H. pylori eludes immune response via cholesterol depletion

Last Updated: 2018-01-01

By David Douglas

NEW YORK (Reuters Health) - Manipulation of cell cholesterol levels allows Helicobacter pylori to escape full elimination by host immunity, according to German researchers.

As Dr. Thomas F. Meyer told Reuters Health by email, "The persistent gastric bacterium Helicobacter pylori modulates host cell cholesterol and this obliterates immunity against this pathogen despite ongoing inflammation. Our study reveals an integrated relation of this pathogen and host cell cholesterol."

In their report, online December 14 in Gastroenterology, Dr. Meyer of the Max Planck Institute for Infection Biology, Berlin, and colleagues note that H. pylori is implicated in severe gastric disease, including peptic ulcer and adenocarcinoma.

The bacterium, they add, extracts cholesterol from host membranes and incorporates it into its outer membrane using the enzyme cholesterol-alpha-glucosyltransferase (cgt). Such processes have been linked to immune evasion and bacterial persistence.

"We previously reported that a cholesterol-rich diet leads to a reduction of the H pylori load concomitant with an increased Th1 response," the researchers write.

To probe the underlying mechanisms, they conducted a series of experiments including human gastric adenocarcinoma cell lines and human primary gastric epithelial cells uninfected or infected with H. pylori or cgt mutant strains of H. pylori.

Infection with H. pylori, but not cgt mutants, blocked interferon gamma (IFNG)-induced signaling via Janus kinase (JAK) and signal transducer and activator of transcription-1 (STAT1). The reduction in IFNG signaling was brought about by depletion of cholesterol which led to disruption of lipid rafts and subsequently reduced activation of JAK and STAT1.

Infection also blocked signaling by interferon beta (IFNB), interleukin 6 (IL6) and IL22. Furthermore, it reduced activation of genes for cytokines that regulate T-cell function and for anti-microbial peptides.

These and associated processes allowed H. pylori to persist in a protective micro-niche in proximity to infected cells while inducing inflammation only in the neighboring, non-infected epithelium. Thus, cgt generates protected islands of diminished defense, promoting pathogen survival.

The findings are helping tackle "questions regarding the role of cholesterol in the modulation of mucosal inflammation and anti-microbial defense, as well as the capacity of certain pathogens to create hot spots of tissue inflammation leading to an increased risk of cancer," said Dr. Meyer.

He and his colleagues conclude that their results place cgt function, cholesterol metabolism, and inflammation "at the crossroads of gastric pathogenesis and cancer."

Dr. Richard M. Peek, who directs the division of gastroenterology at Vanderbilt University Medical Center in Memphis, Tennessee, said the German group "has now utilized a novel model of primary gastric epithelial cells to define how the chronic pathogen, H. pylori, may persist for decades in the human stomach and heighten the risk for diseases such as peptic ulceration and gastric cancer."

"Utilizing an enzyme which depletes cholesterol from host cell membranes," Dr. Peak told Reuters Health by email, "H. pylori abolishes signaling which targets T cells, thereby promoting evasion of the host immune response and persistence of infection."

SOURCE: http://bit.ly/2CmeD9G

Gastroenterology 2017.