We are excited about the opportunity to respond to the NCRR RFA-RR-10-005 """"""""Pathobiology of Emerging Pathogens in Laboratory Animals"""""""". During the past 15 years, 8 novel enterohepatic Helicobacter spp. (EHS) in mice have been formally named, and 9 additional clusters (based on 16S rRNA sequences) of novel species have been cultured and identified in our lab. We have collected, what we believe, is the largest EHS culture collection available worldwide and are poised to characterize these murine strains, both to facilitate their diagnosis and also to establish their pathogenic potential. H. hepaticus, the prototype EHS, causes a persistent enteric infection and is prevalent in academic mouse colonies throughout the world. H. hepaticus infection causes liver cancer, is known to be a strong tumor promoter in several models of hepatocarcinogenesis, and induces inflammatory bowel disease in immunocompromised mice. The presence of EHS has confounded a number of studies, can contaminate tumor cell lines, causes significant morbidity and mortality in immunodeficient mice and selected strains of immune-competent mice, and has been recently associated with reproductive failures in mouse colonies. A 2007 study conducted by us indicated that 85% of mice used in academic settings worldwide are infected with one or more EHS. However the majority of EHS, we and others have identified, are not easily cultured, do not have specific molecular or serological assays for diagnosis, nor is it known whether and under what conditions these H. spp. have pathogenic potential. We therefore intend to develop sensitive and specific molecular assays to diagnose EHS in mice. We anticipate the development of a mini-microarray chip for use by the research community to detect EHS and prevent their colonization in established H. spp. free colonies. Because of the utility of the IL10-/- in our lab and others in using H. hepaticus to dissect etiopathogenesis of IBD, we will employ this model in screening novel H. spp. for pathogenic potential as well as determine the putative role of virulence genes in newly sequenced H. spp. These results will be compared and validated with in vitro tests we have used to predict virulence potential in H. hepaticus.
The specific aims of the project are: 1) To provide morphologic, genetic, and biochemical characterization of novel enterohepatic Helicobacter species (EHS) and develop species specific assays to diagnose EHS isolated from mice;2) To define the relationship of in vitro virulence factors of murine EHS to in vivo pathogenic potential in the IL10-/- mouse model and to determine how the hosts'immune responses influence disease progression;and 3) To identify and characterize virulence determinants in the genome sequences of 3 enteric Helicobacter spp. isolated from rodents and humans with clinical disease, as well as those of H. hepaticus and determine if these genes are operable in inducing IBD in C57BL IL10-/- mice. To accomplish these aims we have assembled a team of scientists who have successfully collaborated together for the last decade to study the etiopathogenesis of H. hepaticus gastrointestinal disease in mice.
This proposal will focus on the diagnosis, characterization and pathobiology of emerging enterohepatic helicobacters (EHS) in mice. The proposal addresses molecular targets for diagnosis and characterization of EHS and will take advantage of sequenced EHS that colonize mice to probe virulence determinants shared among these EHS isolated from both mice and humans.
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