**6. Chronic viral encephalitis and neurodegeneration**

The research on viral encephalitis is a rather dynamic and large field. However, its relationship with neurodegeneration is less explored. As research on viral encephalitis and neurodegenerative disease is progressing on diverse fronts many similarities are being identified between the classical neurodegenerative pathways and viral-induced neurodegeneration [138, 139]. It is well established that many neurotropic viruses result in neuronal dysfunction which can have devastating life threatening consequences for the host [138, 140, 141]. Virus can either directly infect the neurons and kill the cells directly by replication and lysis or by apoptosis as observed in poliomyelitis [139, 142]. Additionally viral-induced encephalitis can damage the neurons in an immune mechanism as all neurotropic virus infections irrespective of the route of entry can trigger both innate and adaptive immune responses [139, 143, 144]. Supporting this concept, a number of viruses have been associated with neurodegeneration outcomes [141]. For example, In addition to causing encephalitis, CMV infection can result in transverse myelitis [145], HIV is associated with severe dementia [146] and Echo virus can cause neuro-muscular disorder [147]. Additionally, yearlong infection with JEV in humans can cause postencephalitic parkinsonism (PEP) which shows symptoms similar to sporadic Parkinson's disease (PD) [148]. Evidence also suggests that H5N1 influenza virus induces many PD-like symptoms [149, 150].

#### *Neurotropic Virus-Induced Meningoencephalomyelitis DOI: http://dx.doi.org/10.5772/intechopen.102674*

Specifically, the virus first infects the peripheral nervous system (PNS) and later gains entry into the CNS where it causes degeneration of susceptible dopamine (DA) neurons in midbrain regions similar to PD patients [149, 151]. Another influenza virus strain H3N2 causes many neurodegenerative symptoms like amyotrophy, MS flares and relapsing delirium [152, 153]. However, the direct role of viruses in neurodegeneration is less understood. Most likely, several viruses have developed means to evade the immune response and are present in subclinical levels [154–156]. The local inflammatory response in the CNS in response to persistent virus infections results in chronic encephalomyelitis even without overt cell death which may lead to neuronal damage resulting in degeneration.

HSV-1 is one of the most common virus infections that can remain dormant in the neurons for life-long [157]. It is highly neurotropic and periodic reactivation is observed to establish productive infection of the neurons [140]. It is one of the largely associated viruses with Alzheimer's disease (AD) [158]. The virus presence is detected in the AD brains, in fact the presence of HSV-1 DNA on APOE gene carriers is a risk factor for AD [159]. Studies also showed HSV-1 DNA and amyloid β to be present in close proximity in AD plaques [160, 161]. Mechanistically, HSV-1 infection can promote neurotoxic Aβ accumulation, tau phosphorylation and cleavage as observed *in vitro* [161–163]. In addition to the direct interaction which the virus exploits to travel to the cell surface it also interferes with post-transcriptional regulation by up regulating microRNA-146a, which is another marker for AD [164].

Parkinson's disease (PD) the second most common neurodegenerative disorder has been linked to Influenza viruses [140, 165]. Highly neurotropic and pathogenic H5N1 virus can enter the CNS, induce encephalitis associated with microglial activation, loss of dopaminergic neurons and accumulation of α-synuclein aggregates in infected regions resembling PD symptoms and pathology [149, 166]. It is well documented that with the 1918 epidemic of H1N1 has greatly increased the incidence of PD [166]. Both H1N1 and H5N1 are found in the substantia nigra region which is also majorly affected in PD patients [167]. In fact, post-mortem brain sections from PD patients show the presence of influenza A virus [168]. No direct mechanism is yet established but is majorly thought to be a contribution of the neuroinflammation process activated by the virus in the CNS [151]. Moreover, HIV infection of the CNS is associated with amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease with characteristic degeneration of the spinal cord and cortical neurons [169, 170]. Several other neurological symptoms are associated with HIV infections; the most common is HIV-associated dementia which shows certain complications presented with MS [171, 172]. HIV-associated dementia (HAD) also has many similarities with AD and PD including the target anatomical region hippocampus and substantia nigra [173]*.* The similarities of HAD with neurodegenerative disorders is reported at genomic, proteomic as well as transcription levels [140].

Modern times have seen a drastic increase in the average life expectancy which has come with its own limitation i.e., the incidence of ageing disorders. As discussed, virus infection can significantly act as co factors of neurodegeneration if not the causative agents. Also, the mechanism of viral and non-viral neurodegeneration is not very different [138, 140]. Both show an involvement of immune system by means of neuroinflammation and direct or indirect damage of neurons. Viruses can significantly modulate the structure and function of cytoskeletal proteins that are instrumental in neuronal dysfunction associated with neurodegeneration [174]. Thus, neurotropic virus infection for encephalitis and neuroinflammation can serve as excellent models for understanding neurodegeneration. Moreover, a better

understanding of targeting the immune system, which has profound implications, especially in viral-induced neurodegeneration and deciphering the critical overlaps and distinctions between classical neurodegeneration and viral-induced neurodegeneration, can lead to developing new and efficient therapeutic strategies.
