Pestiviral endoribonucleases as a key to understand innate immunotolerance

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IVI

Projektnummer

7270200

Projekttitel

Pestiviral endoribonucleases as a key to understand innate immunotolerance

Texte zu diesem Projekt

	Deutsch	Französisch	Italienisch	Englisch
Kurzbeschreibung		-	-

Erfasste Texte

Kategorie	Text
Kurzbeschreibung (Deutsch)	Durch den SNF gefördertes Projekt: SNF \| P3 Forschungsdatenbank \| Project 172796 Interferone sind die wichtigsten Zytokine der antiviralen Abwehr, und so ist es nicht erstaunlich, dass praktisch alle Viren Gegenmassnahmen entwickelt haben. In diesem Projekt wird untersucht, wie die weltweit vorkommenden Pestiviren die antivirale Zytokin-Antwort vermeiden.
Kurzbeschreibung (Englisch)	Interferon (IFN) represents the most important innate defense mechanism against virus infection, and most viruses have developed an enormous variety of strategies to bypass these antiviral effects. Within the family Flaviviridae, the pestiviruses, such as bovine viral diarrhea virus (BVDV) or classical swine fever viruses (CSFV), are the sole members that encode for two additional proteins that act as IFN antagonists, i.e., N-pro and E-rns. As a non-structural protein, N-pro is exclusively expressed in infected cells and leads to the degradation of the transcription factor IRF-3 that is essential for IFN production. By contrast, the non-structural glycoprotein E-rns was shown by others and us to inhibit IFN synthesis induced by immunostimulatory single- (ss) and double-stranded (ds) RNA by virtue of its RNase activity. Notably, as a portion of E-rns is released as soluble protein into the extracellular space, it also inhibits activation of the innate immune response in non-infected cells. However, the precise role in evasion of the hosts IFN response to induce persistence and to impact virulence are still unknown. The aim of this study is to investigate in detail the mechanism of a pestiviral RNase to act as an important IFN antagonist in its natural host environment. This project might shed light on the more fundamental mechanisms of the host to avoid the body’s own immunostimulatory RNA to act as a danger-associated molecular pattern. This “innate immunotolerance” to self nucleic acids and the specific detection of viral nonself is not specific for pestivirus pathogenesis, but is highly relevant across various species and is highly reminiscent of inappropriate innate autoimmune activation that are often accompanied by aberrant IFN induction (called “type-I interferonopathies”). Thus, this project investigates pestiviruses as model pathogens that co-evolved with its host over a long time that might also answer fundamental questions on the discrimination between “self” and “viral nonself RNA”.

Kategorie

Text

Kurzbeschreibung
(Deutsch)

Durch den SNF gefördertes Projekt: SNF | P3 Forschungsdatenbank | Project 172796
Interferone sind die wichtigsten Zytokine der antiviralen Abwehr, und so ist es nicht erstaunlich, dass praktisch alle Viren Gegenmassnahmen entwickelt haben. In diesem Projekt wird untersucht, wie die weltweit vorkommenden Pestiviren die antivirale Zytokin-Antwort vermeiden.

Kurzbeschreibung
(Englisch)

Interferon (IFN) represents the most important innate defense mechanism against virus infection, and most viruses have developed an enormous variety of strategies to bypass these antiviral effects. Within the family Flaviviridae, the pestiviruses, such as bovine viral diarrhea virus (BVDV) or classical swine fever viruses (CSFV), are the sole members that encode for two additional proteins that act as IFN antagonists, i.e., N-pro and E-rns. As a non-structural protein, N-pro is exclusively expressed in infected cells and leads to the degradation of the transcription factor IRF-3 that is essential for IFN production. By contrast, the non-structural glycoprotein E-rns was shown by others and us to inhibit IFN synthesis induced by immunostimulatory single- (ss) and double-stranded (ds) RNA by virtue of its RNase activity. Notably, as a portion of E-rns is released as soluble protein into the extracellular space, it also inhibits activation of the innate immune response in non-infected cells. However, the precise role in evasion of the hosts IFN response to induce persistence and to impact virulence are still unknown.

The aim of this study is to investigate in detail the mechanism of a pestiviral RNase to act as an important IFN antagonist in its natural host environment. This project might shed light on the more fundamental mechanisms of the host to avoid the body’s own immunostimulatory RNA to act as a danger-associated molecular pattern. This “innate immunotolerance” to self nucleic acids and the specific detection of viral nonself is not specific for pestivirus pathogenesis, but is highly relevant across various species and is highly reminiscent of inappropriate innate autoimmune activation that are often accompanied by aberrant IFN induction (called “type-I interferonopathies”). Thus, this project investigates pestiviruses as model pathogens that co-evolved with its host over a long time that might also answer fundamental questions on the discrimination between “self” and “viral nonself RNA”.