Hantavirus infection and innate immunity

Pathogenic hantaviruses replicate within human endothelial cells and cause two diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In order to replicate in human endothelial cells, pathogenic hantaviruses inhibit the early induction of type I interferon (IFN) and establish an IFN resistant state within infected cells. In contrast, the non-pathogenic hantavirus, PHV, induces an early high level IFN response and fails to replicate within human endothelial cells. However, PHV replicates within IFN deficient Vero E6 cells and presumably regulates cellular IFN responses within host endothelial cells. Pathogenic hantavirus Gn proteins have been shown to regulate early innate cellular responses by blocking IFN induction at the level of the TBK1 complex. The cytoplasmic tail of pathogenic hantavirus Gn proteins also containsa degron which directs protein ubiquitination and degradation. Since the activation of TBK1-TRAF3 complexes is regulated by the state of TRAF3 ubiquitination, these findings tie the regulation of TBK1-directed IFN responses to Gn degradation. The mechanism by which hantaviruses regulate TBK1 complex formation and IFN induction is only beginning to unfold. However, it is clear that IFN regulation by the Gn-tail is required for hantavirus success within human endothelial cells. As a result, IFN regulatory elements within the Gn-tail are determinants of hantavirus pathogenesis and viable targets for attenuating pathogenic hantaviruses.