Hantaan Virus Triggers TLR3-Dependent Innate Immune Responses

Abstract

Immediately after viral infection, innate responses including expression of IFN-α/β and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-α/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. STAT1α 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.

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro

“…In contrast to this common feature, the NY-1 hantavirus G1 cytoplasmic tail, but not the corresponding region of PHV, blocked activation of IRF3 by destabilization of the TBK1/TRAF3 kinase/adaptor complex (Alff et al, 2006(Alff et al, , 2008. Moreover, it was shown that the Tolllike receptor 3 (TLR3) is involved in innate responses triggered by HTNV late after infection, which was not required for the induction of antiviral genes by PHV (Handke et al, 2009b). These data indicate that specific antagonistic activities and/or selected recruitment of different pathogen recognition receptors might be decisive for the differential antiviral responses to infection with pathogenic and non-pathogenic hantaviruses.…”

“…Hantaviruses considered to be nonpathogenic, like PHV, were found to enter the cell via integrin-aII/-bI (Gavrilovskaya et al, 1998;Mackow & Gavrilovskaya, 2001). Second, several pathogenic hantaviruses elicit delayed innate antiviral responses when compared with an immediate response triggered by nonpathogenic hantaviruses (Alff et al, 2006(Alff et al, , 2008Geimonen et al, 2002;Handke et al, 2009b;Khaiboullina et al, 2004;Kraus et al, 2004;Spiropoulou et al, 2007). Tumour necrosis factor receptor-associated factor 3 (TRAF3) was indicated to be crucial for innate antiviral responses both to pathogenic and non-pathogenic hantaviruses (Handke et al, 2009b).…”

“…Second, several pathogenic hantaviruses elicit delayed innate antiviral responses when compared with an immediate response triggered by nonpathogenic hantaviruses (Alff et al, 2006(Alff et al, , 2008Geimonen et al, 2002;Handke et al, 2009b;Khaiboullina et al, 2004;Kraus et al, 2004;Spiropoulou et al, 2007). Tumour necrosis factor receptor-associated factor 3 (TRAF3) was indicated to be crucial for innate antiviral responses both to pathogenic and non-pathogenic hantaviruses (Handke et al, 2009b). In contrast to this common feature, the NY-1 hantavirus G1 cytoplasmic tail, but not the corresponding region of PHV, blocked activation of IRF3 by destabilization of the TBK1/TRAF3 kinase/adaptor complex (Alff et al, 2006(Alff et al, , 2008.…”

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

“…TLR3 and TLR4 have been implicated as sensors of hantavirus particles [18][19][20]. Recently, hantavirus-derived RNA was identified as a stimulus of retinoic acid inducible gene I (RIG-I), a cytoplasmic sensor of virus-derived RNA [21].…”

Hantaviruses Induce Antiviral and Pro-Inflammatory Innate Immune Responses in Astrocytic Cells and the Brain

“…Both antiviral and pro-inflammatory responses to hantavirus infection play an important role in the modulation of host defense and disease manifestation (1,6,18,25,38,46,48). Pathogenic rodent-borne hantaviruses, such as HTNV, evade early innate immune responses by downregulating antiviral responsive gene expression immediately after infection.…”