Modeling Paratuberculosis in Laboratory Animals, Cells, or Tissues: A Focus on Their Applications for Pathogenesis, Diagnosis, Vaccines, and Therapy Studies

Abstract

Paratuberculosis is a chronic granulomatous enteritis caused by Mycobacterium avium subsp. Paratuberculosis that affects a wide variety of domestic and wild animals. It is considered one of the diseases with the highest economic impact on the ruminant industry. Despite many efforts and intensive research, paratuberculosis control still remains controversial, and the existing diagnostic and immunoprophylactic tools have great limitations. Thus, models play a crucial role in understanding the pathogenesis of infection and disease, and in testing novel vaccine candidates. Ruminant animal models can be restricted by several reasons, related to space requirements, the cost of the animals, and the maintenance of the facilities. Therefore, we review the potential and limitations of the different experimental approaches currently used in paratuberculosis research, focusing on laboratory animals and cell-based models. The aim of this review is to offer a vision of the models that have been used, and what has been achieved or discovered with each one, so that the reader can choose the best model to answer their scientific questions and prove their hypotheses. Also, we bring forward new approaches that we consider worth exploring in the near future.

Keywords: epithelial cell; ex vivo; experimental infection; in vitro; in vivo; infection model; macrophage; neutrophil; paratuberculosis; rabbit.

Figure 1

Modeling PTB. Relative contribution of the different models discussed in this paper. Data are expressed as the percentage of assays found for each model in PTB research. The information used to calculate these percentages was obtained by searches performed on 7 August 2023 in PubMed using the following keywords: “(mouse OR murine) AND paratuberculosis”, “rabbit AND paratuberculosis”, “(protists OR amoeba) AND paratuberculosis”, “ferret AND paratuberculosis”, “macrophage cell line AND paratuberculosis”, “macrophage cell model AND paratuberculosis”, “epithelial cells AND paratuberculosis”, “neutrophil AND paratuberculosis”, “cells co-culture AND paratuberculosis”, and ”granuloma in vitro AND paratuberculosis”. The inclusion criterion was considered to be a research study (not a review) on the use of an experimental model of infection to evaluate some aspects of PTB. In total, 217 assays were considered that met this criterion. It is important to note that these experiments were published in slightly fewer papers since, in some cases, the authors published results obtained from different models in the same paper. Since this review focuses on PTB or Johne’s disease, those works that refer to MAP but are in the context of Crohn’s disease were excluded. (Created with BioRender.com. BioRender Publication and License Rights agreement number: OB25PTVZ5Q).