytokines." Virulence 9(1): 1669-1684
Becker, J., V. Kinast, M. Döring, C. Lipps, V. Duran, J. Spanier, P. K. Tegtmeyer, D. Wirth, L. Cicin- Sain, A. Alcami and U. Kalinke
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(2019). "Modulation of TAP-dependent antigen compartmentalization during human monocyte-to-DC differentiation." Blood Adv 3(6): 839-850
Döring, M., H. Blees, N. Koller, S. Tischer-Zimmermann, M. Musken, F. Henrich, J. Becker, E. Grabski, J. Wang, H. Janssen, W. Zuschratter, J. Neefjes, F. Klawonn, B. Eiz-Vesper, R. Tampe and U. Kalinke
