Virulence Mechanisms of Gastric Helicobacters Involved in Adhesion and Colonization

Gastric helicobacters are able to survive the acidic environment of the stomach by expressing urease at a high level. The presence of flagella and genes encoding proteins involved in chemotactic behavior allow helicobacters to move actively away from low pH regions toward more neutral regions of the gastric mucosa (Haesebrouck et al. 2009). Once the helicobacters reach the inner mucus layer, their motility decreases, possibly optimizing their attachment to gastric epithelial cells. In contrast to H. pylori, most gastric NHPH are found deep in the gastric pits (Figure 19.2; Haesebrouck et al. 2009).

Binding to mucins and epithelial cells is an important step in the pathogenesis of Helicobacter infections. The transmembrane Muc1 is constitutively expressed by gastric epithelial cells and most likely serves as a first point of adherence for Helicobacter. Experimental infection of BALB/c mice with H. heilmannii resulted in an increased expression of the secreted mucin Muc6 and the transmembrane mucin Muc13 in the first nine weeks post‐infection (Liu et al. 2014), indicating that both mucins might play a role in NHPH adhesion and colonization. Furthermore, H. suis has been shown to bind to acidic glycan structures and glycans terminating with galactose, while type 2 Lewis antigens and terminal α‐GalNAc most likely play a role in adhesion of gastric NHPH to the canine gastric mucosa (Amorim et al. 2014).

Gastric helicobacters harbor a large set of genes encoding outer‐membrane proteins (OMPs). Comparative genomics showed that gastric NHPH lack all known H. pylori adhesins described so far (Bauwens et al. 2018), suggesting that other OMPs function as adhesins in these organisms. Two Helicobacter‐specific OMP families with possible functions in adhesion (family 13, i.e. Hop, Hor and Hom; and family 33, Hof), as well as an outer membrane phospholipase (OMPLA; family 38) and an Helicobacter‐specific VacA‐like cytotoxin family correlated with colonization capacity (family X3) were identified in all gastric helicobacters (Bauwens et al. 2018). Two Hof proteins, HofE and HofF, have been shown to play a role in the adhesion of H. heilmannii to the gastric mucosa and gastric epithelial cells (Liu et al. 2016). The exact role of the other OMPs in NHPH colonization remains to be further elucidated (Bauwens et al. 2018).

Virulence Mechanisms of Gastric Helicobacters Involved in the Induction of Gastric Pathologies

Cytotoxin‐associated gene pathogenicity island (cagPAI) and vacuolating cytotoxin A (VacA) are major H. pylori virulence factors involved in the induction of gastric pathologies. Both factors, however, are absent in all gastric NHPH, except for H. cetorum which carries a functional VacA toxin.

Gamma‐glutamyl transpeptidase (GGT) is a highly conserved and important virulence factor of gastric Helicobacter species (Figure 19.1) This enzyme hydrolyses glutathione and glutamine into glutamate, after which glutamate supplies energy for the bacterium. Degradation of glutamine and glutathione may lead to a deficiency for the host, possibly initiating and/or promoting several pathologies. In vitro research using human gastric epithelial cells has shown that H. suis GGT causes apoptosis or necrosis, depending in part on the amount of reactive oxygen species generated through degradation of the antioxidant glutathione (Flahou et al. 2011). Oral supplementation of glutamine has been shown to temper H. suis induced gastritis and epithelial proliferation in experimentally infected Mongolian gerbils and naturally infected pigs (Zhang et al. 2015; De Bruyne et al. 2016).

Gastric helicobacters also possess other virulence factors, such as flavodoxin protein (FldA), plasminogen‐binding proteins (PgbA, PgbB), L‐asparaginase II (AnsB), high temperature requirement A (HtrA), collagenase (PrtC) and IceA (Vermoote et al. 2011). For H. pylori, these factors have already been associated with the development of gastric lesions. While AnsB plays a role in the cell‐cycle inhibition of fibroblasts and gastric cell lines (Scotti et al. 2010), FldA has been associated with the pathogenesis of mucosa‐associated lymphoid tissue (MALT) lymphomas (Chang et al. 1999). PgbA and PgbB allow H. pylori to bind to host plasminogen, which may contribute to a delay of the natural healing process of gastric ulcers (Vermoote et al. 2011). HtrA is involved in cleavage of E‐cadherin and thereby contributes to the disruption of the gastric epithelial barrier (Hoy et al. 2010). Collagen becomes degraded through the production of PrtC, (Kavermann et al. 2003). Finally, IceA has been associated with peptic ulcer disease and seems to be induced by contact between epithelial cells and H. pylori (Huang et al. 2016). However, the possible role of these virulence factors in the development of gastric pathologies associated with NHPH infections remains unclear.

Canine and feline gastric helicobacters possess a unique gene encoding chondroitinase AC‐type lyase belonging to CAZy family 8 (Namburi et al. 2016). Most likely, this enzyme breaks down chondroitin‐4‐O‐sulfate secreted by chief peptic cells, and since chondroitin‐4‐O‐sulfate regulates the activity of pepsin in the chief cells, its depletion might cause decreased peptic control resulting in ulcer development. It remains, however, unclear how this enzyme can participate in the promotion of gastric disorders in dogs and cats (Namburi et al. 2016).

Virulence Mechanisms of Gastric Helicobacters Involved in Host Immune Evasion

Despite the presence of a host immune response, helicobacters are generally not cleared from the stomach, resulting in lifelong infections. H. pylori has been shown to avoid Toll‐like receptor (TLR) recognition by modulating its surface molecules, such as lipopolysaccharide (LPS) and flagellin. Variation in LPS sialyation patterns may explain why TLR2‐mediated nuclear factor κB (NF‐κB)‐inducing abilities differ between H. bizzozeronii strains (Kondadi et al. 2015). The SfpA/LpxR OMP family (i.e. family 36) has been found in all gastric helicobacters and is possibly involved in LPS modulation by removing the 3′‐acyloxyacyl group of lipid A (Bauwens et al. 2018). Furthermore, all gastric helicobacters show the presence of the jhp0562 glycosyltransferase enzyme, except for H. ailurogastricus. The glycosyltransferase enzyme jhp0562 of H. pylori functions in the synthesis of both type I and type II Lewis antigens, which are present on the LPS of the bacterial outer membrane. Diverse Lewis antigens are generated via intragenomic recombination of jhp0562, and this glycosyltransferase contributes to the process of LPS variation in H. pylori. Finally, the presence of genes involved in sialic acid biosynthesis (neuA, neuB and wecB) may also contribute to host immune evasion by decorating the bacterial surface with sialic acid.

As also described for H. pylori, H. suis GGT has been identified to inhibit proliferation and cytokine production of lymphocytes in vitro through deprivation of extracellular glutamine, a conditional essential amino acid important for normal cell function and maintenance, and through hydrolysis of the antioxidant glutathione (Zhang et al. 2013, 2015). In this same study, H. suis outer‐membrane vesicles were identified as a possible delivery route of H. suis GGT to lymphocytes residing in the deeper mucosal layers (Zhang et al. 2013, 2015).

Other proteins associated with immune‐evasion mechanisms have been found in gastric helicobacters, such as neutrophil‐activating protein A (NapA), catalase (KatA), superoxide dismutase and alkyl hydroperoxide reductase (Vermoote et al. 2011; Joosten et al. 2015). These enzymes have been described to protect H. pylori during acute inflammation since they lower the amount and impact of reactive oxygen species produced by phagocytes. Most likely, they are also involved in the persistence of gastric NHPH, although this needs to be investigated.

H. mustelae produces a unique surface array showed that colonization levels of Hsr‐negative mutants were similar to those of the parent strain up to 9 weeks after infection but were significantly reduced 12–18 weeks after infection (Patterson et al. 2003). These findings indicate that Hsr impacts long‐term survival of H. mustelae, most likely due to the variability of exposed of Hsr epitopes which may contribute to immune evasion (Forester et al. 2001; Patterson et al. 2003).

Dendritic cells might also play a crucial role in promoting tolerance to gastric Helicobacter infections. H. pylori has developed several strategies to influence dendritic cell maturation and cytokine production, skewing them toward a tolerogenic phenotype and thereby directing a regulatory T cell (Treg) response. By eliciting a Treg response, H. pylori succeeds in suppressing gastric immune and inflammatory responses, leading to chronic colonization (Mejías‐Luque and Gerhard 2017). Bosschem et al. (2017) demonstrated that H. suis induces a semi‐maturation of porcine monocyte‐derived dendritic cells, which in turn may elicit Treg expansion. Since H. pylori urease impairs folding and correct transport of MHC II molecules by binding to CD74 and since this enzyme is highly conserved among gastric helicobacters (Beswick et al. 2006), H. suis urease may play a similar role in inducing a Treg immune response.

Finally, it has been shown that H. suis infection can change the mucin composition and glycosylation of the porcine gastric mucus, which in turn decreases the amount of H. suis binding glycan structures (Padra et al. 2019). Furthermore, the H. suis growth‐inhibiting effect of mucins from non‐infected pigs was replaced by a growth‐enhancing effect by mucins from infected pigs. It was hypothesized that H. suis infections impair the mucus barrier by decreasing both the bacteria‐binding ability of the mucins and the innate anti‐proliferation activity of mucus on H. suis. Inhibition of these mucus‐based defenses may create a more stable and inhabitable niche for H. suis, which may contribute to lifelong infections (Padra et al. 2019).

Host Immune Response to Gastric Helicobacters and their Involvement in Pathogenesis

The inflammatory response toward gastric Helicobacter infections plays an important part in the pathogenesis. Chronic inflammation has been associated with epithelial proliferation, metaplasia and/or atrophy, which contribute to the development of gastric cancer.

Once gastric helicobacters penetrate the gastric epithelial barrier, innate host defense mechanisms are triggered and the expression of proinflammatory and anti‐bacterial factors by gastric epithelial cells is stimulated. This leads to the recruitment of neutrophils, monocytes/macrophages and dendritic cells, which infiltrate the gastric mucosa. The secretion of mediators such as histamine, proteases, adenosine and H₂O₂ from neutrophils and mast cells can modify the barrier and/or ion transport function of epithelial cells. Oxidative metabolites from neutrophils can also induce cellular damage, including apoptosis and DNA injury. The longer the period of exposure of a tissue to activated immune/inflammatory cells and mediators, the more cellular damage may accumulate (Ernst and Gold 2000). In response to Helicobacter antigens, dendritic cells and macrophages further amplify the inflammatory response by the production of cytokines, resulting in an adaptive immune response (Wilson and Crabtree 2007). While H. pylori and H. felis mainly induce a T helper (Th) 1/Th17 response, other gastric NHPH seem to induce a Th2/Th17 response, although this depends on the host, which mainly determines the outcome of the immune response (Bosschem et al. 2016). While coinciding Treg responses contribute to the persistent infection of gastric helicobacters infections, Th1‐driven host responses contribute to gastroduodenal disease (Ernst and Gold 2000). Gastric Helicobacter

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