Cell autophagy
It has been recognized that autophagy is not only a lysosome-dependent degradation pathway, but also a defense mechanism. Growing studies have demonstrated the fundamental functions of autophagy in the process of virus infection. On the one hand, autophagy can induce innate immune response to suppress the proliferation of viruses; on the other hand, viruses evolve various strategies to defend against and escape the destructive effects of autophagy, and even use it to promote their own proliferation (S. Y et al., 2014). So far, four main forms of the interaction between virus infection and autophagy have been characterized. Autophagy is utilized by different viruses to boost their proliferation, such as foot-and-mouth disease virus (FMDV), hepatitis C virus (HCV). On the contrary, the inhibition of autophagy leads to a decrease of viral proliferation titer (D. M, P, SF, & FV, 2009; O. D. V et al., 2011). More relevantly, TGEV induced autophagy in the ST and PK-15 cell lines has been observed. Interestingly, silencing the three main autophagic proteins could considerably increase viral load, indicating inhibitory role of autophagy in TGEV replication (G. L et al., 2016). Similarly, suppressing the production of autophagosome is one of the ways used by viral infection. In the regard, herpes simplex virus type I (HSV-1) encoded ICP34.5 protein curbs autophagy by affecting Beclin-1 or eIF2α dephosphorylation, thus promoting self-replication (O. A et al., 2007). Besides these, interfering with autophagy related downstream pathways can be an effective approach to influence autophagy, as well exemplified by influenza A virus (IAV). Although there was no significant change in the IAV replication in the ATG5-deficient MEFs, sharply increased autophagosomes were observed in the IVA infected wild-type MEFs. Further evidence revealed that the IVA encoded M2 protein could prevent the fusion of autophagosomes and lysosomes, thereby confirming inhibited formation of autophagic lysosomes by viral infection (G. M et al., 2009). More importantly, the specific role of autophagy in PEDV proliferation has been verified in a previous study. The viral titer of PEDV was considerably decreased following the inhibition of cellular autophagy with its inhibitors (i.e. 3-MA or CQ), while increased proliferation of PEDV was observed upon the induction of cellular autophagy by its inducer (e.g. rapamycin). Decreased viral titer of PEDV was similarly achieved by silencing the expression of the key autophagy genes Beclin1 and ATG5. These robustly demonstrate the implication of cell autophagy in the replication of PEDV (G. X et al., 2017).
The interaction of viral proteins and host factors
As described above, intensive investigations have not only confirmed the involvement of some structural or non-structural proteins of PEDV, but also verified the important contribution of some identified host factors in the forms of proteins, signaling pathways or physiological processes in target cells to the infection of PEDV. Two features can therefore be deduced: different viral proteins and host factors participate in various stages of PEDV infection, and the contribution of these proteins/factors is mainly achieved by their interaction. To clearly illustrate these, we summarize the major functions of viral proteins of PEDV and host factors in Table 1, and provide an overall view of the participation and interaction of them during PEDV infection in Fig 1. Briefly, at the initial stage of PEDV infection, identified host factors so far, including pAPN, sialic acid, HS, TMPRSS2, MSPL and occludin, are confirmed to interact with the S protein, thereby facilitating the attachment and entry of the PEDV viral particles into target cells. Next, the host factors hnRNPA1 and NPM1 interact with the N protein of PEDV to promote viral transcription and replication. Subsequently, the host factor BST2 inhibits PEDV replication by binding and degrading the N protein of PEDV, while TMPRSS2 plays a role in the release of PEDV. Additionally, intracellular signaling pathways of host cells are regulated to promote the replication and proliferation of virus particles following the invasion of PEDV. For instance, it utilizes p38 MAPK and JNK signaling pathways for optimal replication, while NF-κB may contribute to translocate from the cytoplasm to the nucleus. Similarly, autophagy is beneficial to PEDV replication through autophagy regulatory factors and RNA interference (Table 1, Fig 1).