1.2 Life cycle
Flaviviruses share a common mechanism of propagation in host cells.
Initially, they enter target cells via receptor-mediated endocytosis and
transfer to endosomes. The acidic environment in the endosomal lumen
triggers conformational changes of the glycoprotein on the surface of
the virus, causing the virus envelope to fuse with the endosomal
membranes(Bressanelli et al., 2004).
Subsequently, the disintegration of the viral capsid (‘uncoating’)
delivers the RNA genome to the cytoplasm, completing the entry process.
The positive polarity genomes then serve as templates for translation
and replication. When the viral RNA is translated into a precursor
protein at the endoplasmic reticulum (ER), this polypeptide is
coordinated and post-translationally processed by the viral and host
protease to produce three structural proteins and seven nonstructural
proteins. After translation of input genomic RNA, the RNA-dependent RNA
polymerase (RdRp) NS5 copies complementary negative-stand RNA from
genomic RNA, which serves as a template for the synthesis of new
positive-strand viral RNA(Brinton, 2002).
Immature, non-infectious virions are assembled in the ER, where viral
RNA is complexed with protein C and packaged into an ER-derived lipid
bilayer containing heterodimers of prM and E
proteins(Lorenz et al., 2003;
Mackenzie & Westaway, 2001). The prM
protein acts as a scaffold to prevent the virus from fusing prematurely
during transport out of the cell(L. Li et
al., 2008). Subsequently, PrM is cleaved into M by the cellular
protease furin in the trans-Golgi
network(I. M. Yu et al., 2008). Finally,
mature infectious virus particles are released outside the cell by
exocytosis (Figure 2).
Apoptosis
Apoptosis, also known as programmed cell death (PCD), is a
self-protection mechanism used by multicellular organisms to eliminate
senescent, damaged, or pathogen-infected cells. Apoptosis is regulated
by two classical signaling pathways: the intrinsic and the extrinsic
apoptotic pathways. Apoptotic cells are manifested by cell shrinkage,
chromatin aggregation, DNA fragmentation, mitochondrial swelling, and
finally the formation of apoptotic bodies, which are cleared by
phagocytes(Kennedy, 2015). Studies have
found that apoptosis plays an important role in the pathogenesis of
viral infections. As a key innate defense mechanism, it inhibits virus
replication and clears virus-infected
cells(Benedict, Norris, & Ware, 2002),
which is of great significance for maintaining the healthy development
of organism and the normal function of the immune
system(X. Liu, Kim, Yang, Jemmerson, &
Wang, 1996). However, many viruses have evolved strategies to prevent
or delay the occurrence of apoptosis during virus replication until
sufficient progeny viruses are produced. Moreover, some viruses-induced
apoptosis can enhance the spread of the virus, leading to tissue damage
and disease. In this article, we focus on reviewing the roles played by
flavivirus in the regulation of cell apoptosis, and understanding the
mechanism of flavivirus regulating apoptosis will be helpful for future
research.