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

[1-4]
neurodegeneration and/or neurobehavioral abnormalities . Prolonged CNS infections with neurotropic
pathogens, along with other underlying conditions such as autoimmune responses, vascular diseases, head
injury, cerebral edema, changes in neurotransmitter concentrations, nutritional deficiencies, heavy metal
poisoning, and effects of environmental toxins, might play roles in the pathogenesis of neurodegenerative
[5-8]
and/or neurobehavioral diseases . However, the role of any CNS infections in specific pathogenesis of
neuronal cell death has been not yet been conclusively established.

Intracellular pathogens can invade host cells, protecting them from the host’s systematic immune response .
[9]
However, they face a serious challenge within the infected cell, posed as competent hosts possess innate
immune mechanisms specifically tailored to eradicate foreign invaders. To combat this, infectious agents
follow one or more strategies in order to avoid host immune attack. These sophisticated strategies include:
lysis and escape from the phagocytic compartment; modifying the phagosome microenvironment; surviving
in acidic compartment. Some pathogenic agents might use more than one of the above strategies in order to
successfully survive within the host cell .
[9]

Presently, it is important to highlight interactions between the neurotropic pathogens and the host’s immune
system in the brain micro environment to understand the mechanism of pathogen survival mechanisms, and
also the roles of host and pathogen factors in the pathogenesis of neurodegenerative and/or neurobehavioral
diseases. Thus, it is interesting to revisit and update on innate immunity in the CNS, and also to further
discuss the neuroinflammatory pathways which contribute to massive neurodegeneration in CNS infections
by many different neuropathogens.

Recent studies have shown that pathogen induced autophagy negatively influences its replication, as shown
in the case of Japanese encephalitis virus (JEV) infected mouse neuronal cells; autophagy has been found
[10]
to delay virus-induced cell death . On the other hand, for some neuropathogens (Toxoplasma gondii and
other related parasites), an intrinsic role for autophagy has been identified in persistent infections .
[11]
Besides autophagy being an intrinsic cellular defense mechanism against invading microorganisms, it
can also appear to be linked to a number of other human disorders, such as autoimmune diseases, sterile
inflammation, and even neoplasms . Moreover, knowledge of its roles and regulations in the central
[12]
nervous system remains unclear .
[13]
The main purpose of the present review is to find out possible interactions of neurotropic intracellular
pathogens with neuronal cell autophagic process favoring the pathogen(s) for their intracerebral survival, as
well as multiplication in CNS infectious diseases.

IMMUNE RESPONSES OF THE CENTRAL NERVOUS SYSTEM
The innate immunity of the CNS includes complex signaling pathways and a network of cells. Previously
the brain was considered to be an immunologically privileged site in the human body. However, it is now
known to have the ability to synthesize and release various active mediators, and a few pro-inflammatory
molecules. The human brain also has the capacity to respond to any injury or insult, employing anti-
inflammatory and/or pro-homeostatic mechanisms. Researchers at the University of Virginia, School of
Medicine have discovered the presence of lymphatic vessels in the brain which connect the brain to body’s
immune system .
[14]

A major part of CNS immunity revolves around the temporal relationship between cellular injury and the
inflammatory response. Acute inflammation is the immediate response that occurs upon commencement
of any injury or insult. The blood components, such as polymorphonuclear leukocytes from peripheral