Page 36 - TBE_Book_V2_2019

Chapter 2a: Virology

62
recombinant TBEV with or without the E membrane fusion. A number of identified
protein N-linked glycan. The results suggested substitutions causing escape of the virus from
that glycosylation of the TBEV E protein is the neutralizing effect of monoclonal
69
critical for the intracellular secretory process antibodies, deficiency in the ability to
70
in mammalian cells but cleavage of the N- agglutinate erythrocytes, and a change in
linked glycan after secretion did not affect virus growth properties in cell cultures, mice,
virion infectivity in these cells. On the other or ticks, 60,71-74 have been described.
hand, E protein glycosylation seems to play no
64
significant role in virus reproduction in ticks.
Non-structural proteins
Domain II is formed of 2 long loops that
extend out of domain I and form a finger-like NS1 is a glycoprotein containing 2 or 3
potential glycosylation sites and 12 conserved
structure. Domain II contains a number of 75
beta sheets and 3 disulfide bridges. 61,65 Part of cysteines forming disulfide bridges. It exists
in dimeric forms localized freely in the
the domain responsible for the fusion of viral
envelope with the membrane of the cytoplasm or associated with membranes.
endosome is called the fusion peptide; this Since the protein is highly hydrophilic and
contains no transmembrane domains, its
peptide mediates insertion of the E protein
association with membranes remains poorly
into the endosomal membrane resulting in
fusion of viral envelope with the membrane of understood. Probably, dimerization creates a
66
the endosome. The initiation of fusion is hydrophobic surface of the protein for its
39,76
crucially dependent on the protonation of 1 of peripheral association with membranes.
Alternatively, some species of the protein
the conserved histidines (His323), which
could be anchored into the membrane by
works as a pH sensor at the interface between 39,77
domains I and III of E, leading to the glycosyl-phosphatidylinositol. The intra-
dissolution of domain interactions and to the cellular NS1 is central to viral RNA replication.
63
exposure of the fusion peptide. The NS1 protein along with other non-
structural proteins (see below) and viral RNA
Domain III has the typical fold of an immuno- are targeted towards the luminal side of the
65
globulin constant (IgC) molecule. It contains endoplasmic reticulum, forming a replication
a beta barrel composed of 7 antiparallel beta complex (RC). Intracellular NS1 also interacts
sheets. The lateral part of domain III is with various host proteins to assist viral
believed to be responsible for binding to a replication, translation, and virion production;
61
specific cellular receptor. e.g., interaction of NS1 with 60S ribosomal
78
Amongst the most conserved parts of the E subunits was described. Secretion of NS1
protein, there are 12 cysteine residues protein into the extracellular space appears
forming 6 disulfide bridges with conserved particularly in the form of pentamers or
localization in common with all known flavi- hexamers and occasionally as decamers or
79
67
viruses. dodecamers. This so-called ‘soluble antigen’,
together with membrane-bound NS1 induces
The E protein is also considered to be a major a protective immune response in the host.
80
determinant of TBEV virulence. Amino acid NS1 protein is also known to activate the Toll-
substitutions in E protein often cause decrease like receptors (TLRs), and inhibit the
81
in neuroinvasiveness, although neurovirulence complement system. 82–83
68
is usually not reduced. The highest number
of attenuating mutations in the E protein was NS2A is a small, hydrophobic protein,
revealed in the domain that probably binds to currently with no defined function. It is
39
specific cell receptors and participates in believed to play a role in forming the RC. A

31
31