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A Novel Antiviral Mechanism of Interferon Gamma Targeting Viral Replication Complexes
Başlık:
A Novel Antiviral Mechanism of Interferon Gamma Targeting Viral Replication Complexes
Yazar:
Biering, Scott Benjamin, author. (orcid)0000-0003-1991-629X
ISBN:
9780438087972
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (235 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Seungmin Hwang Committee members: Benjamin Glick; Kay Macleod; Glenn Randall; Howard Shuman.
Özet:
Replication complexes (RCs) of positive-strand RNA viruses [(+)RNA] are membranous structures built from membranes of host organelles. These structures are essential to the viral lifecycle for both promoting viral replication and protecting the virus from the host immune response. Though we understand much about how these structures are formed, we did not know if these conserved viral structures could be targeted by host antiviral defense systems. We recently found such a pathway by which interferon gamma (IFNG) mediates disruption of the murine norovirus (MNV) RC, in a manner dependent on the ATG12-ATG5-ATG16L1 complex but independent of degradative autophagy. However, the mechanism and potential effectors of this antiviral pathway were unknown.
In this dissertation, we show that the RC of MNV is detected via an interaction between the autophagy protein ATG16L1 and viral RNA-dependent RNA polymerase (RdRp), one of the most conserved viral proteins. Recruitment of ATG16L1 brings the entire LC3-conjugation system to the RC, marking it with LC3 and homologs. This LC3 localization to the RC demarcates the structure as a "non-self" target for this IFNG-mediated antiviral activity. Once marked, LC3 and homologs recruited a family of immune effectors known as the interferon (IFN)-inducible GTPases, which destroy the RC. These IFN-inducible GTPases are induced by IFNG and antagonize replication of MNV both in vitro and in vivo. The IFN-inducible GTPases are membranolytic effectors which also disrupt the membranous replication structures of protozoan parasites, bacteria, and fungi. Thus, we have determined that this antiviral activity against the RC of MNV is in fact an evolutionarily conserved anti-microbial pathway by which the host detects "non-self" structures through demarcation with autophagy proteins, which in turn recruit membranolytic IFN-inducible GTPases.
Notlar:
School code: 0330
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(691573.1) | 691573-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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