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Here, we report the first complete genomes of three cultivable treponeme species from bovine digital dermatitis (DD) skin lesions, two comparative human treponemes, considered indistinguishable from bovine DD species, and a bovine gastrointestinal (GI) treponeme isolate. Key genomic differences between bovine and human treponemes implicate microbial mechanisms that enhance knowledge of how DD, a severe disease of ruminants, has emerged into a prolific, worldwide disease. Bovine DD treponemes have additional oxidative stress genes compared to nearest human-isolated relatives, suggesting better oxidative stress tolerance, and potentially explaining how bovine strains can colonize skin surfaces. Comparison of both bovine DD and GI treponemes as well as bovine pathogenic and human non-pathogenic saprophyte Treponema phagedenis strains indicates genes encoding a five-enzyme biosynthetic pathway for production of 2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, a rare di- N -acetylated mannuronic acid sugar, as important for pathogenesis. Bovine T . phagedenis strains further differed from human strains by having unique genetic clusters including components of a type IV secretion system and a phosphate utilisation system including phoU , a gene associated with osmotic stress survival. Proteomic analyses confirmed bovine derived T . phagedenis exhibits expression of PhoU but not the putative secretion system, whilst the novel mannuronic acid pathway was expressed in near entirety across the DD treponemes. Analysis of osmotic stress response in water identified a difference between bovine and human T . phagedenis with bovine strains exhibiting enhanced survival. This novel mechanism could enable a selective advantage, allowing environmental persistence and transmission of bovine T . phagedenis . Finally, we investigated putative outer membrane protein (OMP) ortholog families across the DD treponemes and identified several families as multi-specific adhesins capable of binding extra cellular matrix (ECM) components. One bovine pathogen specific adhesin ortholog family showed considerable serodiagnostic potential with the Treponema medium representative demonstrating considerable disease specificity (91.6%). This work has shed light on treponeme host adaptation and has identified candidate molecules for future diagnostics, vaccination and therapeutic intervention.

Contagious ovine digital dermatitis (CODD) is a severe and common infectious foot disease of sheep and a significant animal welfare issue for the sheep industry in the UK and some European countries. The etiology and pathogenesis of the disease are incompletely understood. In this longitudinal, experimental study, CODD was induced in 18 sheep, and for the first time, the clinical lesion development and associated microbiological changes in CODD affected feet are described over time, resulting in a completely new understanding of the etiopathogenesis of CODD. The majority of CODD lesions (83.9%) arose from pre-existing interdigital dermatitis (ID) and/or footrot (FR) lesions. All stages of foot disease were associated with high levels of poly-bacterial colonization with five pathogens, which were detected by quantitative PCR (qPCR): Treponema medium, Treponema phagedenis, Treponema pedis, Dichelobacter nodosus , and Fusobacterium necrophorum . Temporal colonization patterns showed a trend for early colonization by T. phagedenis , followed by F. necrophorum and D. nodosus, T. medium , and then T. pedis, D. nodosus was present at significantly higher predicted mean log 10 genome copy numbers in FR lesions compared to both ID and CODD, while Treponema species were significantly higher in CODD and FR lesions compared to ID lesions ( p < 0.001). Treatment of CODD-affected sheep with two doses of 10 mg/kg long acting amoxicillin resulted in a 91.7% clinical cure rate by 3 weeks post-treatment; however, a bacteriological cure was not established for all CODD-affected feet. The study found that in an infected flock, healthy feet, healed CODD feet, and treated CODD feet can be colonized by some or all of the five pathogens associated with CODD and therefore could be a source of continued infection in flocks. The study is an experimental study, and the findings require validation in field CODD cases. However, it does provide a new understanding of the etiopathogenesis of CODD and further supportive evidence for the importance of current advice on the control of CODD; namely, ensuring optimum flock control of footrot and prompt isolation and effective treatment of clinical cases.

Leptospirosis is a globally important zoonotic disease of humans and animals, caused by the bacteria Leptospira. A central determinant of virulence is the ability for these bacteria to evade complement, a host defense system that assembles the membrane attack complex to eliminate pathogens. Here, we elucidate a novel immune evasion mechanism in which the leptospiral surface protein LIC13259 forms a disulfide bond with complement component C8γ, preventing binding of C8α. This interaction disrupts the membrane attack complex assembly and promotes bacterial survival. To our knowledge, this represents the first example of a cross-kingdom disulfide bond mediating bacterial pathogenesis. These findings provide novel insights into leptospiral immune modulation and demonstrate the power of AlphaFold-based structural predictions to reveal unique host-pathogen interactions.

This research communication reports the results from questionnaires used to identify the impact of recent research into the disinfection of cattle foot-trimming equipment to prevent bovine digital dermatitis (BDD) transmission on (a) biosecurity knowledge and (b) hygiene practice of foot health professionals. An initial questionnaire found that more than half of participating farmers, veterinary surgeons and commercial foot-trimmers were not considering hand or hoof-knife hygiene in their working practices. The following year, after the release of a foot-trimming hygiene protocol and a comprehensive knowledge exchange programme by the University of Liverpool, a second survey showed 35/80 (43.8%) farmers, veterinary surgeons and commercial foot-trimmers sampled considered they were now more aware of the risk of spreading BDD during foot- trimming. Furthermore, 36/80 (45.0%) had enhanced their hygiene practice in the last year, impacting an estimated 1383 farms and 5130 cows trimmed each week. Participants who reported having seen both the foot-trimming hygiene protocol we developed with AHDB Dairy and other articles about foot-trimming hygiene in the farming and veterinary press, were significantly more likely to have changed their working practices. Difficulties accessing water and cleaning facilities on farms were identified as the greatest barrier to improving biosecurity practices. Participants' preferred priority for future research was continued collection of evidence for the importance and efficacy of good foot-trimming hygiene practices.

Contagious ovine digital dermatitis (CODD) is a significant disease of the ovine foot characterised by severe lameness and progressive separation of the hoof horn capsule from the underlying tissue. Similar to bovine digital dermatitis (BDD), pathogenic members of the genus Treponema including the Treponema medium phylogroup, Treponema phagedenis phylogroup and Treponema pedis are frequently found together in CODD lesions. To date, CODD was only described in Ireland and the United Kingdom. In northern Germany, cases of an unusually severe lameness presented in a sheep flock that had been affected by footrot for several years. These cases were non-responsive to conventional footrot therapies, with some sheep exhibiting substantial lesions of the claw horn that resulted in horn detachment. Lesion swab samples were collected from both clinically affected and asymptomatic animals. In all clinically affected sheep, CODD-associated Treponema phylogroups were detected by polymerase chain reaction. This is the first report of CODD in Germany and mainland Europe, indicating a wider geographic spread than previously considered. In cases of severe lameness attributed to claw lesions in sheep that fail to respond to footrot treatment, CODD should be considered irrespective of geographic location.

Leptospirosis is a zoonotic bacterial disease affecting mammalian species worldwide. Cattle are a major susceptible host; infection with pathogenic Leptospira spp. represents a public health risk and results in reproductive failure and reduced milk yield, causing economic losses. The characterisation of outer membrane proteins (OMPs) from disease-causing bacteria dissects pathogenesis and underpins vaccine development. As most leptospire pathogenesis research has focused on Leptospira interrogans, this study aimed to characterise novel OMPs from another important genomospecies, Leptospira borgpetersenii, which has global distribution and is relevant to bovine and human diseases. Several putative L. borgpetersenii OMPs were recombinantly expressed, refolded and purified, and evaluated for function and immunogenicity. Two of these unique, putative OMPs (rLBL0972 and rLBL2618) bound to immobilised fibronectin, laminin and fibrinogen, which, together with structural and functional data, supports their classification as leptospiral adhesins. A third putative OMP (rLBL0375), did not exhibit saturable adhesion ability but, together with rLBL0972 and the included control, OmpL1, demonstrated significant cattle milk IgG antibody reactivity from infected cows. To dissect leptospire host–pathogen interactions further, we expressed alleles of OmpL1 and a novel multi-specific adhesin, rLBL2618, from a variety of genomospecies and surveyed their adhesion ability, with both proteins exhibiting divergences in extracellular matrix component binding specificity across synthesised orthologs. We also observed functional redundancy across different L. borgspetersenii OMPs which, together with diversity in function across genomospecies orthologs, delineates multiple levels of plasticity in adhesion that is potentially driven by immune selection and host adaptation. These data identify novel leptospiral proteins which should be further evaluated as vaccine and/or diagnostic candidates. Moreover, functional redundancy across leptospire surface proteins together with identified adhesion divergence across genomospecies further dissect the complex host–pathogen interactions of a genus responsible for substantial global disease burden.

BackgroundNon-healing bovine foot lesions, including non-healing white line disease, non-healing sole ulcer and toe necrosis, are an increasingly important cause of chronic lameness that are poorly responsive to treatment. Recent studies have demonstrated a high-level association between these non-healing lesions and the Treponema phylogroups implicated in bovine digital dermatitis (BDD). However, a polymicrobial aetiology involving other gram-stain-negative anaerobes is suspected.MethodsA PCR-based bacteriological survey of uncomplicated BDD lesions (n=10) and non-healing bovine foot lesions (n=10) targeting Fusobacterium necrophorum, Porphyromonas endodontalis, Dichelobacter nodosus and Treponema pallidum/T. paraluiscuniculi was performed.Results P. endodontalis DNA was detected in 80.0% of the non-healing lesion biopsies (p=<0.001) but was entirely absent from uncomplicated BDD lesion biopsies. When compared to the BDD lesions, F. necrophorum was detected at a higher frequency in the non-healing lesions (33.3% vs 70.0%, respectively), whereas D. nodosus was detected at a lower frequency (55.5% vs 20.0%, respectively). Conversely, T. pallidum/T. paraluiscuniculi DNA was not detected in either lesion type.ConclusionThe data from this pilot study suggest that P. endodontalis and F. necrophorum should be further investigated as potential aetiological agents of non-healing bovine foot lesions. A failure to detect syphilis treponemes in either lesion type is reassuring given the potential public health implications such an infection would present.

Leptospirosis is a zoonotic bacterial disease affecting mammalian species worldwide. Cattle are a major susceptible host; infection with pathogenic Leptospira spp. represents a public health risk and results in reproductive failure and reduced milk yield, causing economic losses. The characterisation of outer membrane proteins (OMPs) from disease-causing bacteria dissects pathogenesis and underpins vaccine development. As most leptospire pathogenesis research has focused on Leptospira interrogans, this study aimed to characterise novel OMPs from another important genomospecies, Leptospira borgpetersenii, which has global distribution and is relevant to bovine and human diseases. Several putative L. borgpetersenii OMPs were recombinantly expressed, refolded and purified, and evaluated for function and immunogenicity. Two of these unique, putative OMPs (rLBL0972 and rLBL2618) bound to immobilised fibronectin, laminin and fibrinogen, which, together with structural and functional data, supports their classification as leptospiral adhesins. A third putative OMP (rLBL0375), did not exhibit saturable adhesion ability but, together with rLBL0972 and the included control, OmpL1, demonstrated significant cattle milk IgG antibody reactivity from infected cows. To dissect leptospire host–pathogen interactions further, we expressed alleles of OmpL1 and a novel multi-specific adhesin, rLBL2618, from a variety of genomospecies and surveyed their adhesion ability, with both proteins exhibiting divergences in extracellular matrix component binding specificity across synthesised orthologs. We also observed functional redundancy across different L. borgspetersenii OMPs which, together with diversity in function across genomospecies orthologs, delineates multiple levels of plasticity in adhesion that is potentially driven by immune selection and host adaptation. These data identify novel leptospiral proteins which should be further evaluated as vaccine and/or diagnostic candidates. Moreover, functional redundancy across leptospire surface proteins together with identified adhesion divergence across genomospecies further dissect the complex host–pathogen interactions of a genus responsible for substantial global disease burden.