title: The Helicobacter pylori autotransporter ImaA (HP0289) modulates the immune response and contributes to host colonization.
abstract: The human pathogen Helicobacter pylori employs a diverse collection of outer membrane proteins to colonize, persist, and drive disease within the acidic gastric environment. In this study, we sought to elucidate the function of the host-induced gene HP0289, which encodes an uncharacterized outer membrane protein. We first generated an isogenic H. pylori mutant that lacks HP0289 and found that the mutant has a colonization defect in single-strain infections and is greatly outcompeted in mouse coinfection experiments with wild-type H. pylori. Furthermore, we used protease assays and biochemical fractionation coupled with an HP0289-targeted peptide antibody to verify that the HP0289 protein resides in the outer membrane. Our previous findings showed that the HP0289 promoter is upregulated in the mouse stomach, and here we demonstrate that HP0289 expression is induced under acidic conditions in an ArsRS-dependent manner. Finally, we have shown that the HP0289 mutant induces greater expression of the chemokine interleukin-8 (IL-8) and the cytokine tumor necrosis factor alpha (TNF-α) in gastric carcinoma cells (AGS). Similarly, transcription of the IL-8 homolog keratinocyte-derived chemokine (KC) is elevated in murine infections with the HP0289 mutant than in murine infections with wild-type H. pylori. On the basis of this phenotype, we renamed HP0289 ImaA for immunomodulatory autotransporter protein. Our work has revealed that genes induced in vivo play an important role in H. pylori pathogenesis. Specifically, the outer membrane protein ImaA modulates a component of the host inflammatory response, and thus may allow H. pylori to fine tune the host immune response based on ImaA expression.
authors.affiliation: Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, Santa Cruz, California, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Sause
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Castillo
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ottemann
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000382:microbiology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D016481:Helicobacter Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000143:Acids; D001425:Bacterial Outer Membrane Proteins; D007155:Immunologic Factors; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors