The Role of Campylobacter jejuni in Guillain-Barré Syndrome

By Michelle Lam

Surpassing Salmonella spp. and Escherichia coli, the gram-negative Campylobacter genus has become the leading cause of bacterial gastroenteritis, accounting for 46% of the cases reported by the Centres for Disease Control and Prevention (Altekruse et al., 1999). Campylobacter jejuni is the most common of the Campylobacter spp. involved (Snelling et al., 2005), and is a commensal, microaerophilic bacterium located in the intestinal tract of poultry. Therefore, ingestion of contaminated poultry can result in C. jejuni colonisation in the human intestines (Nyati et al., 2013). This predominates in the mucus layer of the colon epithelium and the crypts of Lieberkühn, where there is an abundance of nutrients and carbon sources that C. jejuni can use for metabolism and growth (Burnham et al., 2018). To facilitate colonisation, C. jejuni possesses a high-velocity, corkscrew-like motility, attributed to its helical-shaped body and amphitrichous flagella (Snelling et al., 2005). 

The lipooligosaccharides (LOS) present on C. jejuni outer membranes are hypervariable, most likely due to selection favouring antigenic variability, in order to more efficiently invade the host immune system (Parker et al., 2008). Some strains possess LOS that resemble human gangliosides found on peripheral nerves. This is thought to lead to the development of Guillain-Barré syndrome (GBS) (Young et al., 2007). Whilst all strains carry common genes necessary for biosynthesis of the LOS inner core and lipid A, some LOS biosynthesis genes have been shown to contain several different loci, each with a unique genetic composition and arrangement, due to genetic recombination between strains (Houliston et al., 2011). These genes encode for glyco- and other transferases which add various monosaccharides to the LOS, resulting in distinct chemical linkages. Diversity in C. jejuni LOS is also a result of monosaccharide derivation from different non-carbohydrate sources, such as CMP-N-acetylneuraminic acid. This is determined by specific genes contained within the LOS biosynthesis locus, thus limiting the types of monosaccharides a strain is able to synthesise. Different LOS biosynthesis locus classes have since been recognised. Strains belonging to classes A, B or C possess genes that transfer galactose, N-acetylgalactosamine and sialic acid to the LOS outer core. The addition of sialic acid is due to expression of the cst gene, which encodes for sialic acid transferase (Parker et al., 2008). Since human gangliosides also contain sialic acid, it is this addition that causes the molecular mimicry between LOS and gangliosides (Godschalk et al., 2007). 

GBS is a rare autoimmune disease affecting the peripheral nervous system (PNS) and is characterised by acute onset of symmetrical muscle weakness, unstable ambulation and hyporeflexia or areflexia. These symptoms originate in the legs and rapidly spread to the upper limbs and face, eventually resulting in the loss of deep tendon reflexes (Esposito et al., 2017). Although the full pathogenesis is yet to be understood, GBS is known to follow an immune response, resulting in the body producing antibodies that cross-react with gangliosides on peripheral neurons (Leonhard et al., 2019). GBS often develops after C. jejuni exposure, supported by studies where the sera collected from GBS patients contained high levels of antibodies targeting C. jejuni LOS (Ang et al., 2002; Yuki, 2001). As a heterogenic disease, GBS can be divided into several subtypes. Acute inflammatory demyelinating polyneuropathy (AIDP) results in the attack of the myelin on peripheral nerves and lymphocytic infiltration, promoting demyelination. GBS can also cause axonal degeneration, exhibited in two sub-types: acute motor axonal neuropathy (AMAN), in which axonal degeneration only occurs in motor nerves; and acute motor-sensory axonal neuropathy (AMSAN), where both sensory and motor neurons are affected. Miller-Fisher syndrome (MFS) is considered to be another, albeit rarer, subtype, in which affected individuals also display ophthalmoplegia and ataxia (Nachamkin et al., 1998).

C. jejuni infection is mainly associated with AMAN, but pathogenesis has been demonstrated in other subtypes. This is reliant on the type of anti-ganglioside antibodies produced after campylobacteriosis. Patients which suffer from AMAN contain serum anti-GM1a, anti-GM1b, anti-GD1a and anti-GalNAc-GD1a antibodies, whereas MFS patients possess anti-GFD1b, anti-GD3 and anti-GQ1b antibodies (van den Berg et al., 2014). It is unknown which anti-ganglioside antibodies are produced in AIDP; however, studies have shown that anti-GM2 antibodies are found in the sera of patients suffering with AIDP following cytomegalovirus infection (Jacobs et al., 1997) and without cytomegalovirus infection (Jacobs et al., 1998), so it is possible that the anti-GM2 antibody is involved in ADIP development following C. jejuni exposure. AMAN anti-ganglioside antibodies target antigens located at the axolemma of the node of Ranvier. This activates the complement system to form the terminal complement complex (TCC) on the axolemma, causing the loss of voltage-gated sodium channels at the nodes, as well as paranodal myelin degradation. Subsequently, macrophages occupy the periaxonal space from the nodes of Ranvier and are able to cause axonal damage. Although AIDP anti-ganglioside antibodies are yet to be identified, their targets are assumed to be on the myelin sheath. When stimulated, this activates the complement system, which assembles the TCC on Schwann cells, causing demyelination via macrophage action (van den Berg et al., 2014).

Nevertheless, GBS development following campylobacteriosis is considered rare, with an estimate of 1.7 in 1,000 patients developing GBS in the following two months. However, this risk is still 77 times greater than observed with the general population (Tam et al., 2006). Additionally, C. jejuni has also been linked to increased severity of GBS, with cases reporting the requirement of ventilator support within 1-2 days of GBS onset, quadriplegia, loss of gait for up to a year and greater axonal degeneration (Nyati et al., 2013). Hence, combined with the well-established association between C. jejuni and GBS pathogenesis, better C. jejuni treatment can protect against GBS. Campylobacteriosis is currently treated using macrolide antibiotics, such as azithromycin. Previously, tetracyclines and fluoroquinolone were commonly used; however, the emergence of antibiotic-resistant strains has resulted in the shift to macrolides (Fischer et al., 2020). In 1981, Campylobacter spp. showed 8.6% resistance to tetracyclines, but more recent studies place this figure at 56% (Tracz et al., 2005). Furthermore, there was almost no fluoroquinolone resistance reported in the early 1990s, although a study conducted in Pennsylvania has more recently reported resistance of 40% (Gupta et al., 2004). These strains are thought to have arisen from large-scale use of antibiotics in farm animals, therefore there is increasing concern regarding controlling this usage and the emergence of macrolide-resistant strains in the future (Fischer et al., 2020).

The prevalence of antibiotic-resistant strains has encouraged research in finding alternative therapeutics to antibiotics. Usage of bacteriophages in live chickens is a potential way in which C. jejuni colonisation can be reduced (Ushanov, 2020). Bacteriophages are already used to control other food-borne pathogens, such as Listeria monocytogenes, where the LMP-102 bacteriophage was approved for use by the U.S. Food and Drug Administration in 2006 (Mahony et al., 2011). Hence, bacteriophages already harbour great potential in the control of food-borne pathogens. Bacteriophages can undergo two different replication methods. Lytic bacteriophages insert their genome into the host cytoplasm, causing the host cell to produce bacteriophage copies. This leads to lysis of the bacterium. Lysogenic bacteriophages integrate their genome into the bacterial chromosome, creating a prophage. The prophage is replicated during binary fission, at first without causing lysis, but eventually undergoing the lytic cycle (Kasman et al., 2020). Thus, lytic bacteriophages are preferred over lysogenic bacteriophages for therapeutic use, since host cell lysis is achieved faster (Ushanov et al., 2020). Indeed, most Campylobacter-specific bacteriophages are lytic, and the subtype amongst these lytic bacteriophages possessing the strongest activity has been identified to be C. jejuni-specific, thus demonstrating the potential of bacteriophages in C. jejuni control (Jäckel et al., 2019). Moreover, bacteriophages present several advantages over antibiotics. Firstly, bacteriophages are able to lyse all host cells, so are effective against antibiotic-resistant and non-resistant strains. Secondly, they are extremely specific for their host bacteria, so are less likely to disrupt the whole microbiome. Finally, bacteriophages are omnipresent, making them easy to isolate. This also means that humans are often exposed to bacteriophages through food and drink consumption, however there is no reported toxicity associated with this. Therefore, bacteriophages have been regarded as safe by the United States Food and Drug Administration (FDA) (Ushanov et al., 2020).

Although the mortality rate of campylobacteriosis is low with a reported rate of 2.4 per 1,000 cases (Smith et al., 1985), it still significantly elevates the risk of GBS pathogenesis compared to the risk without C. jejuni infection. In addition, there is suggestion that GBS cases are more severe with C. jejuni-mediated pathogenesis. Together, with the emergence antibiotic-resistant strains, this constitutes to a growing concern over the future control and treatment of C. jejuni. Finding alternatives to antibiotics, such as identifying suitable bacteriophages or administering a probiotic diet to poultry to reduce C. jejuni colonisation (Ushanov et al., 2020), would aid in the current antibiotic crisis and in the prevention of GBS.


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