Translational Rodent Models for Research on Parasitic Protozoa—A Review of Confounders and Possibilities

Abstract

Rodents, in particular Mus musculus, have a long and invaluable history as models for human diseases in biomedical research, although their translational value has been challenged in a number of cases. We provide some examples in which rodents have been suboptimal as models for human biology and discuss confounders which influence experiments and may explain some of the misleading results. Infections of rodents with protozoan parasites are no exception in requiring close consideration upon model choice. We focus on the significant differences between inbred, outbred and wild animals, and the importance of factors such as microbiota, which are gaining attention as crucial variables in infection experiments. Frequently, mouse or rat models are chosen for convenience, e.g., availability in the institution rather than on an unbiased evaluation of whether they provide the answer to a given question. Apart from a general discussion on translational success or failure, we provide examples where infections with single-celled parasites in a chosen lab rodent gave contradictory or misleading results, and when possible discuss the reason for this. We present emerging alternatives to traditional rodent models, such as humanized mice and organoid primary cell cultures. So-called recombinant inbred strains such as the Collaborative Cross collection are also a potential solution for certain challenges. In addition, we emphasize the advantages of using wild rodents for certain immunological, ecological, and/or behavioral questions. The experimental challenges (e.g., availability of species-specific reagents) that come with the use of such non-model systems are also discussed. Our intention is to foster critical judgment of both traditional and newly available translational rodent models for research on parasitic protozoa that can complement the existing mouse and rat models.

Animal Models in Translational Research: Rosetta Stone or Stumbling Block?

“…This discovery suggests that we need to revisit a great deal of what we thought we knew about our own immune systems and the ways they malfunction in adults, since much of that knowledge is built on studies in chronologically adult, but immunologically immature, animals . This disparity has led to at least one serious translational breakdown: the failure of a clinical trial of an antibody designed to treat rheumatoid arthritis was, in retrospect, explained by the immunological naïveté of the mice used in initial safety assessments . To serve as more effective translational models for immunology − and in some other fields as well − lab mice may need a “dirtier” environment than the carefully controlled, specific‐pathogen‐free facilities that most now inhabit …”

“…The human population is genetically and environmentally diverse, and that diversity is medically − and thus translationally − significant. For example, highly standardized models may not work well for studying diseases such as metabolic disorders, where complex environmental influences play important roles …”

“…Variation in individuals’ personal history, risk exposure, and lifestyle (as well as their genomes) is central to understanding the etiology and treatment of human disease − and, thus, something we need to account for in preclinical animal studies. Yet we can not evaluate the importance of heterogeneity using only inbred models, and standardization itself may limit the strength of inference from lab‐based model systems to real‐world clinical applications . Preclinical research characterized by stringent standardization may yield results that are readily reproducible in other equally standardized labs, but fail to translate to diverse humans in variable real environments: standardization may increase internal validity at the cost of lower external validity, and thus less effective translation.…”

“…Animal models have supported critical advances in biomedical research, offering deep insights into disease biology. But they have been less successful as a basis for advancing human health: the failure of translation from animal models to human patients has often been disappointing, and sometimes startling, despite the power of widely‐applied “Rosetta Stone” models . While we need to continue using models, we must account for the effects of focusing biomedical research in just a few non‐human species.…”

“…There are, of course, many different models; in fact the diversity of animals used in biomedical research has increased steadily over the past three decades, and bibliometric data suggest that the “canonization” of a handful of models by NIH in 1999 has not excluded other species . That said, the vast preponderance of biomedical research in animal models continues to use rats and mice (distantly followed by fruit flies and others) . Within specific areas of research, model selection is often further canalized to defined strains, and sometimes to single transgenic lines that incorporate alleles or lesions associated with a disease of interest (e.g., Ref.…”