Strains of Helicobacter pylori that cause ulcer or gastric cancer typically 
express a type IV secretion system (T4SS) encoded by the cag pathogenicity 
island (cagPAI). CagY is an ortholog of VirB10 that, unlike other VirB10 
orthologs, has a large middle repeat region (MRR) with extensive repetitive 
sequence motifs, which undergo CD4+ T cell-dependent recombination during 
infection of mice. Recombination in the CagY MRR reduces T4SS function, 
diminishes the host inflammatory response, and enables the bacteria to colonize 
at a higher density. Since CagY is known to bind human α5β1 integrin, we tested 
the hypothesis that recombination in the CagY MRR regulates T4SS function by 
modulating binding to α5β1 integrin. Using a cell-free microfluidic assay, we 
found that H. pylori binding to α5β1 integrin under shear flow is dependent on 
the CagY MRR, but independent of the presence of the T4SS pili, which are only 
formed when H. pylori is in contact with host cells. Similarly, expression of 
CagY in the absence of other T4SS genes was necessary and sufficient for whole 
bacterial cell binding to α5β1 integrin. Bacteria with variant cagY alleles that 
reduced T4SS function showed comparable reduction in binding to α5β1 integrin, 
although CagY was still expressed on the bacterial surface. We speculate that 
cagY-dependent modulation of H. pylori T4SS function is mediated by alterations 
in binding to α5β1 integrin, which in turn regulates the host inflammatory 
response so as to maximize persistent infection.IMPORTANCE Infection with 
H. pylori can cause peptic ulcers and is the most important risk factor for 
gastric cancer, the third most common cause of cancer death worldwide. The major 
H. pylori virulence factor that determines whether infection causes disease or 
asymptomatic colonization is the type IV secretion system (T4SS), a sort of 
molecular syringe that injects bacterial products into gastric epithelial cells 
and alters host cell physiology. We previously showed that recombination in 
CagY, an essential T4SS component, modulates the function of the T4SS. Here we 
found that these recombination events produce parallel changes in specific 
binding to α5β1 integrin, a host cell receptor that is essential for 
T4SS-dependent translocation of bacterial effectors. We propose that 
CagY-dependent binding to α5β1 integrin acts like a molecular rheostat that 
alters T4SS function and modulates the host immune response to promote 
persistent infection.