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Site-directed mutagenesis study of host and viral proteins : single nucleotide variants of human TBK1 and functional sites of ebolavirus VP35

茂木, 和 北海道大学

2023.03.23

概要

SFTSV and HRTV were first identified in China in 2009 and in the United States
in 2012, respectively (8, 11). SFTSV and HRTV belong to the species Dabie bandavirus
and Heartland bandavirus, respectively, in the genus Bandavirus, family Phenuiviridae,
order Bunyavirales (7). These emerging viruses are mainly transmitted by tick bites and
cause fatal diseases in humans (5, 6). Clinically, SFTSV infection often results in acute
inflammatory responses accompanied by abnormal induction of immune and
inflammatory cytokines in patients’ sera (23). While they cause serious diseases with
various outcomes from severe and fatal disease to asymptomatic infection, the case
mortality rate has been reported as 6-30%, and 0.1%-0.6% subclinical infection of SFTSV
in humans has also been observed (24, 25). SFTSV-specific drugs and vaccines are
currently unavailable.
Like other phenuiviruses, the SFTSV and HRTV genome consists of threesegmented single-stranded RNA; large (L), medium (M), and small (S). The L and M
segments are of negative polarity, which encode the RNA-dependent RNA polymerase
and glycoproteins, respectively. On the other hand, the S segment encodes the
nucleocapsid protein and the NSs protein with an ambisense strategy (11). Some previous
studies have demonstrated that NSs proteins of SFTSV and HRTV antagonize the IFN-Iinducing signal via the retinoic acid-inducible gene-I (RIG-I) cascade by targeting the
downstream kinases TBK1/IκB kinase-ε (IKKε) (12, 26, 27). TBK1 mediates the
activation of IFN regulatory factor 3 (IRF3), leading to the induction of IFN-I (IFN-α/β)
following viral infections. TBK1 is an 84 kDa (729-amino acid) protein containing 4
domains; N-terminal kinase domain (KD), ubiquitin-like domain (ULD),
scaffold/dimerization domain (SDD) and C-terminal coiled-coil domains (CTD) (Figure
1A and B)(28, 29). In fact, IFNs are almost undetectable in the blood during the course
of SFTSV infection in humans (30). While both SFTSV and HRTV NSs proteins target
TBK1, they associate with different domains of TBK1: the SFTSV NSs protein interacts
with the KD region (31) and the HRTV NSs protein requires the interaction with the SDD
region (32).
Besides the host species difference, single nucleotide variants (SNVs) have also
been found to alter susceptibility to infectious diseases. ...

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