Research Article: Hantavirus Regulation of Type I Interferon Responses

Date Published: August 8, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Valery Matthys, Erich R. Mackow.

http://doi.org/10.1155/2012/524024

Abstract

Hantaviruses primarily infect human endothelial cells (ECs) and cause two highly lethal human diseases. Early addition of Type I interferon (IFN) to ECs blocks hantavirus replication and thus for hantaviruses to be pathogenic they need to prevent early interferon induction. PHV replication is blocked in human ECs, but not inhibited in IFN deficient VeroE6 cells and consistent with this, infecting ECs with PHV results in the early induction of IFNβ and an array of interferon stimulated genes (ISGs). In contrast, ANDV, HTNV, NY-1V and TULV hantaviruses, inhibit early ISG induction and successfully replicate within human ECs. Hantavirus inhibition of IFN responses has been attributed to several viral proteins including regulation by the Gn proteins cytoplasmic tail (Gn-T). The Gn-T interferes with the formation of STING-TBK1-TRAF3 complexes required for IRF3 activation and IFN induction, while the PHV Gn-T fails to alter this complex or regulate IFN induction. These findings indicate that interfering with early IFN induction is necessary for hantaviruses to replicate in human ECs, and suggest that additional determinants are required for hantaviruses to be pathogenic. The mechanism by which Gn-Ts disrupt IFN signaling is likely to reveal potential therapeutic interventions and suggest protein targets for attenuating hantaviruses.

Partial Text

Several studies have established that pathogenic hantaviruses regulate the early induction of IFN responses by interfering with the IRF3 and NF-κB signaling pathways, and the viral Gn-T is likely to regulate early IFN induction [49–51, 87, 89, 95, 96]. The Gn-T has been shown to inhibit RIG-I- and TBK1-directed IFN, ISRE and κB transcriptional responses although the mechanism by which the Gn-T disrupts TBK1-directed IFN signaling responses remains to be defined [49, 50]. Viral proteins that regulate IFN responses, the timing of early IFN regulation, and IFN regulatory mechanisms may differ between hantaviruses. Determinants of IFN inhibition are located in the C-terminal 42 residues of the Gn-T but are likely modified by residues within the full-length tail, the degron in some proteins, and the presence of additional hantavirus proteins (N, NSs and Pol). Identifying residues necessary for IFN regulation will define elements that can be modified in order to attenuate hantaviruses and clarify mechanisms of IFN antagonism [51]. Although regulation of the early IFN response appears to be a crucial factor for the successful replication of hantaviruses in endothelial cells, it is clear that replication alone does not define a hantaviruses pathogenic potential. Thus replication in human endothelial cells is necessary but not sufficient for hantaviruses to be pathogenic and this suggests that additional pathogenic determinants are required for hantaviruses to be human pathogens [105–107, 109–111].

 

Source:

http://doi.org/10.1155/2012/524024

 

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