Hantaan virus (HTNV) causes severe human disease. The HTNV genome consists of three ssRNA segments of negative polarity that are complexed with viral nucleocapsid (N) protein. How the human innate immune system detects HTNV is unclear. RNA helicase retinoic acid-inducible gene I (RIG-I) does not sense genomic HTNV RNA. So far it has not been analysed whether pathogenassociated molecular patterns generated during the HTNV replication trigger RIG-I-mediated innate responses. Indeed, we found that knock-down of RIG-I in A549 cells, an alveolar epithelial cell line, increases HTNV replication and prevents induction of 29,59-oligoadenylate synthetase, an interferon-stimulated gene. Moreover, overexpression of wild-type or constitutive active RIG-I in Huh7.5 cells lacking a functional RIG-I diminished HTNV virion production. Intriguingly, reporter assays revealed that in vitro-transcribed HTNV N RNA and expression of the HTNV N ORF triggers RIG-I signalling. This effect was completely blocked by the RNA-binding domain of vaccinia virus E3 protein, suggesting that dsRNA-like secondary structures of HTNV N RNA stimulate RIG-I. Finally, transfection of HTNV N RNA into A549 cells resulted in a 2 log-reduction of viral titres upon challenge with virus. Our study is the first demonstration that RIG-I mediates antiviral innate responses induced by HTNV N RNA during HTNV replication and interferes with HTNV growth. INTRODUCTIONHuman infections with hantaviruses are on the rise due to enhanced human contact with rodents, their main reservoir (Ludwig et al., 2003;Schmaljohn & Hjelle, 1997;Ulrich et al., 2002). Humans are infected after inhalation of aerosols from excreta shed by chronically infected rodents that do not show obvious symptoms. The outcome of human infection is variable and depends on the infecting hantavirus species. Pathogenic hantavirus species elicit highly lethal diseases, hantavirus cardiopulmonary syndrome (HCPS) or haemorrhagic fever with renal syndrome (HFRS) (Krüger et al., 2001;Muranyi et al., 2005). Hantaan virus (HTNV), the prototype member of the genus Hantavirus in the family Bunyaviridae, causes HFRS with a case fatality rate up to 15 %.Hantaviruses are enveloped and contain a tripartite ssRNA genome of negative polarity (Schmaljohn & Nichol, 2007). It consists of a small, medium and large segment that encode the nucleocapsid (N) protein, envelope glycoproteins (Gn and Gc) and RNA-dependent RNA polymerase (RdRp). The 59 and 39 termini of the hantaviral genome form a panhandle structure. HTNV replication starts with virion attachment to integrin b3 (CD61), a receptor for pathogenic hantaviruses (Gavrilovskaya et al., 1998(Gavrilovskaya et al., , 1999. Recently, decay-accelerating factor (CD55) and receptor for globular heads of C1q (gC1qR) have been defined as additional HTNV receptors (Choi et al., 2008; Krautkrämer & Zeier, 2008). After entry by endocytosis and acidification of endosomes fusion between endosomal membrane and viral envelope takes place. After release of the viral nucleocapsid int...
The tri-segmented RNA genome of hantaviruses facilitates genetic reassortment by segment swapping when cells are co-infected with different virus strains. We found efficient in vitro reassortment between members of two different genetic lineages of the Dobrava-Belgrade virus species, the weakly virulent DOBV-Aa and highly virulent DOBV-Af. In all reassortants, S and L segments originated from the same parental strain, and only the M segment was exchanged. To identify functional differences between the parental strains DOBV-Aa and DOBV-Af in cell culture and to compare them with the reassortants, we studied elements of the innate immunity in virus-infected cells. The contrasting phenotypes of the parental viruses were maintained by the reassortants carrying the respective S and L segments of the parental virus and were not influenced by the origin of the M segment.
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