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.