Antagonism of type I interferon responses by new world hantaviruses.
Evasion of interferon (IFN)-mediated antiviral signaling is a common defense strategy for pathogenic RNA viruses. To date, research on IFN antagonism by hantaviruses is limited and has focused on only a subset of the numerous recognized hantavirus species. The host IFN response has two phases, an initiation phase, resulting in the induction of alpha/beta IFN (IFN-α/β), and an amplification phase, whereby IFN-α/β signals through the Jak/STAT pathway, resulting in the establishment of the cellular antiviral state. We examined interactions between these critical host responses and the New World hantaviruses. We observed delayed cellular responses in both Andes virus (ANDV)- and Sin Nombre virus (SNV)-infected A549 and Huh7-TLR3 cells. We found that IFN-β induction is inhibited by coexpression of ANDV nucleocapsid protein (NP) and glycoprotein precursor (GPC) and is robustly inhibited by SNV GPC alone. Downstream amplification by Jak/STAT signaling is also inhibited by SNV GPC and by either NP or GPC of ANDV. Therefore, ANDV- and SNV-encoded proteins have the potential for inhibiting both IFN-β induction and signaling, with SNV exhibiting the more potent antagonism ability. Herein we identify ANDV NP, a previously unrecognized inhibitor of Jak/STAT signaling, and show that IFN antagonism by ANDV relies on expression of both the glycoproteins and NP, whereas the glycoproteins appear to be sufficient for antagonism by SNV. These data suggest that IFN antagonism strategies by hantaviruses are quite variable, even between species with similar disease phenotypes, and may help to better elucidate species-specific pathogenesis.
Levine
Jessica R
JR
Rocky Mountain Laboratories, Hamilton, MT 59840, USA.
Prescott
Joseph
J
Brown
Kyle S
KS
Best
Sonja M
SM
Ebihara
Hideki
H
Feldmann
Heinz
H
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006476:Orthohantavirus / Q000235:genetics / Q000276:immunology*; D018778:Hantavirus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D014764:Viral Proteins; D016899:Interferon-beta