CNS & Neurological Disorders - Drug Targets, 2014, 13, 1213-1223 1213
The Role of Viruses in Neurodegenerative and Neurobehavioral Diseases
Sajjad Karim
1, Zeenat Mirza
2, Mohammad A. Kamal
2, Adel M.Abuzenadah
1,2, Esam I. Azhar
3,4, Mohammed H. Al-Qahtani
1, Ghazi A. Damanhouri
2, Fahim Ahmad
5, Siew H. Gan
6and
Sayed S. Sohrab
*,31Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
2King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah 21589, Saudi Arabia
3Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah 21589, Saudi Arabia
4Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, PO Box 80216, Jeddah 21589, Saudi Arabia
5Department of Biological Science, Biological Science Building, 4th floor, University of Texas, El Paso, Texas, USA
6Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
Abstract: Neurodegenerative and neurobehavioral diseases may be caused by chronic and neuropathic viral infections and may result in a loss of neurons and axons in the central nervous system that increases with age. To date, there is evidence of systemic viral infections that occur with some neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, and HIV-associated neurocognitive disorders. With increasing lifespan, the incidence of neurodegenerative diseases increases consistently.
Neurodegenerative diseases affect approximately 37 million people worldwide and are an important cause of mortality. In addition to established non-viral-induced reasons for neurodegenerative diseases, neuropathic infections and viruses associated with neurodegenerative diseases have been proposed. Neuronal degeneration can be either directly or indirectly affected by viral infection. Viruses that attack the human immune system can also affect the nervous system and interfere with classical pathways of neurodegenerative diseases. Viruses can enter the central nervous system, but the exact mechanism cannot be understood well. Various studies have supported viral- and non-viral-mediated neurodegeneration at the cellular, molecular, genomic and proteomic levels. The main focus of this review is to illustrate the association between viral infections and both neurodegenerative and neurobehavioral diseases, so that the possible mechanism and pathway of neurodegenerative diseases can be better explained. This information will strengthen new concepts and ideas for neurodegenerative and neurobehavioral disease treatment.
Keywords: Virus, Alzheimer’s disease, amyotrophic lateral sclerosis, HIV associated neurocognitive disorders, multiple sclerosis, neurodegenerative diseases, Parkinson’s disease.
1. INTRODUCTION
Neurodegenerative diseases (NDs) are chronic degenerative disorders of the central nervous system (CNS) that are characterized by the chronic and progressive loss of the structure and function of neurons [1]. In addition, there are neurobehavioral diseases that primarily, but not exclusively, appear in the young, such as autistic spectrum disorders (ASD) that include autism, attention deficit disorder, and Asperger’s syndrome [2]. They affect millions of people worldwide and are the fourth leading cause of death in developed countries. They are also becoming increasingly significant in developing countries. The incidence rate is expected to become higher as lifespan increases.
*Address correspondence to this author at the Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Post Box No- 80216, Jeddah -21589, Saudi Arabia; Tel: +966-554627872, +966-12- 640-1000; Ext. 73530; Fax: +966-12-6952076;
E-mail: [email protected]; [email protected]
Despite intensive research, the underlying causes of most NDs remain poorly understood [1, 3]. Several intracellular mechanisms are involved in classical neurodegenerative diseases: protein degradation, mitochondrial dysfunction, defective axonal transport and apoptosis. There are some important genetic links between neurodegenerative and neurobehavioral diseases, but the genetic changes that occur and the changes in gene expression that have been found in these diseases are complex and are not directly related to simple genetic alterations [2-4]. In addition, chronic viral infections, nutritional deficiencies, exposure to environmental toxins such as heavy metals, autoimmune responses, vascular diseases, head trauma, accumulation of fluid in the brain, and changes in neurotransmitter concentrations are reported to be involved in the pathogenesis of various neurodegenerative and neurobehavioral diseases [2-3, 5-9]. Because viral infections are usually spread systemically, they can enter the immune and other organ systems, which results in a variety of
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symptoms [10]. The pathological mechanisms underlying NDs in humans have gained renewed attention not only because human NDs are a growing cause of concern and disability in aging humans globally but also because of the evolving nature of NDs, possible pathogen involvement and recent evidence from proteomic and genomic fronts show similarities between viral-induced and classical NDs in humans [10-13].
Immune activation within the CNS is classically observed in several immune-mediated disorders. Although the immune responses may contribute directly or indirectly to neuronal damage, not all responses in the CNS are damaging because they may also be involved in repair and regeneration processes. Nevertheless, heightened immune responses can be indicative of underlying pathogenic process, which may shift the delicate balance between the beneficial and detrimental responses [11, 13]. As global research on NDs progresses on various fronts, many similarities between classical NDs and virus-mediated neurodegeneration are becoming increasingly obvious at both the anatomic and sub-cellular levels [12-15].
Supporting these observations, a number of viruses have been shown to be associated with different types of NDs and neurobehavioral diseases, which can guide us to identify the possible mechanisms involved in neurodegeneration. Some of the known viruses associated with these diseases are Hepatitis virus, Herpes Simplex Virus (HSV), Influenza Virus, Cytomegalovirus (CMV), Enterovirus, West Nile Virus (WNV), H5N1, Picornavirus and Borna Disease Virus (BDV) [16]. Viruses can affect neurons by direct killing them through cell lyses or by inducing apoptosis. Thus, regardless of the route of entry of neurotrophic viruses into the CNS, viral infection in the CNS leads to the activation of both innate and adaptive immune responses. Viral antigens preferentially activate toll-like receptors - 3, 7 and 8, which drive innate and adaptive immune responses and lead to neuronal damage. Neuronal injury occurs through direct damage, killing, release of free radicals, cellular activation and inflammation, which ultimately lead to neuronal death [17, 13]. Conversely, the immuno-competent host can clear viruses rapidly. Although several biological studies with numerous examples implicate variety of viruses in classical NDs, the direct role of viruses in human NDs remains partially proven and controversial at best.
Viruses are neurotrophic, infect neurons preferentially and can cause severe and sometimes fatal brain inflammation, thereby rendering neuronal populations vulnerable to degeneration in the face of subsequent insults.
The activated inflammatory pathways may represent opportunities for therapeutic intervention before the onset of NDs [18]. More commonly, viruses may penetrate the CNS asymptomatically during systemic infections either by crossing the blood-brain barrier or through the peripheral nervous system [19]. Viral infections can initiate and propagate chronic neuronal dysfunction, an event that precedes the clinical onset of many NDs [18]. Various reports have been published describing the association of viruses with neurodegenerative and neurobehavioral diseases (Table 1). However, their complex association is still not clearly understood. The primary objective of this review is to provide a detailed and unique snapshot of how viruses lead
to neurodegeneration and their possible involvement in classical human NDs, which will shed light not only on a profound understanding of viruses as mediators or modulators of NDs but also on the future development of effective treatment strategies.
2. ALZHEIMER’S DISEASE
Alzheimer's disease (AD) is the most common form of dementia. It is hallmarked by the loss of neurons in the cerebral cortex and sub-cortical regions and the formation of neurofibrillary tangles and plaques in brain. It is a health, social and economic burden that cannot be cured or reverted.
Currently, more than 26 million patients are reported to be suffering from AD worldwide, and it is estimated that by 2030, the prevalence will increase to 0.56% (World health organization) [1, 20, 21]. Viruses reported to be associated with this disease include Hepatitis virus, HSV, Influenza Virus, CMV, Enterovirus, WNV, H5N1, Picornavirus and BDV [16]. Emerging and intriguing research illustrates that several pathogenic organisms cause chronic infection and AD progression [22-25]. However, the exact mechanisms of viral infection in AD are critical questions that remain unanswered. Therefore, a comprehensive understanding of the complex association between viral infection and NDs is necessary for the design and development of novel drug therapies.
2.1. HCV
The association of HCV with AD has been previously reported [16, 26]. HCV infection also causes chronic inflammation and results in neuropsychological symptoms accompanied by cognitive impairment in AD patients. HCV primarily infects monocytes/macrophages, which cross the blood brain barrier and subsequently cause higher levels of cytokine secretion, resulting in excitotoxicity in the CNS.
HCV infections in the brain tend to increase the risk for AD progression. In addition, HCV infection and viraemia are correlated with microglial activation and altered cerebral metabolism. Elderly patients infected with HCV are reported to have a higher risk of AD, whereas those who have received antiviral therapy have a lower risk of AD [27].
2.2. HSV
The association between Herpes simplex virus type 1 (HSV-1) and AD has been well studied and plays an important role in the active transport of the virus within the neuronal region [1, 28]. HSV-1 can enter into sensory ganglia, and HSV-1 DNA has been reported to be found in the brain of AD patients. For example, a strong association exists between HSV-1 and amyloid plaques, with up to 90%
of the plaques in aged brains found to have HSV-1 DNA.
Recently, the HSV-1 genome was amplified from various AD brain postmortem specimens by polymerase chain reaction (PCR) and carried the type4 allele of the gene coding for apolipoprotein E [29]. HSV infection was reported to be responsible for the molecular hallmarks of neurodegeneration-deficiency of autophagic processes, oxidative stress, misfolded protein aggregate deposition and
Table 1. The role of viruses in neurodegenerative and neurobehavioral diseases.
Disease Viruses Neurological Disorder References
Alzheimer’s Disease
Herpes simplex virus-1, 2 Cognitive changes, neuronal destruction [1, 15-16]
Human herpes virus 6 (HHV6) Meningo encephalitis and leucoencephalitis,
Dead and dying neurons undergoing neuronophagia [1, 16]
Hepatitis C Virus Cognitive impairment [16]
Influenza A virus (H5N1) Mild encephalitis to motor disturbances to coma [14, 16]
Cytomegalovirus (CMV) Transverse myelitis [1, 16]
West Nile Virus (WNV) West Nile encephalitis, meningitis [1, 16]
Picornavirus Brain inflammation, Encephalitis [1, 16, 134]
Borna disease virus (BDV) Patent infection of the limbic system, impairs synaptic plasticity [1, 16, 58]
Parkinson’s Disease
H1N1 Delirium, cycloplegia, encephalitis,
lethargica, GBS, encephalopathy, seizure [1, 16, 125-127]
H2N2 Encephalitis, seizures, muscle paralysis, GBS [1, 128-130]
H5N1 Viral neurotropism [1, 16]
Coronavirus Unknown [131]
St. Louis virus Juvenile parkinson disease, encephalitis [1, 132, 133]
Poliovirus, JC Virus Encephalitis, Infection of oliodendrocytes, astrocytes and neurons [1, 134, 135]
Japanese encephalitis B virus Neuronal death [1, 17, 136]
Multiple Sclerosis
Roseolovirus (HHV-6) Meningo encephalitis and leucoencephalitis [1]
Herpes simplex virus Cognitive changes Neuronal destruction [1, 137]
Variecella zoster virus (VZV), type Infection of trigeminal ganglion [1, 138]
Epstein-Barr virus (EBV) Grey-matter atrophy,
Encephalopathy [1, 139, 140]
Marek’s disease virus (MDV) Unknown [1]
Human T cell leukemia virus type 1 (HTLV-1) Unknown [141]
Human endogenous retrovirus Unknown [142]
Measles virus Myelin damage [1, 143-145]
Mumps virus Unknown [146]
Para influenza virus type 1 Unknown [147]
Canine distemper virus Unknown [148]
Simian virus type 5 Unknown [149]
Coronavirus Unknown [150]
Amyotrophic Lateral Sclerosis
Enterovirus 71 Encephalitis, aseptic meningitis [1, 151]
Human herpesvirus-6 (HHV6) Unknown [152]
HTLV-1 Unknown [94,153]
H3N2 Amyotrophy, encephalopathy [1,154]
Autism Spectrum
Disorders Measles virus Myelin damage [1,110,143]
Congenital rubella, Herpes simplex virus, Mumps, Varicella, Cytomegalovirus (CMV),
Stealth virus, Human herpesvirus-6 (HHV6)
Unknown [1,110]
HIV associated neurocognitive
disorders (HAND)
HIV HIV associated dementia [1,12,113-115]
neuronal death, which supports a strong viral influence on AD development [30-32]. The induction and accumulation of hyperphosphorylated tau in neuronal cells and AD- specific tau phosphorylation is mediated by HSV-1 infection.
The possible genes identified are apolipoprotein E, clusterin, complement receptor 1, phosphatidylinositol binding clathrin assembly protein, amyloid precursor protein and tau, which have implications in viral life cycles. It has also been reported that increased levels of amyloid β (Aβ) deposition and microtubule protein tau phosphorylation occurs in HSV- 1 infection in neuroblastoma cells [33-35], indicating that the possible interaction of HSV-1 particles with amyloid precursor protein exists [36]. The formation of Aβ and associated molecules can be reduced by antiviral therapy for HSV-1 infection [37]. The HSV-infected cells secrete microvesicles (L-particles) and offer a highly plausible mechanism for microvesicular-mediated intracellular communication, which leads to AD after interactions with Aβ [38-39]. The association between HSV and AD in vivo and in vitro has been reported. In addition, it was observed that HSV moves into the brain via axonal transport, thereby playing vital pathological roles in AD development [40].
Recently, it has been observed that the upregulation of specific host miRNA146a, down regulation of complement factor H expression, and induction of AD type pro- inflammatory signaling takes place during HSV-1 infection [41-43]. Moreover, the enhancement of ApoE allelic carriers in HSV-1 infection can be mediated by another herpes virus known as human herpes virus-6 (HHV-6), which was also found in AD patients; however, their direct roles in the pathogenesis of AD is not yet well understood [35].
2.3. Influenza A Virus (H5N1)
Influenza A (H5N1 subtype) is an RNA virus causing diseases in both humans and animals. Between 2003 and 2011, a total of 332 human deaths have been reported from 566 confirmed cases of H5N1 infection [44]. The influenza virus infection leads to a neurotoxic effect that causes neurological disorders such as AD and Parkinson’s Disease (PD) [14], but the exact role and mechanism of influenza virus in disease progression remains unclear and highly debated. Neurotrophic influenza virus activates the immune system in the brain and is reported to significantly contribute to protein aggregation, an important etiology in the development of AD and other CNS disorders [45, 46]. The microglial activation, α -synuclein phosphorylation and aggregation occur due to H5N1virus infection. Considerable damage and dopaminergic neuronal loss in the substantia nigra has been reported in AD patients within 60 days of H5N1 infection, which strongly suggests that neurotropic influenza virus and pandemic H5N1 pathogen can initiate CNS disorders and AD [47].
2.4. CMV
Cytomegalovirus (CMV) belongs to the family Herpesviridae, and the most well documented human cytomegalovirus is human herpes virus-5 (HHV-5) [48, 49].
Human CMV is found worldwide and infects ~ 40% of the human population without specific symptoms [50]. CMV can cause serious neurological defects in infants and major
problems in immunocompromised patients. This virus has a putative role in AD and is re-activated after residing latently for longer periods in AD patients [51]. The presence of CMV in HSV-1 infected brain has been reported, indicating that this virus acts as opportunistic microbe. The direct role of CMV in AD has not yet been ascertained [52].
2.5. Picornavirus
Picornavirus is a positive-stranded RNA virus with an icosahedral capsid that belongs to the family Picornaviridae, a serious pathogen of humans and animals [53]. In humans, it causes "common-cold"-like illnesses and poliomyelitis as well as chronic infections in livestock. Picornavirus infection can lead to memory loss and clinical cognitive memory deficits. Recent studies report that this virus causes brain inflammation, which is associated with both learning disabilities and AD progression [54].
2.6. BDV
BDV is an RNA virus that belongs to the family Bornaviridae and can affect humans, birds and mammals. In addition, it has an affinity for the CNS [55]. BDV is unique among animal RNA viruses because it causes persistent CNS infection in various host species. Based on published reports, this virus has extended its host range and geographical distribution and causes neuropsychiatric disorders, leading to an imbalance in CNS homeostasis and disturbances in both brain development and function. BDV infections are also reported to affect AD pathophysiology due to the affinity of the viral proteins for neurotransmitter receptors that can cause changes in neurotransmission [56-58].
3. PARKINSON’S DISEASE (PD)
PD is a neurodegenerative disorder that is characterized by muscular rigidity, resting tremor, akinesia, depression, dementia, olfactory and sleep disturbances [59, 60]. This disease affects more than 1 million people in the USA alone, and this number is expected to triple within the next 50 years. PD is thought to be a consequence of multiple genetic and neurotoxic effects, resulting in oxidative damage and cell death. The reported pathological features of PD are inflammation, extensive degeneration and dopaminergic neuronic loss of the substantia nigra. The role of viral infection in PD has been published in many reports [61, 62].
There is an evidence of association between PD and virus in genetic changes, including changes in mitochondrial function, degradation of protein, fusion of vesicles, organelle trafficking and oxidative stress related protein function [59].
However, the exact cause and role of inclusion bodies, protein aggregation and degradation defects in PD pathogenesis is still unclear [62].
3.1. The Association of Influenza A Virus with PD Influenza A viruses are single-stranded RNA viruses that belong to the family Orthomyxoviridae. The pathogenic association of Influenza A viruses with PD was elucidated for the first time following the characterization of encephalitis lethargica. However, to date, no strong
relationship has been established between virus infection and PD [18]. Currently, this neurotrophic virus is associated with five flu pandemics H5N1 Influenza A [63-65] and contributes to approximately 500,000 deaths worldwide in yearly epidemics. The most lethal strain was designated as the Influenza A H1N1 subtype and killed approximately 20- 100 million people in the 1918 flu epidemic [66]. Several well-documented reports have been published about the increased incidence of PD associated with both H1N1 Influenza A and the 1918 Spanish influenza pandemic [67, 68]. It is believed that there are strong associations of these viruses in PD, though the exact mechanism has not been completely discovered. It is reported that the H1N1 Influenza A viruses and other viruses associated with the development of PD can enter the CNS and cause pathological changes that result in dopaminergic neuronal loss in the substantia nigra pars compacta, microglial activation, up-regulation of alpha-synuclein, Parkinsonian clusters formation and clear motor deficit at the point of viral infection [69, 70]. Additionally, it has been reported that the A/WSN/33 (H1N1) virus targets the substantia nigra region in PD patients before entering the CNS [71]. In another study, it has been observed that the A/Vietnam/1203/04 H5N1 virus can penetrate the CNS from the peripheral nervous system and promote microglial activation, α - synuclein phosphorylation and aggregation as well as Parkinsonian symptoms in PD patients [72]. Recently, the influenza A virus has been identified in specimens of postmortem PD brain within the substantia nigra pars compacta [73]. Shoji et al. also reported that post encephalitic parkinsonism can develop via Japanese encephalitis virus infection in humans [74].
4. MULTIPLE SCLEROSIS (MS)
MS is a neurodegenerative and chronic inflammatory disease of the CNS that causes damage to myelin sheaths and is particularly prevalent among young adults. Worldwide, approximately 2.5 million peoples were reported to have MS in 2007 by the World Health Organization. The clinical symptoms include muscle weakness, visual disturbances, numbness, prickling sensations, coordination, memory problems, and focal plaques of demyelination in brain and spinal cord [18].
Currently, no medicine is available for MS, but it is expected that in the future, new therapy will potentially minimize MS progression [75]. In addition, neurological damage and nerve cell death occurs via plaque deposition during progressive MS.
Moreover, blood barrier breakdown with local inflammations is observed in MS [76]. The possible association of chronic infection with MS prompted many researchers to investigate the possible role of infectious agents in MS. To date, there are few published reports describing the possible link between viruses and MS disease progression [1, 10].
4.1. HSV
The association of HSV with MS has been shown previously [77]. The occurrences of HSV-1 and HSV-2 were identified in postmortem brain tissue using the PCR amplification and immunohistochemistry methods [78]. The immunofluorescent and PCR methods were also utilized to detect human herpes virus-6 (HHV-6) DNA from peripheral
leukocytes in MS patients [79, 80]. It is also expected that apart from these viruses, other new possible pathogens such as putative retroviruses could be associated with the progressive form of MS [10, 81].
4.2. Roseolovirus
Published evidence and reports have suggested that the HHV-6 plays both direct and indirect roles in MS progression by acting as an activator of other viruses, such as human endogenous retrovirus-W and Epstein-Barr virus (EBV). The virus can remain latent in 90% of young adults [82] and may be reactivated from its latent state to cause secondary progressive MS. The HHV-6 DNA was identified more frequently from the spinal fluid of MS patients compared with other types of neurological disease [83]. A reduction of HHV-6 DNA levels in serum that was treated with interferon-β therapy was recently demonstrated [84].
Interestingly, it was observed that the presence of HHV-6 in blood and serum becomes higher during relapses compared with remission, which leads to a greater risk of severe relapse and deprived response to interferon-β treatment [84].
Furthermore, the relationship between HHV-6 and MS has also been validated in animal models. Recently, this relationship has been demonstrated using the analysis of Interferon regulatory factor polymorphisms rs4728142 and rs3807306 in MS predisposition. In addition, the T allele rs3807306 is an important susceptibility marker for both MS and HHV-6 and was found to be a valuable marker against response to interferon-β therapy [85]. These observations are valuable for the identification of the pathological links between this virus and MS [1].
4.3. Epstein-Barr Virus (EBV)
The association of EBV in MS was first time reported by Fraser and colleagues in 1979 [86]. It is assumed that more than 90% of adults are infected with this virus, which may persist in B-lymphocytes as a latent form throughout their lifetime. Due to the sero-conversion of EBV at a later stage, the risk becomes very high in young adults compared with kids. Recently, more cases of MS in EBV-infected patients have been reported only after EBV sero-conversion, suggesting a temporary relationship between MS and primary EBV infection [87]. A meta-analysis demonstrated that a statistically strong relationship exists between MS and EBV infection [88, 89]. The EBV DNA was detected in the saliva, but not the cerebrospinal fluid (CSF) or plasma, due to the sub-cellular localization of EBV genes [90-92], but the DNA or RNA from EBV was not identified from similar cells by other researchers [93]. However, recent reports further support the strong association between EBV and MS by identifying small RNA coded by EBV from MS brains [94]. So far, EBV has not been identified in the CNS of MS patients. Therefore, more systematic studies are required to determine the possible mechanism and the role of EBV in MS progression [1].
4.4. Varicella Zoster Virus (VZV-HHV3)
The MS epidemiology caused by VZV is nearly similar to that of H1N1 Influenza A virus. However, the viral
genome is more similar to HSV [95]. Additionally, it was reported that the VZV appears more frequently in MS patients than among healthy people [96]. The viral DNA and VZV-like particles in the CSF of MS patients were more frequently found during relapse compared with during remission [97, 98]. VZV plays an important role in MS disease progression, as a reduction in DNA levels and viral particles in the CSF collected from patients with progressive MS has been recently observed [99]. Interestingly, a new study observed that the level of DNA and viral particles in the CSF significantly increased after acute relapse in peripheral blood mononuclear cells [97]. However, in another study, VZV DNA was not detected in the CSF at initial stages, which indicates either that this virus can infect during other stages of MS and act as an accelerator of MS relapse or that it can infect following the appearance of MS [100]. However, an extensive study to identify the exact role of this virus in MS disease is still needed.
5. AMYOTROPHIC LATERAL SCLEROSIS (ALS) ALS is a progressive ND in adults in which central and peripheral motor neurons are affected and symptoms such as weakness, muscle paralysis and finally death occurs due to respiratory failure as a result of the destruction of the upper and lower motor neurons. The presence of Enterovirus sequences has been reported by PCR in spinal cord samples from ALS patients [101], but this report appears controversial because a different group of researchers did not find Enterovirus sequences in ALS patients [102]. In ALS patients, the presence of HHV-6 and retrovirus has been reported [103]. Several other retroviral associations with ALS have been reported such as HIV and Human T- Lymphotropic Virus-1 [104]. The activity of reverse transcriptase in serum and cerebrospinal fluid collected from ALS and non-ALS patients has been reported [105].
Additionally, a higher level of reverse transcriptase activity was observed in ALS patients than in control and HIV infected patients [105-108]. Recent reports showed the expression of distinctive Human endogenous retrovirus-K pol-like sequences in the prefrontal and sensory cortex of ALS patients [109]. The exact role of infections in ALS pathogenesis and progression is not known, but it is assumed that infectious agents can enter the CNS and play an important role in ALS progression. There could be some co- factors of ALS pathogenesis and other opportunistic infections in ALS patients. However, no evidence of ALS disease transmission from human to human or in animals has been reported [1, 10].
6. AUTISM SPECTRUM DISORDERS (ASD)
ASD are neurobehavioral diseases affecting children and lead to improper communication skills, inappropriate relationships and responses with others in their surroundings and community. Most of the affected patients show repetitive actions and fixations to certain objects and are highly sensitive to selected tastes, smells and sounds [2]. It is expected that most such patients may have some similarities in environmental exposure and genetic defects, which are important contributors to disease progression. The symptoms
of ASD suggest that some patients may also be suffering from viral infection. In ASD patients, higher viral titers have been reported due to chronic viral infection [110].
7. HIV ASSOCIATED NEUROCOGNITIVE DISORDERS HIV infection also causes neurological disorder. HIV- related dementia is the most severe form of HIV associated dementia (HAD) and affects approximately 30% of the HIV- infected population. The neuropathological symptoms include the loss of neurons, multinucleated giant cells, microglial nodule activation and pronounced reactive astrocytosis. HAD affects the hippocampus and substantia nigra pars compacta, which is the common anatomical substrate between both AD and PD patients. The pathogenesis of HAD is not yet clear, but viral association is indicated by various factors including the neurotoxicity of viral proteins and the activation of mononuclear phagocytosis and cytokine/chemokine [111]. HIV infection in the brain results in HAD progression [112]. Recently, it was reported that HIV-1 replication occurs in macrophages and CCR5+ T cells within the CNS, which results in the development of dementia [113, 114]. In a study conducted on the brain proteome of HAD and non-dementia patients, a total of 31 significantly altered proteins were identified [12].
In HAD pathogenesis, a strong association of axon guidance and its downstream signaling pathways (e.g., mitogen- activated protein kinase pathway) that concur with AD and PD has been reported [1, 115].
7.1. Possible Mechanism of Viral Pathogenesis, Inflammation and Neurodegeneration
Overall, the association of many viruses in NDs is well known, though the exact mechanism remains unclear. It is known that viruses can enter the CNS by crossing blood brain barrier via different pathways such as passage through infected endothelial cells, blood-CSF barrier and molecular Trojan horses (Fig. 1). Some hypotheses have also been proposed, including hematogenous dissemination and neuronal retrograde dissemination [1]. Apart from HAD, this hypothesis is well studied in other types of viruses associated with NDs [116]. For example, the influenza (A/WSN/33strain), HHV-6, HSV and rabies viruses are believed to enter the CNS via the olfactory epithelium, cranial and trigeminal nerves [117, 118], while the A/Vietnam/1203/04 H5N1 virus utilizes the peripheral nervous system to gain entry into the CNS [1, 70]. It is well documented that the immune system is activated against any type of chronic infection, while viruses triggers the immune system to respond in retaliation. Generally, it has been observed that the immune system in the CNS is activated for a shorter period of time in response to acute neuro- inflammation [119, 120]. Several studies have reported the association of chronic neuro-inflammation with NDs such as AD, PD, MS and ALS [121-124]. Microglial activation plays a significant role in the pathophysiology of NDs and is an important feature of neuro-inflammation, while neurotrophic viruses (HIV and HSV) have been reported to be associated with the triggering of long-term neuro-immune activation.
The pathologic changes can occur by chronic viral-mediated
(a)
(b)
Fig. (1). (a) Viral invasion, inflammation and Neurodegeneration. Neurotrophic viruses can reach the CNS by crossing the BBB or via peripheral nerves. Non-neurotrophic viruses can also invade the brain and trigger local CNS inflammation. Neurons sense and respond to viruses through the expression of TLRs, which leads to the activation of an intracellular signaling cascade that culminates in cytokine and chemokine secretion. The activation of neuronal TLRs by viral challenges and the primary inflammatory reactions may exert a priming action directly on neurons, rendering them more vulnerable to neurodegeneration (Adopted from Deleidi. M. 2012). (b) Summary of Fig.
(1a).
proteins in neural tissues, leading to brain inflammation and NDs [1]. Further systemic and extensive experimental approaches are needed to validate the real associations of the above-mentioned viruses with neurodegenerative and neurobehavioral diseases.
CONCLUSION
This review encompasses the possible role of various types of viruses, including HCV, HSV, H5N1, CMV, Roseolovirus, EBV, VZV, and HIV, among others with NDs. The varied and disputed mechanisms used by these viruses to cause neurodegeneration and neurobehavioral diseases are also highlighted, unveiling all of the related controversies and shedding new light on the topic. In addition to contributing to the understanding of viruses as mediators or modulators of NDs, it is hoped that this review can facilitate future development of effective treatment strategies.
LIST OF ABBREVIATIONS AD = Alzheimer's disease
ALS = Amyotrophic Lateral Sclerosis ASD = Autism Spectrum Disorders Aβ = amyloid β
BDV = Borna Disease Virus CMV = Cytomegalovirus CNS = Central Nervous System CSF = Cerebrospinal fluid EBV = Epstein Barr virus
HAD = HIV associated dementia (HAD) HCV = Hepatitis C Virus
HHV = Human Herpes Virus
HIV = Human Immunodeficiency Virus HSV = Herpes Simplex Virus
MS = Multiple sclerosis
NDs = Neurodegenerative diseases PCR = Polymerase chain reaction PD = Parkinson's disease VZV = Varicella zoster virus WNV = West Nile Virus CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS
We are thankful to King Abdullah City for Science and Technology, Riyadh, Saudi Arabia (KACST Strategic Project ID 10-BIO1073-03 and 10-BIO1258-03) for research funding and support. The authors gratefully acknowledge the
research facility provided by King Fahd Medical Research Center (KFMRC), Center of Excellence in Genomic Medicine Research (CEGMR) and Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia.
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