A Trifector of New Insights into Ovine Footrot for Infection Drivers, Immune Response and Host Pathogen Interactions

Footrot is a polymicrobial infectious disease in sheep causing severe lameness, leading to one of the industrys biggest welfare problems. The complex aetiology of footrot makes in-situ or in-vitro investigations difficult. Computational methods offer a solution to understanding the bacteria involved, how they may interact with the host and ultimately providing a way to identify targets for future hypotheses driven investigative work. Here we present the first combined global analysis of the bacterial community transcripts together with the host immune response in healthy and diseased ovine feet during a natural polymicrobial infection state using metatranscriptomics. The intra tissue and surface bacterial populations and the most abundant bacterial transcriptome were analysed, demonstrating footrot affected skin has a reduced diversity and increased abundances of, not only the causative bacteria Dichelobacter nodosus, but other species such as Mycoplasma fermentans and Porphyromonas asaccharolytica. Host transcriptomics reveals a suppression of biological processes relating to skin barrier function, vascular functions, and immunosurveillance in unhealthy interdigital skin, supported by histological findings that type I collagen (associated with scar tissue formation) is significantly increased in footrot affected interdigital skin comparted to outwardly healthy skin. Finally, we provide some interesting indications of host and pathogen interactions associated with virulence genes and the host spliceosome which could lead to the identification of future therapeutic targets. Impact StatementLameness in sheep is a global welfare and economic concern and footrot is the leading cause of lameness, affecting up to 70% of flocks in the U.K. Current methods for control of this disease are labour intensive and account for approximately 65% of antibiotic use in sheep farming, whilst preventative vaccines suffer from poor efficacy due to antigen competition. Our limited understanding of cofounders, such as strain variation and polymicrobial nature of infection mean new efficacious, affordable and scalable control measures are not receiving much attention. Here we examine the surface and intracellular bacterial populations and propose potential interactions with the host. Identification of these key bacterial species involved in the initiation and progression of disease and the host immune mechanisms could help form the basis of new therapies.