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

various CNS disorders. Also, there is potential for precise anti-inflammatory drugs in future that may
interfere with these genetic mechanisms, allowing more tailored therapeutics.

Modulation of expression profiles of autophagic genes in response to infection
Listeria Monocytogenes is an intracellular Gram positive bacterium which can cause gastroenteritis. Upon its
hematogenous dissemination it can breach BBB and thus cause meningitis, meningoencephalitis, and brain
abscesses. An experiment using quantitative polymerase chain reaction (q-PCR) arrays containing 84 genes
to analyse the expression profiles of autophagic genes in response to L. monocytogenes infection were carried
out in rat brains. It was shown that 7 out of 84 genes were clearly modified with TNF, which functions to
limit brain damage, being the most highly up-regulated gene after infection . The expression of chemokine
[38]
(C-X-C motif) receptor 4, and the insulin-like growth factor 1 that act as co-regulators of autophagy pathway,
were down-regulated. Only the expression of core autophagy gene ATG12 was modulated by infection.

During primary infection, intracellular L. monocytogenes along with infected host cells are usually targeted
for degradation by autophagy. Once entering human body, L. monocytogenes are endocytosed into a vacuole,
and listeriolysin O (LLO) is secreted to perforate the vacuole membrane, and subsequently gain access into
the host cell cytosol. Subsequently, the product of the actA gene induces the polymerization of host actin,
which eventually forms a tail, propelling bacterial movement within host cytosol for cell-to-cell spread. In this
study of utilizing wild-type L. monocytogenes to infect mouse embryonic fibroblast cells, it is demonstrated
that induction of protective autophagy pathway depends on expression of LLO, suggesting that vacuole
permeabilization is a prerequisite for autophagy. On top of that, a mutant L. monocytogenes strain deficient
of bacterial phospholipase production, has been degraded due to autophagy. It suggests that phospholipases
plays a role in evasion of autophagy. Hence, it is hypothesized that the therapeutic target of actA as well
as genes coding for phospholipases, might enhance autophagy, resulting in eradication of intracellular L.
monocytogenes. Thus, identification of genes modulated upon infection in brain cells, as well as the mechanism
of resulting autophagy, may confer a new strategy for therapeutic intervention in infectious disease [39-41] .

Pathogen adaptations to host cell autophagy
Infectious agents which successfully parasitize their target cells have evolved to develop multiple strategies
to dampen autophagy-dependent activation of host immune responses. So far, the types of identified
microbial adaptation mechanisms can be broadly classified as strategies to: (1) prevent autophagy induction;
(2) avoid pathogen recognition by the autophagic machinery; (3) prevent the autophagosome maturation
into autolysosome; and (4) utilize components or functions of the autophagic mechanism to facilitate
intracellular survival, multiplication, and release of intracellular microbes out of the infected cell .
[42]

Herpes simplex viruses (HSVs) are able to inhibit autophagy in neurons, and subsequently confer neuro-
virulence by three main mechanisms, including the blockage of autophagy-stimulatory protein kinase
resource (PKR) signaling, blockage of Beclin-1, or via the activation of mTOR signaling. In HSV-1, the
utilization of a single viral virulence protein ICP34.5 to block the Beclin-1 dependent autophagy has been
shown to be essential for HSV-1 encephalitis . Of interest, it has been suggested that the inefficient fusion
[43]
between lysosomes and autophagosomes in HSV-infected cells is caused by oxidative stress, which is
reported to be associated with neurodegeneration .
[44]
Coxsackievirus has been shown to utilize autophagosomes for replication, in which it limits autophagosome
and lysosome fusion by increasing light chain 3 (LC3) cleavage. It has been hypothesized that this is achieved
by increasing a protein-activated signaling cascade, known as the calpain-dependent pathway .
[45]

A proposed mechanism of L. monocytogenes meningitis is that this intracellular pathogen camouflages and
avoids recognition, subsequently rapidly replicating in the host cytosol by assembling host cell proteins to