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Institute of Virology, Helmut-Ruska-Haus, University Hospital Charité, Charité Campus Mitte, Berlin, Germany
Immediately after viral infection, innate responses including expression of IFN-
/β and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-/β and ISGs in response to an infection is often decisive for virulence. Interestingly, in primary endothelial cells ISGs are induced later by hantaviruses pathogenic to humans than those considered to be nonpathogenic or of low virulence. Here we demonstrate that pathogenic Hantaan (HTNV) and putatively nonpathogenic Prospect Hill hantavirus (PHV) differentially activate innate responses in the established cell lines A549 and HuH7. STAT1 phosphorylation was detectable 3 h after PHV inoculation but not within the first 2 days after HTNV inoculation. The velocity to induce the ISGs MxA and ISG15 correlated inversely with amounts of virus produced. Moreover, expression of the inflammatory chemokine CCL5 was also induced differentially. Both hantaviruses induced innate responses via TRAF3 (TNF receptor-associated factor 3), and TLR3 was required for HTNV-induced expression of MxA, but not for the MxA induction triggered by PHV. Infection of RIG-I-deficient HuH7.5 cells revealed that RIG-I (retinoic acid receptor I) was not necessary for induction of innate responses by PHV. Taken together, these data suggest that HTNV and PHV elicit different signaling cascades that converge via TRAF3. Early induction of antiviral responses might contribute to efficient elimination of PHV. Subsequent to clearance of the infection, innate responses most likely cease; vice versa, retarded induction of antiviral responses could lead to increased HTNV replication and dissemination, which might cause a prolonged inflammatory response and might contribute to the in vivo virulence.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The study was supported by Deutsche Forschungsgemeinschaft (RA 1057/2-1) and Universitäre Forschungsförderung Charité Berlin.
2 W.H. and R.O. equally contributed to this work.
3 Address correspondence and reprint requests to Dr. Andreas Rang, Institute of Virology, Helmut-Ruska-Haus, University Hospital Charité, Charité Campus Mitte, D-10098 Berlin, Germany. E-mail address: andreas.rang{at}charite.de
4 Abbreviations used in this paper: N protein, nucleoprotein; dpi, days postinoculation; FFU, focus forming units; G1, glycoprotein 1; hpi, hours postinoculation; HTNV, Hantaan virus; IKK
, I
B-kinase ; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; ISG, IFN-stimulated gene; MDA-5, melanoma differentiation-associated gene 5; MOI, multiplicity of infection; PAMP, pathogen-associated molecular pattern; PHV, Prospect Hill hantavirus; RIG-I, retinoic acid receptor I; PRR, pathogen recognition receptor; siRNA, small interfering RNA; TBK-1, TRAF-family member-associated NF-B activator binding kinase 1; TRAF3, TNF receptor-associated factor 3.
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