Page 18 - Read Online

Page 6 of 14 Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43

the bacterial cell surface via ActA ot InlK proteins. Also, L. monocytogenes phospholipase C is used to avoid
autophagy by decreasing autophagic flux, diminishing host PI3P stores, and inhibiting the maturation of
[46]
preautophagosomal structures .
It is reported with evidence that autophagy plays a pivotal role as a major defense mechanism in host cells,
not only in the brain, but in other cells as well. Recently, a number of reports have successfully elaborated
the scope of the autophagic process in immunity, being evolved from an antimicrobial defense mechanism
to a complex immunological process that plays a major role in adaptive immunity, innate immunity, and
inflammation. In the support of the importance of autophagy as a key defense mechanism, it is now clear
that highly evolved intracellular pathogens possess specialized anti-autophagic adaptations to block or
hinder their elimination. Looking forward, it will be necessary to further understand how different microbes
manipulate autophagy, and their interaction with host autophagy mechanisms, to provide a potential source
for the development of antimicrobial treatment modalities that antagonize the pro-microbe responses, at
the same time promoting the anti-microbe functions of autophagy.

Autophagy induction and intracellular replication in viral central nervous system infections
There is a growing list of viruses which have been studied for relating their interactions with autophagy.
For numerous viruses, there is a link between infection and autophagy. Certain viruses are responsible for
the induction of an autophagic event, while others are involved in the intermediate processes of autophagy.
Research has shown that autophagy not only plays a role in JEV and dengue infection, but also positively
regulates the virus replication . It is a well-known fact that energy is required for any cellular replication. In
[47]
dengue viral infection, autophagy is shown to be connected to lipid metabolism in the virus, thus providing
[36]
free fatty acids for synthesis of ATP . This strongly suggests that the principle role of autophagy in dengue
virus replication is for the regulating lipid metabolism. In contrast to dengue virus, the autophagic vacuole
shows no evidence of being the site of replication for JEV. However, this finding is not consistent with
the experiments conducted by Jin et al. and Wang et al. , who stated that the accumulation of the
[49]
[48]
autophagosome and the autophagosome-lysosome fusion are essential to promote JEV replication [47-49] . In
addition to initiating autophagy, viral intrusion also affects the intermediate step of the event. Evidence
which supports this statement is the accumulation of p62 protein (which is degraded by autophagy process)
in simian immunodeficiency virus (SIV)-infected brain tissues .
[50]
It is also vital to find out if viral-induced autophagy will result in changes in the number of autophagosomes,
which signifies the initiation of autophagy. Intriguingly, in the SIV-infected neurons, there is a significant
reduction in the autophagosomes, in addition to changes in the distribution of the autophagosomes in the
neurons . The decrease in the number of autophagosomes may be due to the loss of neurons. This observation
[50]
also implies the lack of initiation of autophagy in SIV infection. Further studies to test for the autophagic flux
need to be carried out in order to determine how these two interact. Analysis showed that in SIV-infected
microglia, there was loss of the neuronal processes and a decrease in the number of autophagosomes in the
remaining processes; however the number of autophagosomes in the soma of the neurons remained constant.
These findings demonstrate two reasonings: lack of initiation of the autophagy, and the increased clearance of
the autophagosomes during the intermediate process. Further studies are required to analyze the importance
of autophagosomal distribution in the pathogenesis of viral infection in microglia. It is interesting to note
that rapamycin pre-treatment (an autophagy inducer) protected against the neurotoxic effects of the SIV,
although the pre-treatment failed to recover the number of neurons to baseline level . This indicates that
[50]
autophagy might be one of the many pathways which serves to protect neurons in viral infections.

Increased hepatitis C virus replication and neurotoxicity with elevated autophagy
Even though hepatitis C virus (HCV) is a hepatotropic virus, this infection is also considered a systemic
disease with extra-hepatic manifestations. Up to 50% of patients with chronic HCV infection have