Performing Department
(N/A)
Non Technical Summary
Clostridioides difficile is an important pathogen of food animals (especially piglets), and causes the diarrheal disease C. difficileinfection (CDI). In swine operations, C. difficile is routinely recovered from piglets and sows. Colonized piglets can shed C. difficile over prolonged periods of time, causing additional cycles of infection. A specific phylogenetic lineage of C. difficile (RT078) is commonly found in agriculturally-important animals. RT078 strains have also been recovered from human patients, leading to the contention that farms/food may be reservoirs of the pathogen. RT078- mediated CDI may thus be considered as a quintessential One Health problem. Indeed, our 10-year, prospective CDI surveillance of Arizona hospitals and swine operations aligns closely with that of the CDC's Emerging Infections Program and reveals that C. difficile RT078 is prevalent in both agricultural, and human healthcare, settings. Despite its importance to both animal and human health, the mechanisms underlying RT078 virulence and transmission is poorly understood. Our recently published preliminary data indicate that RT078 strains have significantly different biology compared to other, human-prevalent, C. difficile lineages.
Animal Health Component
100%
Research Effort Categories
Basic
20%
Applied
80%
Developmental
(N/A)
Goals / Objectives
We hypothesize that C. difficile RT078 strains express multiple unique molecular traits which enable their dominance in theagricultural setting.In this project, we will test this hypothesis by (1) employing newly developed modeling approaches to identify host (porcine)factors engaged by C. difficile; (2) using multi-omics to identify C. difficile RT078 factors important for disease; and (3)performing functional studies in vitro and in neonatal piglets to interrogate C. difficile RT078 virulence.
Project Methods
Whole-genome sequencing suggests that the RT078 C. difficile lineage harbors unique biological traits compared with other,more human-dominant lineages. However, the molecular nature of such traits, or the mechanisms underlying RT078 virulenceand transmission within/from veterinary populations are unknown. Thus, there is a significant gap in knowledge.Our recent prior research reveals that RT078 strains express a lineage-specific proteome and cell-surface architecture. Thus,we hypothesize that C. difficile strains in the RT078 lineage harbor a unique virulence repertoire that potentiates dominance inthe agricultural/veterinary setting. This will be tested in three systems-biology-driven, and procedurally independent, Aims.Specific Aim 1: To model host-pathogen interactions. This fulfills the need to identify host factors that support C. difficileRT078 infection. Our approach is to generate an interactome-based molecular atlas of host (porcine) proteins involved inengagement with C. difficile.Specific Aim 2: To study RT078 C. difficile via multi-omics analysis. This fulfills the need to identify C. difficile factors thatplay a role in establishing infection. Our approach is to analyze C. difficile RT078 clinical isolates and identify core- and pangenomemolecules predicted to be involved in CDI establishment and immune response.Specific Aim 3: To evaluate C. difficile RT078 virulence traits. This fulfills the need to functionally characterize C. difficilepathogenic factors. Our approach is to employ in vitro and in vivo assessments of C. difficile infection in veterinary-relevant celllines and an animal model.