Abstract
The orthohantavirus Puumala virus (PUUV), which is transmitted by bank voles (Clethrionomys glareolus), and other vole-borne hantaviruses contain in their small (S) genome segment two overlapping open reading frames, coding for the nucleocapsid protein and the non-structural protein NSs, a putative type I interferon (IFN-I) antagonist. To investigate the role of NSs of PUUV and other orthohantaviruses, the expression pattern of recombinant NSs constructs and their ability to inhibit human IFN-I promoter activity were investigated. The NSs proteins of PUUV and related cricetid-borne orthohantaviruses showed strong inhibition of IFN-I promoter induction. We identified protein products originating from three and two methionine initiation codons in the NSs ORF of PUUV during transfection and infection, respectively. The three putative start codons are conserved in all PUUV strains analysed. Translation initiation at these start codons influenced the inhibitory activity of the NSs products, with the wild-type (wt) construct expressing two proteins starting at the first and second methionine and showing strong inhibition activity. Analysis of in vitro-generated variants and naturally occurring PUUV NSs proteins indicated that amino acid variation in the NSs protein is well tolerated, suggesting its phenotypic plasticity. The N-terminal 20-amino-acid region of the NSs protein was found to be associated with strong inhibition and to be highly vulnerable to amino acid exchanges and tag fusions. Infection studies using human, bank vole, and Vero E6 cells did not show obvious differences in the replication capacity of PUUV Sotkamo wt and a strain with a truncated NSs protein (NSs21Stop), showing that the lack of a full-length NSs might be compensated by its N-terminal peptide, as seen in transfection experiments. These results contribute to our understanding of virus-host interactions and highlight the importance of future innate immunity studies in reservoir hosts.
Highlights
Rodent-borne orthohantaviruses belong to the family Hantaviridae in the order Bunyavirales and are distributed all over the world
Our transfection studies indicated the synthesis of different NSs protein variants of various cricetid-borne orthohantaviruses that can be explained by translation initiation at multiple start codons, M1, M14, or M24, by a leaky scanning mechanism
These three putative start codons were found to be conserved in NSs open reading frame (ORF) of all Puumala virus (PUUV) strains analyzed
Summary
Rodent-borne orthohantaviruses belong to the family Hantaviridae in the order Bunyavirales and are distributed all over the world. Infections with pathogenic orthohantaviruses can cause hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS) in humans [1]. In Europe, Puumala virus (PUUV) is responsible for most HFRS cases. Myodes glareolus), which are widely distributed in Europe and parts of Asia, act as reservoir hosts of this virus [2]. The small (S) segment of most bunyaviruses, in addition to the nucleocapsid (N) protein, encodes a non-structural (NSs) protein in an overlapping or antisense open reading frame (ORF) [3]. The ORF encoding NSs is only present in orthohantaviruses associated with rodents of the family Cricetidae (voles, lemmings, and New World rats/mice)
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