1447Gastric histopathology by Helicobacter pylori cagA status in Arctic Canada

Background Our community-driven projects address concerns of Canadian Arctic Indigenous communities about Helicobacter pylori (Hp) infection, responsible for elevated gastric cancer mortality in the region. Community research partners wished to learn whether bacterial characteristics determine severity of Hp-related disease in their communities. We aimed to describe gastric histopathology by cagA genotype of Hp isolated from residents of 7 Indigenous communities in the Northwest Territories and Yukon. Methods Participants underwent gastroscopy with 5-6 biopsies taken for histopathological assessment and 2 biopsies taken for tissue culture during 2008-2017. We used multiple PCR reactions and DNA sequence analysis to classify Hp genotypes as cagA+ or cagA-. A single pathologist used the updated Sydney classification system to grade severity of 5 gastric pathology outcomes: Hp density; chronic gastritis; active gastritis; atrophy; and intestinal metaplasia. We estimated prevalence of each outcome with 95% confidence intervals (CI) by gastric subsite and cagA status. Results Of 262 Hp isolates assessed, 142 (54%) were cagA+. Prevalence of moderate-high Hp density, severe chronic gastritis, moderate-severe active gastritis, atrophy, and metaplasia were (%[CI]): respectively, 78[70-85], 44[36-53], 65[56-72], 55[46-63], 25[18-33] in cagA+ participants and 61[52-70], 35[27-44], 31[23-40], 32[23-41], 8[4-15] in cagA- participants. cagA+ participants had higher prevalence of all outcomes in antrum and corpus. Conclusion Hp-infected Indigenous residents of Arctic Canada who harbored cagA-positive strains had higher prevalence of more severe gastric pathology than those with cagA-negative strains. Key messages Community-driven research answers questions posed by those who bear the disease burden.

Associations of Interleukin-1β with H. pylori-Induced Gastric Atrophy and Syndrome of Dampness-Heat in the Spleen and Stomach in Subjects with H. pylori-Related Gastric Diseases

H. pylori-related gastric diseases (HPGD) are a series of gastric mucosal benign and malignant lesions associated with H. pylori infection. Exploring the pathogenesis of HPGD will be of great significance to prevent and treat gastric malignancy. Traditional Chinese medicine (TCM) syndrome is the essence of TCM, reflecting the state of whole body. Potential similarities of TCM syndrome may provide a new perspective in understanding development and treatment of diseases. To seek an early warning signal for gastric malignant pathology and similarities of TCM syndrome from the viewpoint of molecular biology, we examined the relationships among H. pylori, gastric pathology, and TCM syndrome and effects of Interleukin-1β (IL-1β) gene polymorphisms and expression on gastric pathology and TCM syndrome in HPGD. The results indicated that detection of H. pylori with differentiation of TCM syndrome may have a predictive function to gastric pathology. H. pylori may lead to gastric atrophy via enhancing IL-1β mRNA expression, and IL-1β mRNA overexpression in gastric mucosa may be one of the generality characteristics for H. pylori-negative subjects with syndrome of dampness-heat in the spleen and stomach.

The HopQ-CEACAM Interaction Controls CagA Translocation, Phosphorylation, and Phagocytosis of Helicobacter pylori in Neutrophils

ABSTRACT The cag type IV secretion system (cag-T4SS) of Helicobacter pylori exploits specific cellular carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), such as CEACAM1, -3, -5, and -6, as cellular receptors for CagA translocation into human gastric epithelial cells. We studied the interaction of H. pylori with human CEACAM1, CEACAM3, and CEACAM6 receptors (hCEACAMs) expressed on myeloid cells from CEACAM-humanized mice. Human and CEACAM-humanized mouse polymorphonuclear neutrophils (PMNs) allowed a specific HopQ-dependent interaction strongly enhancing CagA translocation. Translocated CagA was tyrosine phosphorylated, which was not seen in wild-type (wt) murine neutrophils. In contrast, human or murine bone marrow-derived macrophages and dendritic cells (DCs) revealed a low hCEACAM expression and bacterial binding. CagA translocation and tyrosine-phosphorylation was low and independent of the HopQ-CEACAM interaction. Neutrophils, but not macrophages or DCs, from CEACAM-humanized mice, significantly upregulated the proinflammatory chemokine MIP-1α. However, macrophages showed a significantly reduced amount of CXCL1 (KC) and CCL2 (MCP-1) secretion in CEACAM-humanized versus wt cells. Thus, H. pylori, via the HopQ-CEACAM interaction, controls the production and secretion of chemokines differently in PMNs, macrophages, and DCs. We further show that upon H. pylori contact the oxidative burst of neutrophils and phagocytosis of H. pylori was strongly enhanced, but hCEACAM3/6 expression on neutrophils allowed the extended survival of H. pylori within neutrophils in a HopQ-dependent manner. Finally, we demonstrate that during a chronic mouse infection, H. pylori is able to systemically downregulate hCEACAM1 and hCEACAM6 receptor expression on neutrophils, probably to limit CagA translocation efficiency and most likely gastric pathology. IMPORTANCE Helicobacter pylori is highly adapted to humans and evades host immunity to allow its lifelong colonization. However, the H. pylori mouse model is artificial for H. pylori, and few adapted strains allow gastric colonization. Here, we show that human or CEACAM-humanized, but not mouse neutrophils are manipulated by the H. pylori HopQ-CEACAM interaction. Human CEACAMs are responsible for CagA phosphorylation, activation, and processing in neutrophils, whereas CagA translocation and tyrosine phosphorylation in DCs and macrophages is independent of the HopQ-CEACAM interaction. H. pylori affects the secretion of distinct chemokines in CEACAM-humanized neutrophils and macrophages. Most importantly, human CEACAMs on neutrophils enhance binding, oxidative burst, and phagocytosis of H. pylori and enhance bacterial survival in the phagosome. The H. pylori-CEACAM interaction modulates PMNs to reduce the H. pylori CagA translocation efficiency in vivo and to fine-tune the expression of CEACAM receptors on neutrophils to limit translocation of CagA and gastric pathology.