Balancing viral replication in spleen and liver determines the outcome of systemic virus infection

Abstract

The innate immune system limits virus replication during systemic infection by producing type I interferons (IFN-I) but still has to allow viral replication to achieve maximal innate and adaptive immune activation. Some spleen and lymph node resident antigen presenting cells (APCs) show limited response to IFN-I due to expression of the endogenous inhibitor of IFN-I signaling, Usp18. Therefore, virus in this spleen niche replicates despite high levels of IFN-I. This enforced viral replication leads to an exorbitant propagation of viral antigens and viral RNA. Viral antigen leads to massive activation of the adaptive immune system, while viral RNA to activated innate immunity. In contrast to these APCs, liver resident Kupffer cells, take up most of the systemic virus and suppress its replication in response to IFN-I. In addition, virus specific CD8 + T cells which are primed in the spleen migrate to the liver and kill virus infected cells. In this review we discuss the different mechanisms, which influence immune activation in spleen and antiviral mechanisms in the liver and how they determine the outcome of virus infection.

Zusammenfassung

Während einer systemischen Infektion begrenzt das angeborene Immunsystem die Ausbreitung des Virus. Typ-I-Interferon (IFN-I) ist eines der wichtigsten Zytokine, das die Replikation von Viren in Körperzellen hemmt und somit die Ausbreitung verhindert. Trotz hoher IFN-I-Konzentration kann es dennoch zur Virusreplikation in Milz und Lymphknoten kommen. Spezialisierte Antigen-präsentierende Zellen (APZ), die Usp18 exprimieren, das die IFN-I-Wirkung blockiert, replizieren Viren, was zur massiven Produktion von viraler RNS und Antigenen führt. Virale RNS aktiviert angeborene Immunzellen, während virale Antigene zu massiver Aktivierung des adaptiven Immunsystems führen. Im Gegensatz zu APZ in der Milz reagieren leberansässige Makrophagen, sogenannte Kupffer-ZeIlen, sehr stark auf IFN-I und supprimieren somit die Virusreplikation. Damit kommt es in der Milz zur starken Immunaktivierung, während die Leber systemische Viruspartikel aufnimmt und deren Vermehrung inhibiert. Immunzellen, die in der Milz aktiviert werden, wandern von dort häufig in die Leber, um die Ausbreitung des Virus zu verhindern. In dieser Übersichtsarbeit diskutieren wir die verschiedenen Mechanismen, die die Aktivierung des Immunsystems beeinflussen.

Schlüsselwörter

Hepatitis C - Virushepatitis - Leber - Immunaktivierung - Hepatitis B

Key words

Hepatitis C - virushepatitis - liver - immune activation - hepatitis B

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