Characterization of a caprine model for the subclinical initial phase of Mycobacterium avium subsp. paratuberculosis infection

Abstract

BackgroundParatuberculosis caused by Mycobacterium avium subsp. paratuberculosis (MAP) is difficult to control due to a long phase of clinically non-apparent (latent) infection for which sensitive diagnostics are lacking. A defined animal model for this phase of the infection can help to investigate host-MAP interactions in apparently healthy animals and identify surrogate markers for disease progress and might also serve as challenge model for vaccines. To establish such a model in goats, different age at inoculation and doses of oral inoculum of MAP were compared. Clinical signs, faecal shedding as well as MAP-specific antibody, IFN-γ and IL-10 responses were used for in vivo monitoring. At necropsy, about one year after inoculation (pi), pathomorphological findings and bacterial organ burden (BOB) were scored.ResultsMAP infection manifested in 26/27 inoculated animals irrespective of age at inoculation and dose. Clinical signs developed in three goats. Faecal shedding, IFN-γ and antibody responses emerged 6, 10–14 and 14 wpi, respectively, and continued with large inter-individual variation. One year pi, lesions were detected in 26 and MAP was cultured from tissues of 23 goats. Positive animals subdivided in those with high and low overall BOB. Intestinal findings resembled paucibacillary lesions in 23 and multibacillary in 4 goats. Caseous and calcified granulomas predominated in intestinal LNN. BOB and lesion score corresponded well in intestinal mucosa and oGALT but not in intestinal LNN.ConclusionsA defined experimental infection model for the clinically non-apparent phase of paratuberculosis was established in goats as suitable basis for future studies.

A Bovine Enteric Mycobacterium Infection Model to Analyze Parenteral Vaccine-Induced Mucosal Immunity and Accelerate Vaccine Discovery

“…The need for a bovine MAP infection model is evident in the differences in MAP infection and immunopathology in surrogate animal models, including closely related small ruminants. Oral challenge of goats ( 22 , 23 ) and lambs ( 44 ) with a Type II cattle MAP strain revealed greater MAP tropism for DPP and other major mucosal immune induction sites (i.e., ileocecal valve PP and proximal colon PP) than the CPP. In contrast to goats, the CPP is the predominant site of persistent MAP infection in cattle ( 29 , 33 , 45 , 46 ).…”

“…Pathogen-induced immunopathology is also vastly different in goats and calves challenged with Type II cattle strains. In goats, MAP infection of DPP resulted in excessive tissue inflammation and lesion development in the PPs and surrounding intestinal mucosa ( 22 , 23 ). This observation is not consistent with our observations of MAP infection in the DPP of calves at 12 months post-infection ( 29 ), or naturally MAP-infected cows ( 25 ).…”

“…Moreover, animal models for vaccine screening, such as mice and goats, fail to recapitulate bovine MAP enteric infection. For example, in the goat model, persistent MAP infection is consistently established in major enteric mucosal immune induction sites such as discrete Peyer’s patches (DPP) in the jejunum, the ileocecal valve PP and the proximal colon PP but is not consistently present in the continuous PP (CPP) ( 22 , 23 ). In contrast, MAP is consistently detected in CPP in both naturally infected ( 24 , 25 ) and experimentally challenged calves and cows.…”

Biomarkers for Early Stages of Johne’s Disease Infection and Immunization in Goats

“…In addition to better understanding of disease progression, such analysis is expected to yield targets for further development into a diagnostic assay for early stages of Johne’s disease. Similar to others ( Aranday-Cortes et al, 2012 ; Bhuju et al, 2012 ; Churbanov and Milligan, 2012 ; Kohler et al, 2015 ), we focused our analysis on the transcriptome of PBMC stimulated cells with M. paratuberculosis lysate to further increase biomarker specificity to M. paratuberculosis infection and/or vaccination. Many transcriptomic analyzing tools largely depend on information from an annotated genome.…”

Complete Genome Sequence of JII-1961, a Bovine Mycobacterium avium subsp. paratuberculosis Field Isolate from Germany

“…This strain was isolated in 2003 from an ileocecal lymph node of a clinically diseased cow and was characterized by multitarget genotyping ( 9 ). Furthermore, JII-1961 was used as an inoculation strain for a new defined animal model for JD in goats focusing on the period of latent infection ( 10 ).…”