Infectious Agents and Neurodegenerative Diseases

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REVIEW ARTICLE

Infectious Agents and Neurodegenerative Diseases: Exploring the Links Mohammad Zubair Alam1, Qamre Alam1, Mohammad Amjad Kamal2,3, Asif Ahmad Jiman-Fatani4,5, Esam I. Azhar6,7, Mohammad Azhar Khan8 and Absarul Haque1,* 1

King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Metabolomics & Enzymology Unit, Fundamental and Applied Biology Group, King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; 3Enzymoics / Novel Global Community Educational Foundation, 7 Peterlee Place, Hebersham, NSW 2770, Australia; 4Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, P.O. Box 80205, Jeddah 21589, Saudi Arabia; 5Clinical and Molecular Microbiology Laboratory, King Abdulaziz University Hospital, P.O. Box 80205, Jeddah 21589, Saudi Arabia; 6Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdul Aziz University, Jeddah, Saudi Arabia; 7 Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; 8Faculty of Applied Sciences and Biotechnology, Shoolini University, Bajhol, HP, India 2

ARTICLE HISTORY Received: July 27, 2016 Revised: October 03, 2016 Accepted: October 04, 2016 DOI: 10.2174/15680266176661701031 64040

Abstract: Recent studies have shown that bacterial and viral infections are risk factors for various neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS), Alzheimer’s disease (AD), and Lyme disease (LD). However, it is still controversial how the infections play a role in neurological diseases progression. Infections in central nervous system may lead multiple damages in infected and neighboring cells. The infection leads to the activation of inflammatory processes and host immune responses, which acts as defense mechanism and also causes damage to the host neuronal functions and viability. Several bacterial and viral pathogens have been reported for neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in combination with other factors, like aging, metabolic diseases and the genetic makeup of the host. We will focus in this review on the possible link between neurodegeneration and infections particularly Chlamydophila pneumoniae, Borrelia burgdorferi, Mycoplasma etc.

Keywords: Neurodegenrations, Inflammation, infection, Mycoplasma, Chlamydophila pneumoniae, Borelia bugdorferi, MS, ALS, AD, LD. INTRODUCTION Neurodegenerative diseases are the main causes of dementia. Interestingly, the causes neurodegenerative diseases involving central nervous system (CNS) are mostly mysterious and are not clearly identified [1]. Many factors have been reported to be associated with the neurodegenerative diseases including genetic makeup, nutritional deficiencies, environmental contaminants, certain metals, infectious agents (bacteria and viruses), autoimmune and vascular diseases, accumulation of fluid in the brain. All these factors, among many more, causes the alterations in signal transmission in nerve cells, which are responsible for the pathogenesis of various neurodegenerative diseases [1-3]. The mutation in nerve cells, which results in neuron degeneration, dysfunction and even death, leads to neurological disorders and dementia [1, 3]. The over-expression of oxidative free radicals that are responsible for lipid, protein and genetic *Address correspondence to this author at the King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Tel: +96626401000 Ext. 25185; Fax: +966- 26952076; E-mail: [email protected] 1568-0266/17 $58.00+.00

structural changes are basically found in all neurological diseases [4-5]. Increasing number of epidemiologic and experimental studies have been implicated in various infections like bacterial, viral, fungal and parasitic agents as potential risk factors for neurological diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis etc [6]. Infectious agents produce certain toxic compounds and free radicals that promote the neurological damage [7-8]. Moreover, these infectious agents (bacteria, viruses, fungi and parasites) are known to produce aggregates of unfolded and misfolded proteins, deficient autophagic processes, synaptopathies and death of nerve cells [9]. The peripheral nervous system (PNS) is usually more accessible to infections whereas CNS has many layers for protection making it restrictive to infectious agents. The pathogenic bacteria and viruses can find their way into the CNS through transcytosis across blood brain barrier or they can gain entry through intraneuronal transfer from peripheral nerves [7, 10]. The bacteria such as Chlamydia, Borrelia, Brucella and Mycoplasma, which are devoid of cell wall and many viruses have been described as major infectious organisms that infect peripheral and central nervous system and © 2017 Bentham Science Publishers

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contribute to the pathology and progression of many neurological diseases [11]. Infections of the CNS produce multiple damages in infected and nearby cells and illicit the immune system causing the activation of inflammatory processes resulting in neuronal dysfunctions and dysviability [6]. The present review is focused on bacterial and viral agents associated with neurological diseases in one way or the other. Some fungal and parasitic agents are also discussed. AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that results from degenerations of motor neurons of brain or spinal cord or both causing muscular weakness and atrophy. The degenerations of motor nerve cells lead to the paralysis and death. Muscular weakness and paralysis due to nerve cells damages in brain and spinal cord constitute the main diagnostic properties of ALS [12]. It is estimated that mortality among ALS patients is about 60% within three years of clinical presentation and nearly 10% survive for over 8 years [13]. A number of factors have been implicated for the pathogenesis and progression of ALS including gene mutation resulting in defective protein recycling, improper and deficient nutrition, head injury, environmental contaminants, autoimmunity, and several infections such as Chlamydophila pneumonia (formerly known as Chlamydia pneumonia), Borrelia burgdorferi, HIV, HTLV-1 and Mycoplasma [11, 14]. Most of the cases of ALS are sporadic whereas few cases have been observed familial wherein a number of mutations in several genes such as SOD1, TARDBP, or FUS gene have been identified [15-16]. In recent years, the analysis of spinal cord samples from ALS patients using Polymerase Chain Reaction (PCR) revealed the presence of viral, bacterial and fungal sequences, which attracted interest to look into the role of infectious agents in this neurological disease [17]. However, the role of infections in ALS has become controversial since some researchers have not found viral or bacterial infections or their DNA in the samples of patients with and without ALS [1819]. Still it is possible that infectious agents, who are capable of piercing through brain or spinal cord may involve in the etiology of ALS [20]. In a case control study to determine Mycoplasma species using PCR test in 75 subjects in whom 20 were identified clinically as having ALS and remaining 55 were healthy, it was found that 50% of ALS patients were positive for Mycoplasma sp. On the other hand only six (10.91%) were positive for Mycoplasma, which is statistically significant. The researchers have concluded that there was a strong link between Mycoplasma infection and the development of ALS [21]. Another study conducted on 13 ALS patients and 44 normal individuals for the presence of mycoplasmal DNA using PCR found 46% patients and 9% healthy controls were having mycoplasmal DNA in their blood. Six patients and two healthy individuals were positive for M. fermentans. The presence of M. fermentans was further confirmed through IgM against Lipid-Associated Membrane Proteins (LAMPs), which were positive in six patients and 13 healthy individuals [14]. Nicolson and colleagues has reported mycoplasmal DNA sequences in blood specimens in 30 of 36 ALS patients. On the other hand, less than 9% of controls were found positive for Mycoplasma infections. Further, they observed that 20 out of 30 (66.67%) ALS pa-

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tients positive for Mycoplasma infection were infected with M. fermentans, 7/30 (23.33%) were infected with M. hominis and 2(6.67%) were found having M. pneumoniae infection [22]. All these and other similar reports point towards the involvement of Mycoplasma in the pathogenesis and its progression of ALS. Borrelia burgdorferi, which is primary causal agent of lyme disease, is also a common infection in ALS patients. Halperin and colleagues has reported 50% of 19 ALS patients were serologically positive to B. burgdorferi whereas only 10.5% were seropositive among the 38 control individuals to this microorganism [23]. Chronic infection of B. burgdorferi was also reported in a 61 year old female patient wherein improvement of ALS condition was observed following antibiotic therapy [24]. Cerebrospinal fluid (CSF) and brain samples from ALS patients have also been found positive for fungal antigens against several Candida species such as C. famata, C. albicans, C. glabrata, C. parapsilosis, whereas control samples were negative for the same antigens [25]. Further, the researchers analyzed brain samples from control and ALS patients for the presence of fungal DNA by PCR. They found various fungal DNA products in three ALS patients but no fungal DNA could be detected in the control samples. Malassezia globosa, Trichoderma viride and Candida albicans were found in all samples. One sample was positive for Cryptococcus neoformans. To establish their findings, the researchers also carried out proteomic analyses of brain tissue and found the presence of several fungal peptides in the ALS brain samples [25]. Infectious viruses have also been frequently observed with ALS patients, particularly human herpes virus-6 (HHV6), HIV and other retroviruses. In a study on 56 ALS patients, 33(59%) patients were found positive for reverse transcriptase activity in their serum in comparison to 3(5%) of 58 control subjects [26]. The reverse transcriptase activity was also tested on serum and CSF samples from HIVnegative patients with ALS in a separate study. Of 23 HIVnegative ALS patients, reverse transcriptase activity was observed in 56% patients whereas only 19% of 21 controls were positive for it [27]. McCormick and colleagues has tested 22 serum and 25 CSF samples from ALS patients and found that 11 patients were positive for reverse transcriptase activity in their serum samples; however, only 1(4%) sample of CSF from ALS patients was positive for reverse transcriptase activity. Contrary to these results, 93% of 14 control subjects were negative in reverse transcriptase assay [28]. Human T-lymphotropic Virus Type-I (HTLV-I) have also been found associated with ALS-like Symptoms [29]. It is clear from above discussion that the viral and bacterial infections have been found associated with the ALS but it is not clearly known whether they are also associated in pathogenesis or progression of ALS. They may be simple opportunistic infections, which are responsible for the morbidity of the disease [20]. Further research is required to determine the exact association of ALS pathogenesis and its progression with regard to the role of chronic bacterial, fungal and viral infections. The association of various infecting agents with ALS and other neurological diseases isolated from various sources and their method identifications are summarized in Table 1.

Infectious Agents and Neurodegenerative Diseases

Table 1.

Current Topics in Medicinal Chemistry, 2017, Vol. 17, No. 11

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Infectious agents associated with neurological diseases.

Neurological disease

Infectious agent

Source of isolation

Detection method

Reference

Mycoplasma

Blood

PCR

[21],[14],[22]

Mycoplasma

Blood

IgM/Western blot assay

[14]

Borrelia burgdorferi

Blood

Serology

[23]


CSF

PCR

[24]

Candida famata, C.albicans, C.glabrata, C.parapsilosis, Penicillium, Malassezia globosa, Trychoderma viridae

CSF, brain

Antibody, PCR

[25], [27], [28]

HHV-6

Blood, CSF

Reverse transcriptase assay

[26]

Blood, CSF

Antibody, PCR

[39], [40]

Blood

Antibody

[41], [45]

CSF

PCR

[42], [43], [44], [46]

VZV

Historical infection

NA

[47]

HHV-6

Blood

PCR

[51]

HSV, HHV-6, VZV

Tissue from Gray and white matter

PCR

[52]

HSV

Blood

Antibody

[74]

HSV

Brain

PCR

[78], [79]

HHV-6

Brain, CSF

PCR, antibody

[78], [80]

EBV

Blood, brain

Antibody, PCR

[81]

C. pneumoniae

Brain

PCR

[82], [83]

C. pneumoniae

Brain

Antibody

[84]

Helicobacter pylori

Blood

Antibody

[86]

Helicobacter pylori

Tissue

Histology

[87]

Treponema

Brain

PCR

[92]


Brain

PCR

[92]

B. burdogferi

Blood

Antibody

[106]

Bartonella species, Yersinia enterocolitica, Chlamydophila pneumoniae, Chlamydia trachomatis, Babesia species, Mycoplasma pneumoniae

NA

NA

[107], [108], [109]

ALS

C. pneumoniae

MS

AD

LD

MULTIPLE SCLEROSIS Among neurological diseases, multiple sclerosis (MS) is the most prevalent affecting approximately a million individuals around the globe. It is more common in developed countries compared to the developing world. According to one estimate, nearly 250000 – 350000 peoples are affected with MS and about 3000 deaths per year [30]. It was described by Dr. Jean Martin Charcot who named it la sclerose en plaque [31]. Multiple sclerosis is an autoimmune inflammatory disease of the CNS which generally visible with optic neuritis in its initial stage. In general, a T helper-1 (Th-1)

mediated autoimmune component driven by myelin proteinspecific, pro-inflammatory cytokine secreting T-cells is believed to mediate the pathogenesis of this disorder. The characteristic features of MS include infiltration of T cells, macrophages and B cells, myelin and axon degradation [3233]. Like many other autoimmune diseases, MS is also more common among females than males and it usually appears in middle ages (20 – 40 years). Impaired vision, alterations in motor, sensory, coordination systems and cognitive dysfunction are some general among many other clinical manifestations of MS. These manifestations are usually recurring (re-


lapsing-remitting) over time, but a considerable MS subset progresses without remitting [32]. In progressive MS, neurological damages occur by the formation of plaques on the nerve cells. Moreover, collapse in blood-brain barriers has also been reported associated with inflammation of glial cells [32, 34]. There are studies, which found evidences that MS has a genetic component, furthermore, twin studies and epidemiological data suggest that MS is not an inherited rather it is an acquired disease [35-36]. Since last two decades, researchers have been exploring infections as source for MS and patients have been examined for various viral and bacterial infections. Many of these studies have linkage between chronic infections and MS [30, 37-38]. The discovery of intrathecal IgG and DNA of C. pneumoniae in CSF from a vast majority of MS patients constitutes the strongest evidence in support for an infectious cause of MS [38-40]. Sriram and colleagues were successful in culturing C. pneumoniae from CSF of 64% of total 37 MS patients whereas merely 11% were culture positive for C. pneumoniae among 27 other neurological diseases (OND) controls. Further, PCR assay demonstrated that 97% of CSF samples from MS patients were positive for ompA gene encoding the major outermembrane protein of C. pneumoniae in contrast to 18% among controls. Elevated levels of CSF antibodies to C. pneumoniae elementary antigens were detected in 86% MS patients that were 3 times over and above those observed in OND controls, which was further confirmed by western blot assay [39]. In another study, C. pneumoniae specific intrathecal IgG was detected in 17% of MS patients, 22% in other inflammatory neurological disorders (OIND) patients whereas only 2% of non-inflammatory neurological disorders (NIND) patients were positive for intrathecal IgG. This particular study established that humoral immune response to C. pneumoniae in CNS is not limited to MS rather it is shared by several other inflammatory neurological diseases [41]. A pilot study conducted by Layh-Schmitt and colleagues identified C. pneumoniae in CSF in 50% of 10 MS patients using PCR. They further found C. pneumoniae in 13.5% of 37 patients having definite MS or its variants. Interestingly, none of 56 patients having other neurological diseases was PCR positive for C. pneumoniae [42]. Another study detected C. pneumoniae DNA using PCR in 11 out of 16 CSF samples from MS patients [43]. A German study found 21% and 43% of 58 MS and 47 OND patients respectively had Chlamydial DNA in CSF samples determined by nested PCR method. However, the same study failed to detect C. pneumoniae in 67 neurologically healthy controls [44]. A Japanese study found the presence of C. pneumoniae in 9 out of 28 MS patients and in only 2 out of 15 patients with OND. Moreover, the study found the raised titers of C. pneumoniae specific antibody in 20% of 66 MS patients and in 4% of patients with OND [45]. Dong-Si and coworkers investigated CSF samples from 84 definite MS patients and 89 OND patients using nested PCR to detect ompA gene of C. pneumoniae. They reported the presence of C. pneumoniae DNA in fifty percent of MS patients whereas among OND group, 28.1% were positive for chlamydial DNA. They further probed the 20 MS patients and 16 OND patients which were PCR positive for chlamydial heat shock protein 60-mRNA and 16S rRNA. HSP60-mRNA was detected in

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15 MS patients. On the other hand, only 18.8% of 16 OND patients were positive for HSP60-mRNA. C. pneumoniae16S rRNA was detected in 70% and 18.8% in MS and OND patients respectively [46]. A number of studies also reported the association of several viruses in MS. In a study, 66% of 126 MS patients were having history of Varicella Zoster Virus (VZV) infection whereas 66 out 157 controls were encountered with VZV in their life. Remarkably, it was observed that VZV infection history was statistically significant among relapsingremitting and secondary progressive subtypes of MS but nit in other types. It was estimated that earlier history of VZV infection increases the risk for MS up to three fold [47]. The viruses from Herpesviridae family has been found often associated with MS are herpes simplex virus (HSV), varicella zoster virus (VZV), human herpes virus-6 (HHV-6), EpsteinBarr virus (EBV) and cytomegalovirus (CMV) [47]. An Iranian study has found out of 82 MS patients, 78 (95.1%) were positive for anti-VZV antibodies and 21 (25.6%) were for VZV DNA positive, suggesting thereby the hypothesis that VZV may contribute to the subsequent development of MS [48]. Another study found VZV DNA in the CSF samples from all 53 MS patients during relapse but during remission, VZV DNA was found in the CSF from only 5 MS patients (31%). On the other hand, VZV DNA was not found in any CSF from 21 controls [49]. Makhani and coworkers have determined EBV in 247 prospectively followed children with acquired demyelinating syndromes (ADS) and observed that EBV infection was more common in children with MS than those with monophasic ADS [50]. Alvarez and colleagues investigated with the help of PCR 102 blood samples from MS patients and 102 blood samples from control subjects in an attempt to detect the presence of simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6 (HHV-6), human herpes virus 7 & 8. They found HHV-6 in 49.02% MS patients whereas among the control group this virus was only present in 21.5% individuals. According to their observations, the HHV-6 can play a major role in the multiple sclerosis [51]. The HSV, HHV-6 and VZV were found more frequently among MS patients compared to the controls in a study conducted by Sanders and coworkers. However, the presence of these herpes viruses was statistically not significant [52]. The prevalence of HHV-6 DNA was found significantly higher in MS patients compared to the control group [53]. It is supposed that any infection worsen the disease symptoms of multiple sclerosis, which consequently lead to more neurodegeneration. However, there are some studies that reported the beneficial effects on the disease symptoms of MS. A study conducted in female brown Norway rats wherein a persistent chronic infection was established in rats by inoculating them with Staphylococcus aureus. This infection inhibited the development of experimental autoimmune encephalitis (EAE) and remarkably reduced inflammatory infiltration and demyelination of the optic nerves. The researchers of this study concluded that S. aureus infection plays a vital role in preventing autoimmune inflammation of the CNS through secretion of extracellular adherence proteins [54]. Another study suggested the role beneficial role of Helicobacter pylori infection among MS patients. The study observed that patients with H. pylori infection were having


lower incidence of MS. Interestingly, MS patients with H. pylori infection demonstrated lower neurological complications [55].


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Alzheimer’s disease (AD) is the major cause of dementia in developed countries, and is the leading socioeconomic problem in healthcare. World Alzheimer Report has estimated that more than 45 million people worldwide are living with dementia in 2015 [59-60]. These estimates are 12-13% higher compared to the estimates for 2009. The financial burden of dementia has increased globally from US$ 604 billion in 2010 to US$ 818 billion in 2015, which constitutes an increase of 35.4%. AD is a degenerative neurological disorder wherein sever loss of neurons is occurred more particularly the cholinergic system [61], separation of the afferent and efferent hippocampal connections [62], loss of corticocortical glutamatergic association fibres [63] and massive cerebral shrinkage [64]. Pathologically, it is distinguished by the presence of plaques containing amyloid and neurofibrillary tangles [65] containing the hyperphosphorylated microtubule protein, tau [66]. Plaques and tangles are widely believed to be the factors leading to the neuronal damage in Alzheimer’s disease [67]. Multifactorial causes of AD have been found in several epidemiological studies including bacterial and viral infections [59, 68-69].

positivity [73]. There are evidences that suggest association between herpes simplex virus-1 (HSV-1) infection and AD, which binds to all classes of lipoproteins namely VLDL, LDL, and HDL. The viral glycoprotein B binds to APOA1 and APOE containing lipoproteins [74]. Interestingly, HSV1 also binds to complement receptor 1, which is a key player in Alzheimer’s disease genetics [75-76]. Seropositivity of anti-HSV-1 IgM was observed associated significantly with the subsequent development of AD [77-78]. Herpes simplex viral DNA was also found in the beta-amyloid containing plaques that characterize Alzheimer’s disease [79]. Herpes simplex virus type 1 establishes a permanent infection in the peripheral nervous system of most individuals after primary infection. This infection remains latent, but certain nonspecific inflammations can trigger its reactivation [80-81]. Wozniak and coworkers has reported that reactivation of HSV-1 induces synthesis of intrathecal antibodies. They measured antibody indices for HSV-1 using indirect ELISA for Ig-G antibody in serum and CSF and found intrathecal HSV-1 Ig-G synthesis in 14 out of total 27 AD patients. Further, the PCR findings corroborated the presence of HSV-1 DNA in several elderly brains suggesting virus replication [81]. The latent HSV-1 was detected in brain from AD patients and from aged normal subjects using PCR [82]. In a study, it has been observed that Herpes Simplex Virus-2 (HSV-2) infection induced the accumulation of hyperphosphorylated tau and the amyloid-β peptides Aβ40 and Aβ42 in human neuroblastoma cells. Further, the HSV-2 infection was found associated with a noticeable reduction in the amount of Aβ40 secreted and in the proteolytic fragments of amyloid-β precursor protein (APP). These results indicated that HSV-2 infection inhibits the nonamyloidogenic pathway of APP processing and impairs Aβ secretion in these cells (Kristen et al. 2015). Human herpes virus 6 is frequently detected both in AD and in healthy elderly brains. In a study, HHV-6 has been found with higher frequency (72%) in AD brains than in healthy brains (40%) [83]. However, it is highly unlikely that alone HHV-6 causes AD, but its infection might activate some diseases or viruses that act as opportunists. Wozniak, Shipley, Combrinck, Wilcock and Itzhaki 81] reported the detection of HHV-6 antibodies in 22% CSF samples from AD patients whereas no sample was found positive in the control group. In a different study, EBV was found in 6% of AD brains, whereas 45% of peripheral blood leukocytes samples from AD patients and 31% from controls were positive for EBV [84].

It has been reported that infectious burden comprising CMV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori was associated with AD particularly in the aged people suggesting accumulative infections were associated with AD [70]. It is a well established fact that inflammation has a strong relationship with neurodegeneration since various cytokines like IFN-γ, TNF-α, IL-1β and IL-6, were found associated in the progression of AD [71-72]. Barnes and colleagues employed a solid-phase enzyme-linked immunosorbent assay to detect immunoglobulin G antibody responses to CMV on 849 archived samples. Among these samples, 73.4% were positive for serologic evidence of exposure to CMV, out of which 93 persons subsequently developed AD with in average of next 5 years. The findings point to the increased risk of AD associated with CMV sero-

The bacterial infections of brain in AD patients have been reported by several researchers. The infection of C. pneumoniae has been observed in most of the neurological diseases since it has tropism for neural tissue [85]. In an investigation, postmortem brain samples from AD patients were analyzed for the presence of C. pneumoniae using PCR assay. Interestingly, out of total 19 AD brain samples, 17 were positive for C. pneumoniae. On the other hand, among 19 control samples 18 were negative for this organism [85]. Gerard and co-workers have assessed the presence of C. pneumoniae in postmortem brain tissues from 25 AD patients and 27 control subjects by targeting C. pneumoniae specific genes Cpn1046 and Cpn0695. Twenty out of 25 AD samples were positive for these genes whereas only 3 out of 27 control samples were positive for these genes. Moreover,

In contrast to all these studies suggesting the presence of C. pneumoniae in MS patients, there are several other studies that have not found any involvement of C. pneumoniae and other bacterial infections in the CNS or CSF of MS patients. A study on 85 Iranian MS patients and 50 control subjects found no correlation between either C. pneumoniae IgG or IgM in control group and MS patient [53]. Lindsay and Patel were unable to find any evidence for the presence of DNA of spirochetes, Campylobacter, Mycoplasma, Chlamydia, Bartonella, Mycobacteria and Streptococcus in CNS of MS patients [56]. Hammerschlag and colleagues investigated a large number of normal and pathological specimens obtained from postmortem brain tissues of patients with multiple sclerosis and with other neurological or non-neurological diseases, however; none of their result was positive, thereby suggesting that C. pneumoniae is not involved in inflammatory demyelination [57]. A study on possible relationship of multiple sclerosis with EBV among Indian MS patients found only weak association of EBV infection with MS [58]. ALZHEIMER’S DISEASE


immuno-histochemical analyses showed that astrocytes, microglia, and neurons all served as host cells for C. pneumoniae in the AD brain [86]. Presence of C. pneumoniae in AD brain was also confirmed in another study where immunoreactivity for C. pneumoniae antigens was observed in neurons, neuroglia, endothelial cells, frontal and temporal cortices with numerous C. pneumoniae specific antibodies. Interestingly, immunolabelling with two different anti-beta amyloid antibodies revealed that immunoreactivity was in the regions amyloid deposition. Beta amyloid deposition is the characteristic feature of AD brain [87]. A meta-analysis study estimated that infection with C. pneumoniae increases the chances for developing AD to nearly five-fold [88]. Helicobacter pylori infection in AD patients is also a hot topic among researchers in the field of dementia. Seropositivity for anti H. pylori IgG antibodies were found higher among 30 AD patients compared with 30 age-matched control individuals [89]. In another investigation, investigators have included 50 patients with AD and 30 control non-AD patients but having iron deficiency in their study. Using histological method to detect H. pylori infection, the investigators found that 88% of AD patients were positive for H. pylori infection whereas only 46.7% in control group were found infected with H. pylori, which is a significant difference [90]. Amazingly, successful eradication of H. pylori in AD patients was observed to be beneficial in the management of AD compared with those AD patients where eradication was not achieved or successful [91]. A similar observation was also reported in another study where eradication of H. pylori was found associated with a decreased risk of AD progression compared with no H. pylori eradication [92]. Other pathogens that have been found associated with AD are Treponema pallidum and Borrelia burgdorferi [93-95]. In an analytical study, different species of spirochete Treponema have been detected using specific PCR and antibodies. Treponemas were found in 90% of 247 AD brain samples. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Notably, co-infection with several spirochetes as the causal agent was also observed in AD. The most spirochetal infection occurs years or decades before the manifestation of dementia [94]. LYME DISEASE Lyme disease is a multisystemic infection for which the usual causative agent has been a spirochete called Borrelia burgdorferi. This spirochete, B. burdogferi, is transmitted by ticks from the genus Ixodes. The ticks become infected with B. burgdorferi while feeding on the blood of natural reservoir hosts such as mice, squirrels, shrews, and other small vertebrates. In North America, B. burgdorferi is most common species [96-97]. Other species of Borelia have also been reported for the causal organism for lyme disease. In Europe, B. afzelii, B. garinii, B. burgdorferi, B. spielmanii, and B. bavariensis have reported to cause the disease. Additional three species B. bissettii, B. lusitaniae, and B. valaisiana have very sporadically been detected in patients, but are not recognized as important pathogens [98-103]. B. afzelii and B. garinii infections report for most Lyme borreliosis cases in Europe, whereas B. garinii is predominant in Asia. B. afzelii

Alam et al.

is mostly associated with skin manifestations, B. garinii seems to be the most neurotropic, and B. burgdorferi seems to be the most arthritogenic [104]. Lyme disease is more prevalent in North America, Europe and Asia. In the United States, Lyme disease is the most commonly reported vectorborne illness [105], with more than 25,000 Lyme disease cases reported annually since 2007 [106-107]. The incidence in France is estimated to be 9.4 infected persons per 100,000 inhabitants [108]. The noteworthy organ pleiotropism of B. burdogferi results in diverse disease manifestations such as acute arthritis, myocarditis, and neuroborreliosis. Lyme neuroborreliosis affects 15 to 25% of patients with erythema migrans, the red skin-rash that in humans signals the point of entry of B. burgdorferi, and may involve both the peripheral and CNS [109]. The lyme disease is also frequented by other infections. The concurrent infections can be transmitted with B. burgdorferi or it can occur independently. The most important of these co-infections are caused by Bartonella species, Yersinia enterocolitica, C. pneumoniae, Chlamydia trachomatis, Babesia species and Mycoplasma pneumoniae. Infections caused by these pathogens in patients result in clinical symptoms similar to those occurring in Lyme disease. This applies particularly to infections caused by Bartonella henselae, Yersinia enterocolitica, and Mycoplasma pneumoniae. C. trachomatis primarily causes polyarthritis. C. pneumoniae not only causes arthritis but also affects the nervous system and the heart, which renders the differential diagnosis difficult. The co-infections may exacerbate Lyme disease through immune system modulation and are considered as the major cause for resistance to therapy [110-111]. The association of various infecting agents in different neurological diseases is shown in Fig. (1). OTHER NEUROLOGICAL DISEASES The Parkinson’s disease (PD) is a neurological disorder in which muscular rigidity, resting tremor and akinesia are major characteristics. In this disease, a progressive loss of dopamine neurons has been reported as the disease pathology. The disease is also associated with the presence of Lewy bodies and alpha-synnuclien [112-113]. A few studies have suggested chronic infection in the pathogenesis of PD. The PD patients showed some relief to the disease symptoms when treated for gastrointestinal H. pylori infection [114115]. Autism spectrum disorders (ASD) are neurological disorders in which patients are usually unable to communicate properly, form relationship with others and respond to the environment appropriately. Though exact causes of ASD are unknown but it seems that several factors may be responsible such as genetic defects, exposure to chemicals, heavy metals and biological agents. It has been observed that infection is an important element in the development of ASD since increased titers to several pathogens like viruses, bacteria and fungi have been reported in ASD patients [11, 116]. The parasite, Taenia solium is the causative agent of neurocysticercosis in which the common symptoms are epilepsy, headache, dizziness, stroke and neuropsychiatric dysfunction. It occurs when cysts formed by the infection grow within the brain [117]. Toxoplasmosis is caused by the infection of Toxopasma gondii, a protozoan. Usually, toxoplasmosis causes no apparent symptoms in adult humans. It is



7

Fig. (1). Figure showing association of different infectious agents with major neurological diseases.

generally spread by eating poorly cooked food containing cysts, exposure to infected cat feces and from mother to a child during pregnancy if mother is infected [118].

MS

= Multiple Sclerosis

ND

= Neurological Diseases

CONCLUSION

PCR

Though the association of infectious agents in neurological diseases has been reported in various studies, but it is not clear whether these infectious agents are responsible for the neurological diseases. Nevertheless, it can be concluded that neurological disease progression are affected by certain infections. Moreover, the neurological diseases made the patient vulnerable for several opportunistic infections that contribute to the disease progression. Infections of brain cells also contribute to stimulate autoimmune responses against nerve cell antigens. Further basic and clinical research is required to determine the involvement of certain infections in the pathogenesis and progression of various neurological diseases.

OND = Other Neurological Diseases = Polymerase Chain Reaction

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS Authors would also like to thank Deanship of Scientific Research (DSR), King Abdulaziz University for providing grant, bearing number: 529-141-1436 for the establishment of state of the art research facilities at King Fahd Medical Research Center. REFERENCES

LIST OF ABBREVIATIONS

[1]

AD

= Alzheimer’s disease

ALS

= Amyotrophic lateral sclerosis

[2]

CNS

= Central Nervous System

[3]

CSF

= Cerebrospinal fluid

[4]

EBV

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