Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

• Published in: The Journal of immunology (1950) 2009-03, Vol.182 (5), p.2849-2858
• Main Authors: Handke, Wiebke, Oelschlegel, Robin, Franke, Renate, Kruger, Detlev H, Rang, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Transformed; Cell Line, Tumor; Chemokine CCL5 - biosynthesis; Chemokine CCL5 - genetics; Chlorocebus aethiops; Cytokines - physiology; DEAD Box Protein 58; DEAD-box RNA Helicases - physiology; Gene Expression Regulation, Viral - immunology; GTP-Binding Proteins - biosynthesis; GTP-Binding Proteins - genetics; Hantaan virus - immunology; Hantaan virus - pathogenicity; Humans; Immunity, Innate; Interferon-alpha - physiology; Interferon-beta - physiology; Myxovirus Resistance Proteins; Receptors, Immunologic; Signal Transduction - immunology; STAT2 Transcription Factor - physiology; TNF Receptor-Associated Factor 3 - physiology; Toll-Like Receptor 3 - physiology; Ubiquitins - physiology; Vero Cells; Virus Activation - immunology; Virus Replication - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0802893

Immediately after viral infection, innate responses including expression of IFN-alpha/beta and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-alpha/beta 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. STAT1alpha 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.