Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases

Garth L. Nicolson, PhD

Disclosures

Lab Med. 2008;39(5):291-299. 

In This Article

Multiple Sclerosis

Multiple sclerosis (MS) is the most common demyelinating disease of the CNS, and it can occur in young as well as older people. In MS, inflammation and the presence of autoimmune antibodies against myelin and other nerve cell antigens are thought to cause the myelin sheath to break down, resulting in decrease or loss of electrical impulses along the nerves.[38,39] In the progressive subset of MS, neurological damage occurs additionally by the deposition of plaques on the nerve cells to the point where nerve cell death occurs. In addition, breakdown of the blood-brain barrier in MS is associated with local inflammation caused by glial cells.[38,39] The clinical manifestations of demyelinization, plaque damage, and blood-brain barrier disruptions are variable but usually include impaired vision, alterations in motor, sensory, and coordination systems, and cognitive dysfunction. Often these are cyclic (relapsing-remitting subset) over time, but a substantial MS subset progresses without remitting.[39]

There is strong evidence for a genetic component in MS.[40,41] Although it has been established that there is a genetic susceptibility component to MS, epidemiological and twin studies suggest that MS is an acquired, rather than an inherited, disease.[42]

The possibility that MS is linked to chronic infections has attracted attention.[43,44] In fact, MS patients show immunological and cytokine elevations consistent with chronic infections.[44,45,46] A possible infectious cause for MS has been under investigation for approximately the last decade, and patients have been examined for various viral and bacterial infections.[44,47] One of the most common findings in MS patients is the presence of antibodies and DNA of C. pneumoniae in their CSF.[47,48,49] For example, Sriram and colleagues[48] examined relapsing-remitting (N=17) and progressive (N=20) MS patients for the presence of C. pneumoniae in CSF by culture, PCR, and immunoglobulin reactivity with C. pneumoniae elementary body antigens. They were able to isolate C. pneumoniae from 64% of MS patients' CSF versus 11% of patients with other neurological diseases. High rates of PCR-positive (MOMP gene) patients (97% MS-positive versus 18% with other neurological diseases) as well as serology-positive patients (86% MS-positive, confirmed by enzyme-linked immunosorbant assays [ELISA] and Western blot analysis) were found in MS.[48] Further examination of MS patients for oligoclonal antibodies against C. pneumoniae revealed that 14 of 17 patients were positive, whereas none of the control non-MS patients had antibodies that were absorbed by C. pneumoniae elemental body antigens.[49]

Other studies have also found evidence for the presence of C. pneumoniae in MS patients but at lower incidence. Fainardi and colleagues[50] used ELISA techniques and found that high-affinity antibodies against C. pneumoniae were present in the CSF of 17% of 71 MS cases compared with 2% of 52 patients with noninflammatory neurological disorders. They found that the majority of the progressive forms of MS were positive compared with patients with remitting-relapsing MS. The presence of C. pneumoniae antibodies were also found in other inflammatory neurological disorders (N=51), and thus it was not specific to MS.[50] Using immunohistochemistry, Sriram and colleagues[51] performed a study of formalin-fixed CNS tissue from MS and non-MS neurological disease controls and found that in a subset (7 of 20) of MS patients, chlamydial antigens were localized to ependymal surfaces and pariventricular regions. Staining was not found in 17 CNS tissue samples from other neurological diseases. Frozen tissues were available in some of these MS cases, and PCR amplification of C. pneumoniae genes was accomplished in 5 of 8 CNS tissue samples from MS patients but none in 17 frozen CNS tissues from other neurological diseases. In addition, they examined CSF sediment by immuno-gold-labeled staining for chlamydial antigens and found by electron microscopy that the electron-dense bodies resembling bacterial structures correlated with PCR-positive results in 10 of 11 MS cases.[51] The same group also used different nested PCR methods to examine additional C. pneumoniae gene sequences in the CSF of 72 MS patients and linked these results to MRI evidence of MS-associated lesions.[52] Similarly, Grimaldi and colleagues[53] linked the presence of C. pneumoniae infection with abnormal MRI results in 23 of 107 MS patients with more progressive disease. In addition, a higher rate of C. pneumoniae transcription was found by Dong-Si and colleagues[54] in the CSF of 84 MS patients. The above, among other data,[55,56,57] support the presence of C. pneumoniae in the CNS of MS patients, at least in a subset of more progressed patients that are most likely the progressive forms of MS.

Not all studies have obtained evidence, however, for the presence of C. pneumoniae[58,59] or other bacteria[60] in the CNS of MS patients. Hammerschlag and colleagues[61] used nested PCR and culture to examine 12 frozen brain samples from MS patients but could not find C. pneumoniae in any of the tissue samples. Alternatively, in one study, C. pneumoniae was found at similar incidence in MS and other neurological diseases, but only MS patients had C. pneumoniae in their CSF.[59] Swanborg and colleagues[62] have reviewed the evidence linking C. pneumoniae infection with MS and have concluded that they are equivocal due to negative reports, and they also speculated that specific genetic changes may be necessary to fulfill the role of such infections in the etiology of MS.

Another possible reason for the equivocal evidence linking MS etiology with infection, such as C. pneumoniae, is that multiple coinfections could be involved. In addition to C. pneumoniae found in most studies, MS patients could also have Mycoplasma species, B. burgdorferi, and other bacterial infections as well as viral infections.[63] When multiple infections are considered, it is likely that >80% of MS patients have obligate intracellular bacterial infections caused by Chlamydia (Chlamydophila) or other bacteria that can be intracellular, such as Mycoplasma, Borrelia, and other infections. These infections were found only singly and at very low incidence in age-matched subjects.[63] In spite of these findings, others did not find evidence of Mycoplasma species in brain tissue (N=30), CSF, or peripheral blood (N=57) of MS patients.[64]

Viruses have also been associated with MS. Certain viruses have been found in MS patients, such as HHV6, but these viruses have also been found at lower incidence in control samples.[62] Sanders and colleagues[65] used PCR to examine postmortem brain tissue (N=37) and controls (N=61) for the presence of neurotrophic viruses. They found that 57% of MS cases and 43% of non-MS neurological disease controls were positive for HHV6, whereas 37% and 28%, respectively, were positive for herpes simplex virus (HSV1 and HSV2) and 43% and 32%, respectively, were positive for varicella zoster virus; however, these differences did not achieve significance, and the authors concluded that "an etiologic association to the MS disease process [is] uncertain." They also found that 32% of the MS active plaques and 17% of the inactive plaque areas were positive for HHV6.[65] Challoner and colleagues[66] used sequence difference analysis to search for pathogens in 86 MS brain specimens. Using PCR, they found that >70% of the MS specimens were positive. They also used immunocytochemistry and found staining around MS plaques more frequently than around white matter; nuclear staining of oligodendrocytes was also seen in MS samples but not in controls.[66] Using immunofluorescent and PCR methods, HHV6 DNA has also been found in peripheral leukocytes in the systemic circulation of MS patients.[67,68] However, using PCR methods, others did not find herpesviruses in the peripheral blood or CSF of MS patients.[69,70]

Although significant information (reviewed in[43,44,70]) points to an infectious process in MS, this remains a controversial concept. As evidence emerges of new possible pathogens in MS, such as a new putative retrovirus,[71] these reports must be intensively examined and further studies initiated. Since most studies have found that the progressive form of MS, rather than relapsing-remitting forms of MS, were associated with chronic infections, infections might be more important in MS progression than in its inception. Various infections may also nonspecifically stimulate the immune system.[43] As in other neurodegenerative diseases, multiple factors appear to be involved in the pathogenesis of MS. Thus, like ALS, MS progression may turn out to be more likely linked to chronic infections, rather than its inception.

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