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).