Helicobacter pylori dampens gut epithelial self-renewal by inhibiting apoptosis, a bacterial strategy to enhance colonization of the stomach.
Colonization of the gastric pits in the stomach by Helicobacter pylori (Hp) is a major risk factor for gastritis, gastric ulcers, and cancer. Normally, rapid self-renewal of gut epithelia, which occurs by a balance of progenitor proliferation and pit cell apoptosis, serves as a host defense mechanism to limit bacterial colonization. To investigate how Hp overcomes this host defense, we use the Mongolian gerbil model of Hp infection. Apoptotic loss of pit cells induced by a proapoptotic agent is suppressed by Hp. The ability of Hp to suppress apoptosis contributed to pit hyperplasia and persistent bacterial colonization of the stomach. Infection with WT Hp but not with a mutant in the virulence effector cagA increased levels of the prosurvival factor phospho-ERK and antiapoptotic protein MCL1 in the gastric pits. Thus, CagA activates host cell survival and antiapoptotic pathways to overcome self-renewal of the gastric epithelium and help sustain Hp infection.
Mimuro
Hitomi
H
Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Suzuki
Toshihiko
T
Nagai
Shigenori
S
Rieder
Gabriele
G
Suzuki
Masato
M
Nagai
Takeshi
T
Fujita
Yukihiro
Y
Nagamatsu
Kanna
K
Ishijima
Nozomi
N
Koyasu
Shigeo
S
Haas
Rainer
R
Sasakawa
Chihiro
C
D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D001426:Bacterial Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D005849:Gerbillinae; D016481:Helicobacter Infections / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C080866:cagA protein, Helicobacter pylori; C096335:B59 protein, human; D017027:Protein Tyrosine Phosphatases