Helicobacter pylori infection in infant rhesus macaque monkeys is associated with an altered lung and oral microbiome.

It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age.

Helicobacter pylori Infection in Infant Rhesus Macaque Monkeys is Associated with an Altered Lung and Oral Microbiome.

Background: It is estimated that more than half of the world population has been infected with . Most newly acquired infections occur in children before 10 years of age. We hypothesized that early life infection could influence the composition of the microbiome at mucosal sites distant to the stomach.

Vaccination with attachment proteins protects against gastric cancer.

Most cases of gastric cancer are caused by chronic infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of infection by antibiotics. We reported on a protective mechanism where gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by .

Host immune response mediates changes in copy number and virulence potential of .

is the major risk factor for gastric cancer. harboring the type IV secretion system (T4SS) and its effector CagA encoded on the pathogenicity Island (PAI) increases the risk. PMSS1 has a multi- genotype, modulating copy number dynamically from zero to four copies.

Maintenance of Type IV Secretion Function During Helicobacter pylori Infection in Mice.

The type IV secretion system (T4SS) encoded on the pathogenicity island (PAI) secretes the CagA oncoprotein and other effectors into the gastric epithelium. During murine infection, T4SS function is lost in an immune-dependent manner, typically as a result of in-frame recombination in the middle repeat region of , though single nucleotide polymorphisms (SNPs) in or in other essential genes may also occur. Loss of T4SS function also occurs in gerbils, nonhuman primates, and humans, suggesting that it is biologically relevant and not simply an artifact of the murine model.

Identification of Pathogenicity Island Genes Associated with Loss of Type IV Secretion Function during Murine Infection with Helicobacter pylori.

Chronic colonization in animal models often leads to downregulation of the type IV secretion system (T4SS), typically by recombination in , which is an essential T4SS gene. However, 17 other pathogenicity island (PAI) genes, as well as some non-PAI genes, are also essential for T4SS function. To get a more complete picture of how regulates the T4SS during animal colonization, we examined in 534 mouse-passaged isolates that lost T4SS function, defined as a normalized interleukin-8 (IL-8) value of <0.

Impact of Helicobacter pylori Virulence Factors on the Host Immune Response and Gastric Pathology.

Helicobacter pylori chronically infects nearly half the world's population, yet most of those infected remain asymptomatic throughout their lifetime. The outcome of infection-peptic ulcer disease or gastric cancer versus asymptomatic colonization-is a product of host genetics, environmental influences, and differences in bacterial virulence factors. Here, we review the current understanding of the cag pathogenicity island (cagPAI), the vacuolating cytotoxin (VacA), and a large family of outer membrane proteins (OMPs), which are among the best understood H.

CagY-Dependent Regulation of Type IV Secretion in Helicobacter pylori Is Associated with Alterations in Integrin Binding.

Strains of that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the pathogenicity island (PAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4 T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density.

Evidence for a primate origin of zoonotic Helicobacter suis colonizing domesticated pigs.

Helicobacter suis is the second most prevalent Helicobacter species in the stomach of humans suffering from gastric disease. This bacterium mainly inhabits the stomach of domesticated pigs, in which it causes gastric disease, but it appears to be absent in wild boars. Interestingly, it also colonizes the stomach of asymptomatic rhesus and cynomolgus monkeys.

The Helicobacter pylori type IV secretion system promotes IL-8 synthesis in a model of pediatric airway epithelium via p38 MAP kinase.

Epidemiologic studies have reported an inverse relationship between childhood Helicobacter pylori infection and development of allergic asthma. Because lung epithelium plays an important role in allergic asthma pathogenesis, we hypothesized that H. pylori may directly influence airway epithelial cell innate immune function, particularly in early childhood.

Host Determinants of Expression of the Helicobacter pylori BabA Adhesin.

Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression.

Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques.

Most strains express the BabA adhesin, which binds to ABO/Leb blood group antigens on gastric mucin and epithelial cells and is found more commonly in strains that cause peptic ulcers or gastric cancer, rather than asymptomatic infection. We and others have previously reported that in mice, gerbils, and rhesus macaques, expression of is lost, either by phase variation or by gene conversion, in which the paralog recombines into the locus. The functional significance of loss of expression is unknown.

Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence.

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers.

Fallacy of the Unique Genome: Sequence Diversity within Single Strains.

Many bacterial genomes are highly variable but nonetheless are typically published as a single assembled genome. Experiments tracking bacterial genome evolution have not looked at the variation present at a given point in time. Here, we analyzed the mouse-passaged strain SS1 and its parent PMSS1 to assess intra- and intergenomic variability.

Characterization of the Cag pathogenicity island in Helicobacter pylori from naturally infected rhesus macaques.

Helicobacter pylori commonly infects the epithelial layer of the human stomach and in some individuals causes peptic ulcers, gastric adenocarcinoma or gastric lymphoma. Helicobacter pylori is a genetically diverse species, and the most important bacterial virulence factor that increases the risk of developing disease, versus asymptomatic colonization, is the cytotoxin associated gene pathogenicity island (cagPAI). Socially housed rhesus macaques are often naturally infected with H.

CagY Is an Immune-Sensitive Regulator of the Helicobacter pylori Type IV Secretion System.

Background & Aims: Peptic ulcer disease and gastric cancer are caused most often by Helicobacter pylori strains that harbor the cag pathogenicity island, which encodes a type IV secretion system (T4SS) that injects the CagA oncoprotein into host cells. cagY is an essential gene in the T4SS and has an unusual DNA repeat structure that predicts in-frame insertions and deletions. These cagY recombination events typically lead to a reduction in T4SS function in mouse and primate models.

Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori.

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le(b) blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown.

Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era.

Importance: Clostridium difficile is a major cause of health care-associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment.

Objective: To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox-/PCR+) for CDI.

The Serum Immunoglobulin G Glycosylation Signature of Gastric Cancer.

Biomarkers may facilitate detection of gastric cancer at an earlier stage and reduce mortality. Here we sought to determine if the glycosylation profile of serum immunoglobulin G (IgG) could distinguish patients with non-atrophic gastritis (NAG), duodenal ulcer (DU) and gastric cancer (GC). Serum IgG was released and analyzed using nano-LC-TOF mass spectrometry.

Evidence of convergent evolution in humans and macaques supports an adaptive role for copy number variation of the β-defensin-2 gene.

β-defensins are a family of important peptides of innate immunity, involved in host defense, immunomodulation, reproduction, and pigmentation. Genes encoding β-defensins show evidence of birth-and-death evolution, adaptation by amino acid sequence changes, and extensive copy number variation (CNV) within humans and other species. The role of CNV in the adaptation of β-defensins to new functions remains unclear, as does the adaptive role of CNV in general.

A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques.

The evolution rate and genetic changes that occur during chronic infection with Helicobacter pylori have been analysed, but little is known about the genomic changes during the initial, acute bacterial infection phase. Here we analyse the rate and pattern of genome evolution in H. pylori from the genomes of two input strains isolated from human volunteers with asymptomatic infection, and the genomes of two output strains collected 20 and 44 days after re-infection.