Störung des zellulären nukleozytoplasmatischen Transports durch den Virulenzfaktor NSs des Rifttalfieber Virus

Das Rifttalfieber Virus (engl.: Rift Valley Fever Virus, RVFV) gehört zur Gattung Phlebovirus innerhalb der Familie Phenuiviridae und infiziert vorwiegend Wiederkäuer. Dort verursacht es unter anderem fötale Missbildungen, Fehlgeburten oder ein letales, hämorrhagisches Fieber. Im Menschen führt das...

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Bibliographic Details
Main Author: Lau, Simone
Contributors: Weber, Friedemann (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2020
Online Access:PDF Full Text
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Rift Valley fever virus (RVFV, genus: Phlebovirus, family: Phenuiviridae) mostly infects ruminants where it causes fetal malformations, abortions or a lethal hemorrhagic fever. In humans, RVFV causes a mild, febrile disease. In some cases, however, it can progress to severe disease with hepatitis, retinitis or hemorrhagic fever. RVFV infected cells are no longer capable to mount an effective immune response due to the virulence factor NSs. It suppresses host cell transcription by degrading the p62 and p44 subunits of the general transcription factor TFIIH and inhibits interferon-β-promoter activation. Moreover, NSs targets the protein kinase PKR for proteasomal degradation, which leads to ongoing viral translation. Since inactivating these NSs functions does not rescue host gene expression, NSs may engage additional strategies to stall an effective interferon response. This work elucidates additional functions of RVFV NSs. It induces a retention of host cell mRNA in the nucleus, which reduces the competition for viral RNA for the translation machinery. In this regard, the mRNA export receptor NXF1 exhibited a redistribution and perhaps blockade upon infection. Furthermore, NSs affects the nuclear pore complex (NPC). RVFV NSs causes a redistribution of Nup214 and Nup358 from the NPC into the cytoplasm, which may affect translocation and directed release of mRNPs. In turn, NSs needs components of the NPC, since NSs import into the nucleus is defective and viral titers decrease upon Nup98 depletion. Although Nup214 and Nup358 are also involved in protein import, this function is unaffected by RVFV infection. RVFV rather induces the dislocation of specific proteins. In particular, components of the spliceosome were dislocated, indicating an impact of RVFV infection on cellular splicing events. Moreover, the ability to block mRNA export is not exclusive for RVFV NSs since it was also observed for other members of the order Bunyavirales. However, this seems to be mediated by different mechanisms, since this work revealed that La Crosse Virus (LACV) induces an mRNA export block independent of NSs. This is most likely due to an NPC integrity loss and the degradation of mRNA export factors induced indirectly by apoptosis.