A Differential Innate Immune Response in Active and Chronic Stages of Bovine Infectious Digital Dermatitis.

Kaitlyn M Watts,Cristina Fodor,Eduardo R Cobo,Jeroen De Buck,Priyoshi Lahiri,Herman W Barkema,Karin Orsel,Caroline Beninger,Rakel Arrazuria,Cameron G Knight

doi:10.3389/fmicb.2018.01586

Abstract

Digital dermatitis (DD) commonly associated with Treponema spp. infection is a prevalent infectious bovine foot disease characterized by ulcerative and necrotic lesions. Lesions associated with DD are often classified using the M-stage scoring system, with M0 indicating healthy heel skin and M4 indicating chronic lesions. Current treatments utilizing antimicrobials or chemical footbaths are often ineffective and rarely cure DD lesions. Understanding the function of the innate immune response in the pathogenesis of DD will help to identify novel therapeutic approaches. In this study, the expression of the local innate host defense peptides cathelicidins and β-defensins was investigated in cows with DD and associated with the presence of treponemes and inflammatory reactions. Samples from active ulcerative DD lesions (M2) had considerable epidermal neutrophilic infiltration and increased gene expression of β-defensin tracheal antimicrobial peptides compared to control skin. Samples from acute lesions also had elevated local Cxcl-8 and TLR4 gene expression and abundant treponemes as identified by direct visualization, immunohistochemistry, and culture. Conversely, the anti-inflammatory peptide IL-10 was elevated in skin from chronic (M4) lesions, whereas bovine cathelicidin myeloid antimicrobial peptide 28 (Bmap-28) was increased in skin from oxytetracycline-treated M2 lesions. Experiments using cultured human keratinocytes challenged with Treponema spp. isolated from clinical cases of bovine DD showed that structural products from treponemes are able to initiate the innate immune response, in part through TLR2 signaling. These findings indicate that neutrophil influx, Cxcl-8, and β-defensin are key markers of active DD. Cathelicidins and IL-10 seem important in response to treatment or during the chronic proliferative stages of the disease.

Highlights

Bovine digital dermatitis (DD) is an infectious disease of cattle characterized by ulcerative and necrotizing foot lesions
To gain insights into the skin innate immune response during the various stages of DD infection, we investigated the expression of cytokines, host defense peptides, and Tlrs in cattle with active and chronic DD lesions
As neutrophilic infiltration and Cxcl-8 gene expression were increased in active bovine DD lesions, we investigated whether keratinocytes are a source of this neutrophil chemokine

Summary

Introduction

Bovine digital dermatitis (DD) is an infectious disease of cattle characterized by ulcerative and necrotizing foot lesions. The pain and lameness caused by DD are among the cattle industry’s most prominent animal welfare concerns. Digital dermatitis is a polymicrobial disease (Zinicola et al, 2015); the fastidious, anaerobic, and highly motile spirochetes of the genus Treponema (collectively referred to as treponemes) are suspected to be the primary causative agents (Dopfer et al, 1997). Various Treponema spp. are consistently detected in active bovine DD lesions and are often absent from healthy feet (Walker et al, 1995; Dopfer et al, 2012; Krull et al, 2014). The cause of DD has not yet been definitively identified (Zinicola et al, 2015; Krull et al, 2016)

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Conclusion