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Page 4 of 14 Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43

Previously, studies on autophagy have been focused on its occurrences and association with nutrient
deprivation, as well as age-associated issues. However, recently, there has been a significant increase in
[12]
studies focusing on immunological functions of autophagy . In the context of infection, immunity, and
neurodegeneration, autophagy seems to have a pivotal role in neuronal homeostasis . Its dysfunction
[31]
has been linked to several neurodegenerative diseases such as Parkinson’s, Huntington’s, and Alzheimer’s
diseases. As the first line of defense in brain, the autophagic pathway is known to be involved in both
physiological and pathological processes. However, its immunological role in the CNS environment is not
yet clearly studied.

Interplay between inhibitory cytokines and the autophagy process has recently been reported, which
reveals a novel mechanism by which autophagy could control the immune response. Interactions between
autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27 are evident from
[12]
earlier studies . IL-37 and IL-35 are two newly discovered anti-inflammatory cytokines. IL-37 inhibits
the production of pro-inflammatory cytokines in response to inflammation . IL-35 suppresses T cell
[32]
[33]
proliferation predominantly, and thereby inhibits its effector functions . The possible interactions between
above two anti-inflammatory cytokines, and autophagy have also been recently . However, no such
[12]
interaction in the context of the CNS environment is discussed in literature.

AUTOPHAGY INDUCTION AND ITS ALTERATION FOLLOWING INFECTION
Accumulating evidence demonstrates that autophagy plays a protective role against infectious diseases by
diminishing intracellular pathogens, including bacteria, viruses, and parasites. The following section will
summarize the interplay between autophagy induction and infection due to various microbial agents.

Several intracellular bacterial agents, such as Anaplasma phagocytophilum, Brucella abortus, Coxiella
burnetii, Legionella pneumophila, and Staphylococcus aureus, have the potential to alter the autophagic
pathway to their own advantage . These bacterial agents might stimulate their uptake and internalization
[9]
into autophagosomes by secretion of special effector molecules . Moreover, these pathogens seem
[34]
to be efficiently grown within auto-phagosome compartments. Additionally, survival of some of these
microorganisms is experimentally inhibited by using some autophagy inhibitors, and even their survival is
compromised when grown within cells of deficient or defective ATG5 gene [35,36] .

Some studies have reported that some pathogenic bacteria also have ability to manipulate autophagy
regulation processes at gene transcription level. For instance, Francisella tularensis, Yersinia enterocolitica,
and Burkholderia cenocepacia can down-regulate the transcription of important autophagy-related (ATG)
genes. Thus, they reduce the activity of autophagy at cellular level during infection. Conversely some
pathogens up-regulate autophagy at gene level, which could augment inflammation at the site of infection.
As previously discussed, prolonged inflammation could result in further injury to surrounding body tissues.
In addition, the autophagic pathway is known to be exploited by RNA viruses (e.g. mouse hepatitis virus,
rhinovirus and poliovirus), for promoting RNA replication with membrane scaffold . In this review, the
[37]
interactions between different CNS intracellular pathogens and autophagic genes, along with the resulting
autophagic and inflammatory processes are being studied.

The presence of pathogenic antigens can induce autophagic genes through a stratified array of principal
immunological processes, and therefore result in augmented autophagy and inflammation at the site of
infection, which limits bacterial proliferation. However, as mentioned above, excessive autophagy and
inflammatory process do put surrounding healthy brain tissue at risk.

A detailed understanding of molecular mechanisms in neuroinflammatory and neural cell death/autophagy
dysfunction pathways might identify interesting targets for drug-discovery and biomarker identification in