Pathogenesis, molecular genetics, and genomics of Mycobacterium avium subsp. paratuberculosis, the etiologic agent of Johne’s disease

Authors: RATHNAIAH, G - University Of Nebraska; ZINNIEL, D - University Of Nebraska; Bannantine, John; Stabel, Judith; GROHN, Y - Cornell University; COLLINS, M - University Of Wisconsin; BARLETTA, R - University Of Nebraska

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/20/2017
Publication Date: 11/6/2017
Citation: Rathnaiah, G., Zinniel, D., Bannantine, J.P., Stabel, J.R., Grohn, Y.T., Collins, M.T., Barletta, R.G. 2017. Pathogenesis, molecular genetics, and genomics of Mycobacterium avium subsp. paratuberculosis, the etiologic agent of Johne’s disease. Frontiers in Veterinary Science. 4:187. https://doi.org/10.3389/fvets.2017.00187.
DOI: https://doi.org/10.3389/fvets.2017.00187

Interpretive Summary: Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne’s disease in ruminants causing chronic diarrhea, malnutrition and muscular wasting. Neonates and young animals are infected primarily by ingestion of the bacteria, and the bacteria subsequently colonize in the intestine. The host immune response in the late stages of infection cause a thickening of the intestinal wall, leading to poor absorption of nutrients and wasting of the animal. This manuscript provides a comprehensive review of basic pathogenesis of disease, diagnostics used to detect infection, and potential therapies with anti-mycobacterial agents. A highlight of this review is a discussion of current commercial vaccines that are available to reduce clinical disease and shedding. This discussion includes the development of novel vaccines based upon genetic mutants of MAP. Further analysis of candidate vaccine strains development is also provided with critical discussions on their benefits and shortcomings, and strategies to develop a highly efficacious live-attenuated vaccine capable of differentiating infected from vaccinated animals (DIVA). This review provides current information on the status of tools for preventing and detecting Johne’s disease in livestock.

Technical Abstract: Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne’s disease in ruminants causing chronic diarrhea, malnutrition and muscular wasting. Neonates and young animals are infected primarily by the fecal-oral route. MAP attaches to, translocates via the intestinal mucosa, and is phagocytosed by macrophages. The ensuing host cellular immune response leads to granulomatous enteritis characterized by a thick and corrugated intestinal wall. We review various tissue culture systems, ileal loops, and mice, goats and cattle used to study MAP pathogenesis. MAP can be detected in clinical samples by microscopy, culturing, PCR and an enzyme-linked immunosorbent assay. There are commercial vaccines that reduce clinical disease and shedding, unfortunately, their efficacies are limited and may not engender long-term protective immunity. Moreover, the potential linkage with Crohn’s disease and other human diseases makes MAP a concern as a zoonotic pathogen. Potential therapies with anti-mycobacterial agents are also discussed. The completion of the MAP K-10 genome sequence has greatly improved our understanding of MAP pathogenesis. The analysis of this sequence has identified a wide range of gene functions involved in virulence, lipid metabolism, transcriptional regulation and main metabolic pathways. We also review the transposons utilized to generate random transposon mutant libraries and the recent advances in the post-genomic era. This includes the generation and characterization of allelic exchange mutants, transcriptomic analysis, transposon mutant banks analysis, new efforts to generate comprehensive mutant libraries and the application of transposon site hybridization mutagenesis (TraSH) and transposon sequencing (Tn-Seq) for global analysis of the MAP genome. Further analysis of candidate vaccine strains development is also provided with critical discussions on their benefits and shortcomings, and strategies to develop a highly efficacious live-attenuated vaccine capable of differentiating infected from vaccinated animals (DIVA).