Infection by the gastric pathogen Helicobacter pylori (HP) causes gastritis and peptic ulcers, and is a risk factor for gastric cancer, even though most infections are asymptomatic. We propose that (i) the remarkable genetic diversity among HP strains contributes to this range of symptoms, (ii) that persons at high risk of HP infection, such as those in Peru, often carry multiple strains, and (iii) that such co-colonization might allow horizontal gene transfer and faster person-specific adaptation, contribute to increased virulence, and facilitate the spread of antibiotic resistance. In this FIRCA collaboration with Dr. R. Leon Barua and the Gastrointestinal Physiology Working Group (GPWG) in lima, peru, we will obtain strains resistant to clinically useful antibiotics that are needed in the parent grant for studies of HP antibiotic resistance mechanisms and on gene transfer between HP strains during experimental coinfection of gnotobiotic piglets. We will test and extend the ideas sketched above, and more generally enhance the research described in the parent grant by analyzing HP strains biopsy material from infected Peruvians making annual visits to Dr. Leon Barua's, GPWG clinic. First, we will test (a) how frequently persons living in Peru carry just one, vs. multiple HP strains, and (b) whether resident HP populations tend to change or remain constant over time. This will involve characterization of pools and of single colony isolates of HP from patients that making their recurrent annual visits to the clinic, HP characterizations will include phenotypic (drug resistance) tests, and sensitive and efficient arbitrarily primed PCR (RAPD) DNA fingerprinting, and PCR-based tests for variable segments of HP genes, especially those associated with high virulence. Second, in cases of co- colonization, we will use the phenotypic and DNA fingerprint data obtained above to test an idea that HP grows in the gastric mucosal primarily a single cell clones, perhaps from a special protected niche occupied by very few 'stem"""""""" cells. This idea emerged during piglet coinfection experiments that led to the parent grant, and is supported by our preliminary results with human biopsies. The proposed research will extend and enhance the parent grant. We will benefit immensely from the expertise of our collaborators in the epidemiology and pathophysiology of Hp infection, and from their special set of heavily HP-infected patients. In return, we will provide training in molecular genetics to GPWG researchers that will enhance our collaboration for years to come, and more generally, benefit the Peruvian scientific community.
| (2000) Cross-national comparisons of the prevalences and correlates of mental disorders. WHO International Consortium in Psychiatric Epidemiology. Bull World Health Organ 78:413-26 |
