Host Determinants of Expression of the Helicobacter pylori BabA Adhesin

Abstract

Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2−/− mice that do not have functional B or T cells, and in MyD88−/−, TLR2−/− and TLR4−/− mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Leb expression or the capacity of BabA to bind Leb. Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Leb.

Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques

“…However, neither immunoproteomic studies (38,39) nor serologic responses in macaques (23) have identified BabA or BabB as an immunodominant antigen and its expression appears to have no effect on gastritis. Furthermore, BabA expression is lost in recombination-activating gene-deficient mice that do not express functional B or T cells (46). Therefore, while the basis for selection against BabA expression is unknown, it is not likely classical immune evasion and it does not require the capacity to attach to Leb.…”

Pathogenesis of Helicobacter pylori infection

“…showed an independent selective pressure for loss of BabA expression and overexpression of BabB. In addition, loss of BabA expression was reported to be independent of adaptive immunity or Toll‐like receptor signaling …”

Pathogenesis of Helicobacter pylori infection

“…Observed mechanisms of negative selection of bab A included phase variation by slipped stranded mispairing and gene conversion with bab B, which may directly confer a fitness advantage . In addition, the negative selection of bab A was observed even in the absence of host TLR signaling …”

“…BabA is known to be important in the initial colonization of H. pylori, but was negatively selected after a few days' and up to 20 weeks' infection in both mice and rhesus macaques. 32,33 Observed mechanisms of negative selection of babA included phase variation by slipped stranded mispairing and gene conversion with babB, which may directly confer a fitness advantage. 33 In addition, the negative selection of babA was observed even in the absence of host TLR signaling.…”

“…33 In addition, the negative selection of babA was observed even in the absence of host TLR signaling. 32 Another H. pylori OMP family member which showed intriguing results was OipA. The oipA "on" H. pylori reached mid-logarithmic phase faster than the oipA "off" strains.…”