Matrix protein mediated shutdown of host cell metabolism limits vesicular stomatitis virus-induced interferon-alpha responses to plasmacytoid dendritic cells.
Upon infection with many different viruses, plasmacytoid dendritic cells (pDC) produce large amounts of type I interferon (IFN-alpha/beta). To address why upon vesicular stomatitis virus (VSV) infection pDC, but not conventional myeloid DC (mDC), are induced to produce IFN-alpha, pDC and mDC were differentiated from bone marrow cells (BM-DC). Upon VSV infection BM-pDC produced IFN-alpha, whereas BM-mDC did not. Notably, upon infection with VSV-M2, a VSV variant expressing a M51R mutant matrix (M) protein that showed a reduced sequestration of host cell metabolism, BM-pDC and BM-mDC mounted massive IFN-alpha responses. Both DC subsets showed comparable RNA levels of retinoic acid inducible gene-I (RIG-I) and Toll-like receptor (TLR) 7 and were able to respond upon triggering with double-stranded RNA (dsRNA) or single-stranded RNA (ssRNA) analogs. Moreover, upon VSV-M2 infection IFN-alpha production by both DC subsets was largely dependent on viral replication. Interestingly, upon virus infection BM-pDC, but not BM-mDC, up-regulated mRNA levels of nuclear export factors Nup96/98, probably reflecting cellular mechanisms to circumvent viral escape strategies. Collectively, these results indicated that cell types induced to produce IFN-alpha upon viral infection are not primarily defined by cellular receptor configurations but rather by complex virus/host cell interactions.
Waibler
Zoe
Z
Division of Immunology, Paul-Ehrlich-Institut, D-63225, Langen, Germany. waizo@pei.de
Detje
Claudia N
CN
Bell
John C
JC
Kalinke
Ulrich
U
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000097:blood; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D018353:Rhabdoviridae Infections / Q000276:immunology* / Q000821:virology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology* / Q000502:physiology; D014763:Viral Matrix Proteins / Q000502:physiology*; D014779:Virus Replication; D000097905:Roundabout Proteins
D016898:Interferon-alpha; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051199:Toll-Like Receptor 7; D014763:Viral Matrix Proteins; C094460:M protein, Vesicular stomatitis virus; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C119239:nuclear pore complex protein 96; C093350:nuclear pore complex protein 98