The Helicobacter pylori virulence effector CagA abrogates human β-defensin 3 expression via inactivation of EGFR signaling.
Antimicrobial peptides are constituents of the first-line innate mucosal defense system that acts as a barrier to establishment of infection. The highly successful human gastric pathogen, Helicobacter pylori, is able to persistently colonize its host despite inducing expression of several antimicrobial peptides, including human β-defensin 3 (hBD3). We find that hBD3 is highly active against H. pylori in vitro and is rapidly induced during early infection via EGFR-dependent activation of MAP kinase and JAK/STAT signaling. However, during prolonged infection, hBD3 was subsequently downregulated by the H. pylori virulence determinant CagA. Upon translocation into host cells, CagA activated the cellular tyrosine phosphatase, SHP-2, terminating EGFR activation and downstream signaling and increasing bacterial viability. Chemical inhibition and knockdown of SHP-2 expression rescued hBD3 synthesis and bactericidal activity. Thus, we reveal how cagPAI-positive H. pylori strains use CagA to evade a key innate mucosal defense pathway to support the establishment of persistent infection.
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, Berlin, Germany.
Bianca
B
Bauer
Ervinna
E
Pang
Carsten
C
Holland
Mirjana
M
Kessler
Sina
S
Bartfeld
Thomas F
TF
Meyer
D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015870:Gene Expression; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D050296:Microbial Viability; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction; D014774:Virulence; D023083:beta-Defensins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C422950:DEFB103A protein, human; D023083:beta-Defensins; C080866:cagA protein, Helicobacter pylori; C512478:EGFR protein, human; D066246:ErbB Receptors; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11