Comment; Molecular biology is showing us so many potential connections and possible interactions to promote and/or inhibit infection–things we had no prior suspicion of. Fascinating! Koch’s famous postulates may be on their way to obselescence!
Davide Cossu1,2, Kazumasa Yokoyama1,2* and Nobutaka Hattori1,2
- 1Department of Neurology, Juntendo University, Tokyo, Japan
- 2Advanced Research Institute for Health Science, Juntendo University, Tokyo, Japan
Multiple sclerosis (MS) is caused by a complex interaction of genetic and environmental factors. Numerous causative factors have been identified that play a role in MS, including exposure to bacteria. Mycobacteria, Chlamydia pneumoniae, Helicobacter pylori, and other bacteria have been proposed as risk factors for MS with different mechanisms of action. Conversely, some pathogens may have a protective effect on its etiology. In terms of acquired immunity, molecular mimicry has been hypothesized as the mechanism by which bacterial structures such as DNA, the cell wall, and intracytoplasmic components can activate autoreactive T cells or produce autoantibodies in certain host genetic backgrounds of susceptible individuals. In innate immunity, Toll-like receptors play an essential role in combating invading bacteria, and their activation leads to the release of cytokines or chemokines that mediate effective adaptive immune responses. These receptors may also be involved in central nervous system autoimmunity, and their contribution depends on the infection site and on the pathogen. We have reviewed the current knowledge of the influence of bacteria on MS development, emphasizing the potential mechanisms of action by which bacteria affect MS initiation and/or progression.
Introduction
Multiple sclerosis (MS) has a complex pathophysiology that results from multiple and unclear interactions between genetic and environmental factors. Accumulating evidence over the years also supports the role of infectious agents, particularly viruses, in the etiopathogenesis of MS. Among these, Epstein–Barr virus (EBV) seems to be the strongest candidate as a risk factor (Olsson et al., 2017). In fact, MS risk is higher among individuals with history of mononucleosis or who experienced an EBV infection in childhood (Ascherio and Munger, 2010). Subclinical EBV infection is present in over 95% of all individuals, including those with MS; however, the MS incidence and prevalence differ in each country. Therefore, coinfection with another pathogen, including bacteria, could explain the difference between high- and low-risk areas for MS.
There are several examples of virus–bacteria interactions (Almand et al., 2017), which mainly occur when the pathogens colonize the same site during infection, although sometimes viruses can act at different locations within the host (Steed and Stappenbeck, 2014). For instance, the human immunodeficiency virus targets a wide variety of immune cells, causing depletion of CD4+ T cells and up-regulation of CD14+ cells, which likely contributes to the susceptibility of co-infection with Mycobacterium tuberculosis (Pawlowski et al., 2012). Moreover, during co-infection, the cell wall lipids of mycobacteria can modulate the host cell response, resulting in increased viral propagation and overall worsening of the disease (Pawlowski et al., 2012).
Another kind of virus–bacteria interaction is immune system subversion, such as occurs with the interaction between EBV and periodontopathic bacteria. The latter could induce EBV reactivation via chromatin modification, and virally-infected B cells cause tissue inflammation, decreasing the ability to defend against bacteria, thereby facilitating the progression of periodontal diseases (Gao et al., 2017). A case-control study provided evidence for an association between chronic periodontitis and female patients with MS in Taiwan (Sheu and Lin, 2013). The antigenic epitopes shared between Mycobacterium avium sp. paratuberculosis and EBV, which are cross-recognized by antibodies targeting self-epitopes in MS patients, provided additional evidence of a possible synergistic effect of viral–bacterial coinfection in inducing the pathology (Mameli et al., 2014).
Considering that bacteria are found in many sites of the human body including the brain (which is usually microbe free) and that viruses may efficiently spread from the site of primary infection to other tissues, we speculate that synergistic interactions between multiple pathogens may play a role in the pathogenesis of neuroinflammatory diseases like MS.
There are several possible explanations regarding the role of bacteria or viruses in predisposing an individual to MS autoimmunity. According to the hygiene hypothesis, exposure to pathogenic organisms early in life can confer protective immunity, whereas infections in adulthood can trigger an autoimmune reaction in susceptible individuals (Fleming and Fabry, 2007). Another alternative theory suggests that MS could be caused by a pathogen that is more common in regions of high MS prevalence, where the pathogen is endemic and, in most individuals, causes an asymptomatic infection, but reactivation of the infection several years later can lead to central nervous system (CNS) disease such as MS (Kurtzke and Heltberg, 2001).
In this review, we will describe the current understanding of bacterial pathogens associated with MS and the diversity of mechanisms used by such pathogens to colonize and influence the human CNS.
Conclusion
In 1890, Robert Koch formulated postulates for determining that a particular bacterium is the cause of a specific disease. According to these criteria, the causative organism must be found and isolated in every case of the disease and absent in the healthy subjects. Despite the importance of these postulates in the development of microbiology, there are many limitations associated with them, and with the advent of new molecular and genetic techniques in the fields of microbiology and medicine, these criteria of causation have been revised several times. Nevertheless, these criteria for infectious disease causality are still considered of contemporary relevance and might still have some use.
To date, none of the bacteria related to MS have fulfilled Koch’s postulates, and a causative relationship between a specific bacterium or vaccination with a live attenuated organism and MS has yet to be established. Current data suggest that multiple infections along with non-infectious environmental factors might trigger the development of MS in a certain genetic background. It is possible that a single bacterium need not be responsible for MS, but different pathogens may initiate events that trigger a common immune-pathologic pathway. In addition, an infectious pathogen may not be causative, but it may still influence the development and progression of MS, having a protective role or exacerbating disease manifestation during immunological maturation.
Interestingly, the existence of an abnormal immunological mechanism has been shown to operate in the pre-disease stage of MS, which in turn favors the phenomenon of epitope spreading (Achiron et al., 2010). Considering that the time interval between a bacterial infection and MS initiation may not be immediate and that a long period between the two events may be needed, bacteria could be one of several environmental factors responsible for the activation of this apoptotic process in a time-dependent mechanism.
Another issue is that most pathogens related to MS, with few exceptions, seem to be highly prevalent in the general population; however, the increase of MS incidence is not ubiquitous and depends on various environmental and/or genetic factors such as latitude, ethnicity, and development of the country.
Future research should concentrate on combining data obtained from animal models and epidemiological studies, in order to better explain specific aspects of host–pathogen interactions and, consequently, define the role of bacteria in the etiology and pathogenesis of MS.
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