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Helicobacter pylori Not just for ulcers
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Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Dec 24, 2015

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Page 1: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Helicobacter pylori

Not just for ulcers

Page 2: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Pre-lecture discussion questions

• What is the germ theory of disease?• What are some of the initial ways in which it

was demonstrated?• What is a germ-free animal and how are they

produced?• What are the effects of being germ-free?

Page 3: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

H. pylori

Page 4: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Stomach Microbiota

• at rest: pH 4 – 5.• At full function: pH 1- 2.

• Once thought to be sterile.• Not very diverse.

Page 5: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

H. pylori

• Gram negative, spiral, flagella.• Adapted to high acid.• High urease activity.– C-14 test.

Page 6: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.
Page 7: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

H. Pylori Infection Rates

• Historically: 70 – 80% (or higher?).• <10% of U.S. children.• Much higher for those over 60.• Much higher for those in under-developed

countries.

• Association pre-dates our species.

Page 8: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Gastric antral biopsies from an H. pylori–positive patient (left) and an H. pylori–negative patient (right; photomicrographs courtesy of Zhiheng Pei, M.D., Ph.D.). The H. pylori–positive biopsy shows deeper staining of the epithelial cells, indicating tissue reactivity.

http://www.med.nyu.edu/medicine/labs/blaserlab/v1-sld_H-pylori.html

Page 9: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Peptic Ulcers

• Inflammation and bleeding.• Lining of distal stomach or duodenum.

• Often a precursor to gastric cancers.

Page 10: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.
Page 11: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

HP-NAP = H. pylori Neutrophil-activating protein

Page 12: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Clin. Microbiol. Rev. October 2010 vol. 23 no. 4 713-739

Page 13: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Dysregulation of the apical-junctional complex by H. pylori. H. pylori preferentially adheres to the apical-junctional complex of epithelial cells and alters localization of apical-junctional component proteins, disrupts epithelial barrier function, cell adhesion, and cell polarity, and induces an invasive phenotype. Translocated CagA interacts with PAR1, preventing phosphorylation of PAR1 by blocking PAR1 kinase activity, which culminates in disruption of the tight junction. In addition, functional urease activity can disrupt the tight junction via a mechanism involving MLC phosphorylation, which can be regulated by MLCK and Rho kinase. VacA can also increase tight junction permeability to low-molecular-weight molecules and ions.

Page 14: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Barry Marshall

• (1984-5) Fulfills Koch’s postulates with H. pylori.– But only for gastritis (not peptic ulcers).

• Nobel Prize in 2005.

Page 15: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Electron photomicrograph of Helicobacter pylori colonizing the stomach of a human volunteer who ingested the organism as part of an experimental inoculation. The spiral microaerophilic bacteria live in the mucus layer that overlays the gastric epithelium. Photo copyright, Martin J. Blaser, 1989.

Page 16: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Cag Island

• Horizontally acquired.• 40 kb, 31 genes.• Type IV secretion system.• CagA is translocated to host cells.– Alters host cell morphology.

• cagA+ strains – highest risk of ulcers & gastric cancer.

Page 17: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Type IV Secretion System

Page 18: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Helicobacter exploits integrin for type IV secretion and kinase activationTerry Kwok, Dana Zabler, Sylwia Urman, Manfred Rohde, Roland Hartig, Silja Wessler, Rolf Misselwitz, Jürgen Berger, Norbert Sewald, Wolfgang König & Steffen BackertNature 449, 862-866(18 October 2007)

Page 19: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.
Page 20: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Lack of H. pylori

• Gastro-esophageal reflux disease (GERD).• Esophageal adenocarcinoma.– Inc. in last 40 years.

• Disregulated leptin & ghrelin.– Obesity, type 2 diabetes, metabolic disease.

• Asthma!

Page 21: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Asthma Study in Mice

• Neonatal H. pylori (cag+) infection protected.– Stimulated Regulatory T (Treg) cells.

Arnold et al. (2011). J. Clinical Investigation.

• But H. pylori cag genes stimulates IL-8 (pro-inflammatory) release.

Page 22: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

• Timing of H. pylori colonization matters.– Early (infancy) is probably better.

• Balance of cagA+ to cagA-??

Page 23: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Lessons from H. pylori

• Koch’s postulates.• Horizontal gene transfer.• Toxin delivery and action.• Adaptation to acidic environment.• Role of normal microbiota.– Effects of antibiotics & sanitation.– Bacteria can affect cancers.– Bacteria impact the immune system.– Bacteria effect overall metabolism.

Page 24: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Hygiene Hypothesis

• Martin Blaser prefers “Disappearing Microbiota.”

• Others refer to “Missing Old Friends.”

Page 25: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Germ Theory of Disease

• Not so straightforward.

Page 26: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Other Missing “Old Friends?”

• Epstein-Barr Virus.– Herpes Viruses.

• Mycobacterium tuberculosis.• Trichuris trichuria.• Ancylostoma duodenale/Necator americanus.• More?

Page 27: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Trichuriasis

• Whipworm (nematode).

• Trichuris trichiura. • 4 cm adults.• 3,000 – 20,000 eggs

per day.• Feed on undigested food.

604M

Page 28: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Trichuriasis

Page 29: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Hookworm

• Can lead to longstanding anemia.– Affects physical & cognitive development.– Low birth weight & reduced maternal health.

Ancylostoma duodenale576M

Page 30: Helicobacter pylori Not just for ulcers. Pre-lecture discussion questions What is the germ theory of disease? What are some of the initial ways in which.

Summer Reading

• An Epidemic of Absence by Moises Velasquez-Manoff.