The Role of Fungi in the Etiology of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Infectious triggers of MS are being actively investigated. Substantial evidence supports the involvement of the Epstein-Barr virus (EBV), though other viruses, bacteria, protists, and fungi are also being considered. Many links between fungi and diseases involving chronic inflammation have been found recently. Evidence linking MS and fungi is reviewed here. The HLA-DRB1*15 allele group is the most important genetic risk factor of MS, and is a risk factor in several other conditions linked to fungal infections. Many biomarkers of MS are consistent with fungal infections, such as IL-17, chitotriosidase, and antibodies against fungi. Dimethyl fumarate (DMF), first used as an industrial fungicide, was recently repurposed to reduce MS symptoms. Its mechanisms of action in MS have not been firmly established. The low risk of MS during childhood and its moderate association with herpes simplex virus type 2 suggest genital exposure to microbes (including fungi) should be investigated as a possible trigger. Molecular and epidemiological evidence support a role for infections such as EBV in MS. Though fungal infections have not been widely studied in MS, many lines of evidence are consistent with a fungal etiology. Future microbiome and serological studies should consider fungi as a possible risk factor for MS, and future clinical studies should consider the effect of fungicides other than DMF on MS symptoms.

Fungal Translocation: A Driving Force Behind the Occurrence of Non-AIDS Events?

“…Very recently, it was shown in a mouse model that chronic transient candidemia, while being cleared quickly from the circulation, led to highly localized cerebritis that, in the long term, could lead to substantial neuronal loss and progressive cognitive impairment [17]. There is also emerging but still limited evidence that the gut mycobiome is intricately involved in neurological disease and that fungal components may play a role in Alzheimer disease and multiple sclerosis [18][19][20]. For PLWH on suppressive ART, it has been shown that βDG was detectable in CSF, with a trend toward higher CSF βDG levels in individuals with neurocognitive impairment [21].…”

Can environmental factors increase the risk of multiple sclerosis? A narrative review

“…HLA-DRB1 allele, which is the most important genetic risk factor for MS, is associated with fungal infections. Many cytokines and markers involved in fungal infection such as interleukin 17, chitotriosidase and antibodies against fungus are also involved in MS disease and can be pathogenic 44 . In relation to the diet, the conducted experiments prevented people with MS from a high-fat diet, high in cholesterol, sugar, and sodium, to prevent the exacerbation of disease symptoms 38 .…”

Spondyloarthritis, Acute Anterior Uveitis, and Fungi: Updating the Catterall–King Hypothesis

“…While the existence of an as-yet-unrecognized genital infection may seem to be far-fetched at first, such a hypothesis has been proposed to explain the sexual risk factors of multiple sclerosis ( 9 , 14 ) and prostate cancer ( 7 , 8 , 13 ) based on evidence completely unrelated to spondyloarthritis (Table 4 ). Recent studies have implicated fungal infections in multiple sclerosis ( 5 , 206 – 208 ) and prostate cancer ( 4 , 15 , 172 ), and these infections appear to be intracellular in both cases (Table 4 ) ( 4 , 209 , 210 ).…”

“…Similarly, circulating CD4+ T cells in uveitis patients are more sensitive than controls to fungal antigens ( C. albicans ) after a 24-h antigen exposure period ( 127 ), whereas sensitivity to bacterial antigens ( Staphylococcus aureus, Clostridium tetani , and Mycobacterium tuberculosis ) and protist antigens ( Toxoplasma gondii ) are similar in both groups ( 127 ). Intermediate uveitis is associated with multiple sclerosis onset ( 128 ) and with the HLA-DRB1*1501 allele ( 129 ), which are both associated with the immune response to fungi ( 5 ). A small study reported that oral dimethyl fumarate, a fungicidal compound known to be effective in multiple sclerosis and psoriasis, improved chronic idiopathic uveitis symptoms in four patients ( 130 ).…”

“…Recent studies have linked the immune response against fungi with prostate cancer ( 4 ) and multiple sclerosis ( 5 ). Sexual risk factors of prostate cancer ( 6 – 8 ) and multiple sclerosis ( 9 – 12 ) suggest that there may exist an as-yet-unrecognized sexually transmitted infection (STI) etiologically involved in these two diseases ( 4 , 5 , 13 , 14 ). Epidemiological evidence suggests this elusive STI may be a fungal infection ( 15 ).…”