Micro Ch. 22: Helicobacter pylori

What do host cells detect when H pylori is present? But why does the host typically ignore h pylori?

LPS and flagella however they are less immunogenicity other pathogens, phase variation (molecular mimicry), VacA

h pylori evades host immunity through

vacuolating toxin (VacA) that suppresses T cell responses

The bacteria have multiple flagella at one pole

(lophotrichous).

h pylori colonizes approx half of the world but leads to overt clinical diseases in what percent of infected individuals

10-15%

What features permit H. pylori to colonize the stomach when other bacteria cannot survive in this harsh environment? • H. pylori is a robust producer of urease, which catalyzes the hydrolysis of urea into ammonia and carbon dioxide, and ammonia production is an important survival mechanism for this organism within the acidic gastric environment. • H. pylori also utilizes multiple polar flagella to facilitate locomotion through the mucus gel layer overlaying the gastric epithelium. • Further, H. pylori possesses multiple chemotaxis systems to direct locomotion toward the mucus layer and gastric epithelium. Upon contact with the gastric epithelium, H. pylori utilizes a number of adhesins that allow for colonization amid gastric peristalsis

How can H. pylori be eliminated from the stomach? • The stomach presents unique barriers to antibiotic efficacy that are usually not encountered within other anatomic niches of the human body. • These include an acidic pH, peristalsis, active secretion, and a semipermeable mucous barrier overlaying the epithelium. • Some antibiotics are less effective at lower pH (e.g., amoxicillin, clarithromycin), while other antibiotics (e.g., metronidazole) rapidly induce resistance in H. pylori strains, which decreases therapeutic efficacy. • Many antibiotics exert only minimal bacteriostatic or bactericidal effects. Therefore, elimination of H. pylori requires multiple drugs for prolonged durations (10 to 14 days) to overcome these obstacles.

h pylori diagnosis

Noninvasive: Rapid urease test, histology, and microbial culture on endoscopic biopsy. Path: Giema stain, Steiner stain, Warthin starry stain Urea breath test does not require endoscopy and is easy to perform. Biochemical confirmation includes tests for urease, catalase, and oxidase. Other tests are based on H. pylori-specific serology and stool antigens by immunoassay. Testing stool for antigen is highly accurate.

Treatment: Major cause of peptic ulcer disease. Treat with antibiotics. Proton-pump inhibitors may have a direct suppressive effect on H. pylori. H. pylori stays in lumen and is non-invasive.

TREATMENT: ➢ Combination of the following: o Rantidine (H2 blocker) plus Bismuth salts (Pepto Bismol) plus Amoxicillin plus Metronidazole. ➢ Tetracycline can be substituted for amoxicillin in penicillin allergy. ➢ Alternative combination: o Omeprazole (proton pump blocker) plus Clarithromycin plus Metronidazole.

what host cell receptors facilitate H pylori colonization of gastric epi

blood group antigen-binding adhesin, BabA, and sialic acid-binding adhesin, SabA (see Fig. 22-3). BabA binds Lewisb (Leb) blood-group anti

Virulence factors of H. pylori?

VIRULENCE FACTORS: ➢ Endotoxin: (O-antigens): provides antigenic variation ➢ H. pylori has a great ability to resist destruction by stomach acid. ➢ Flagella with corkscrew motility enables movement into and within the protective mucus layer of the stomach. ➢ Enzymes: o Urease generates ammonium ions to buffer gastric acid; this enables survival within the hostile acidic environment o Mucinase helps to break through the protective mucus layer. ➢ Microaerophilism enables survival within the mucus layer of the stomach. ➢ Adhesion factors: o Mediate attachment to epithelial cells of the stomach.

h pylori causes damage by

VacA can cause cell death of gastric epi - another virulence factor CagA disrupts tight junctions between cells low level inflammation leads to persistent superficial gastritis (asymptomatic in most persons) but 10% may develop ulcers, atrophic gastritis, gastric cancer, gastric MALT LYMPHOMA

• Curved, Gram-negative, rod-shaped bacteria were identified on the gastric mucosal surfaces of all samples, and cultures grew Helicobacter pylori. • In addition to acid reduction therapy with a PPI, the patient began a 10-day course of amoxicillin and clarithromycin. A repeat endoscopy 6 weeks after completion of therapy showed healing of his ulcer, and biopsies of his stomach showed resolution of gastritis. No H. pylori was found on histologic examination or culture. • The patient remained symptom free after 6 months and required no further therapy.

Was H. pylori the cause of the patient's 7-year bout of recurrent duodenal ulceration? • Helicobacter pylori-induced chronic gastritis is the most common cause of peptic ulcer disease in the United States. • However, there are other etiological factors that can also lead to ulceration in the absence of infection. These include ingestion of aspirin or other nonsteroidal anti-inflammatory medications (NSAIDs), hyperacidity due to unrestrained gastrin production by a gastrin secreting tumor (Zollinger-Ellison syndrome), Crohn disease, or gastric colonization by other rare microbial species (e.g., Gastrospirillum).

if someone has a penicillin allergy , they use

amoxillin

Strongly urease-positive, they produce ammonia and carbon dioxide from urea. produce lots of ammonia, a highly conserved trait in all. This is probably vital in acid-gastric environments. They are

catalase positive and oxidase positive.

what does urease do?

catalyzes the hydrolysis of urea into ammonia and carbon dioxide to neutralize the surrounding acidic environment; increases ph in stomach

h pylori spread and multiplication

colonizes mucus layer and ep surface of stomach adheres to ep thorugh multiple outer membrane proteins

case study: 45 year old african america=burning epigastric pain... 7 years earlier he had abdominal pain, initially treated with PPI for 8 weeks to reduce gastric acid, symptoms resloved. however, 4 months later, it came back. he had an ulcer, then had PPI again... family has a history of this disease.. ulcer still present... it showed chronic acid gastritis... then began therapy w/ amoxicillin and clarithromycin, no future therapy needed

curved gram - helicobacter pylori

treat..

eliminate from stomach until negative test for the bacterium 4 or more weeks after the completion of therapy

helicobacter pylori is

gram negative helical shaped high genetic diversity

CagA + strains

have higher degree of inflammation and damage than CagA- higher IL-8

discovered by marshal and warren in gastritis patients. stong link established between gastroduodenal diseases, including chronic gastritis and non-hodgikins lymphoma of the stomach, and presense of h. pylori. classified as class 1 carcinogen for gastric cancer in 1994

helicobacter pylori

highly motile, gram -, fastidious, high degree of genetic diversity, multiple falgella at one pole, cat. + and ox. +

helicobacter pylori

infects half of the worlds pop., now 2/3... person to person spread, fecal to oral or oral to oral route. most common bacterial infection in humans. usually asymptomatic

helicobacter pylori

VacA cytotoxin strains of H pylori are

more frequently associated with peptic ulcer disease and increased inflammatory infiltrates within gastric antrum causes apoptosis of epi cells alter permeability and pH

what disrupts the gastric mucus?

mucinase breaks through layer

risk factors for h pylori

poor socioeconomic status, familial overcrowding, ethnicity, and infection rates endemic to the country of origin

know how helicobacter survives and multiplies in the stomach*** bc of harsh conditions

produce urease which can buffer the local environment by production of ammonium from urea

The bacteria have multiple flagella at one pole (lophotrichous). They are nutritionally fastidious and microaerophilic, growing best in an atmosphere of

reduced oxygen (5%).

what are the different noninvasive tests for h. pylori?

serologic test, urea breath test, stool antigen test

treatment of h pylori

triple therapy - 2 antibiotics with a protein pump inhibitor

CagA (cytotoxin-associatated gene)

type IV secretion system translocated into host epithelial cells following attachment, where it can be modified by phosphorylation of tyrosine residues. activates several host signaling pathways through either phosphorylation-dependent or phosphorylation-independent mechanisms leading to cell morphological changes, including disruption of junctional complexes and adherens junctions and increases in cell motility and proliferation

what is responsible for interfering w/ gastic acid secretion?

urease

what are the multiple virulence factors of h. pylori?

urease production, chemotaxis, highly motile, microaerophilism, adhere to gastric epi

what are the different invasive tests for h. pylori?

urease test, histology, culture

know treatments for this

use proton pump inhibitors which reduces gastric acid production. use multiple antibiotics and antiacid

h pylori prevention

vaccine not yet developed

CASE • A 45-year-old African American male was evaluated for recurrent burning epigastric discomfort. • Seven years earlier, he had noted abdominal pain that often woke him from sleep, was associated with nausea, and improved with meals. He was initially treated with a proton pump inhibitor (PPI) for 8 weeks to reduce the production of gastric acid, and his symptoms resolved. • However, 4 months later, his symptoms recurred.

• At endoscopy, a 1-cm ulcer was seen in the duodenal bulb. The patient was once again given PPI therapy. However, four times in the ensuing 6 years, his burning epigastric pain recurred. • The patient's mother and one of his two siblings also had a history of peptic ulcer disease. Another endoscopy showed that a duodenal ulcer was still present. Biopsies from two sites in the stomach were taken for histologic examination and culture. These specimens showed chronic active gastritis with elevated numbers of neutrophils and mononuclear cells in the lamina propria and the glandular epithelium in addition to lymphoid follicle formation (Fig. 22-1).

First-line therapy for H. pylori consists of a proton pump inhibitor (PPI) twice a day and clarithromycin and amoxicillin or metronidazole for at least 7 but preferably 10 days.

• If this regimen fails to eradicate the bacterium, the physician should initiate quadruple therapy, which consists of a PPI, bismuth subsalicylate, tetracycline, and metronidazole, for 14 days. • Another appealing second-line regimen is sequential therapy consisting of 5 days of a PPI and amoxicillin followed by 5 days of triple therapy consisting of a PPI, clarithromycin, and metronidazole. • Although successful eradication of H. pylori requires multiple medications, the absolute failure rate for treating the infection is very low, in part because of the multiplicity of treatment regimens available. For example, quadruple therapy achieves cure rates of approximately 90% in patients who have failed previous therapies and who are colonized with strains resistant to metronidazole and clarithromycin.

SOURCE AND TRANSMISSION:

➢ Human GI tracts are the only reservoirs for H. pylori. ➢ Horizontal transmission occurs via the fecal-oral route; especially in crowded living conditions. ➢ There is a direct relationship between increased age and increased likelihood of H. pylori infection in developed countries.