An established principle of modern research into bacterial pathogenesis is that no in vitro, in situ, or in silico model can accurately account for the myriad host defense mechanisms and host tissue complexity that a pathogen will encounter in a live animal. This fact was appreciated over 100 years ago by Robert Koch and the early pioneers of pathogenesis research, who recognized that an animal model of infection that mimicked a human disease was a crucial component in establishing a microbial etiology for any given disease (Kaufmann & Schaible, 2005). The postulates described by Koch continue to the present day to be the “gold standard” by which etiology is established (Kaufmann & Schaible, 2005). In the spirit of Koch, the early pioneers of the molecular era of pathogenesis research (most notably Stanley Falkow) have expanded on the principles elaborated by Koch to use animal models to develop our modern understanding of the molecular basis of microbial pathogenesis, in order to establish a functional link between any given gene product of a pathogen and its capacity to cause disease (Falkow, 1988; Falkow, 2004) (Table 1). Thus, the availability of animal models that can faithfully reproduce a human disease continues to be a foundational component of modern microbial pathogenesis research.
For research into the pathogenesis of diseases caused by Streptococcus pyogenes, the groundbreaking work of the labs of Joseph Ferretti, Patrick Cleary and June Scott (Ji, McLandsborough, Kondagunta, & Cleary, 1996; Perez-Casal, Price, Maguin, & Scott, 1993; Simon & Ferretti, 1991) established a methodology for the manipulation of the S. pyogenes genome, and opened the door for the analysis of pathogenesis that followed the principles elaborated by Falkow. This work spurred the development of new in vivo models that could be used to investigate the role of specific virulence factors in S. pyogenes pathogenesis. However, for S. pyogenes, the development of in vivo models has proven to be challenging for a number of reasons: First, S. pyogenes is a strictly human pathogen and is exquisitely adapted to its human host to the extent that many of its important virulence factors (for example, its several secreted superantigens and its plasminogen activator streptokinase (Kasper, et al., 2014; Sun, et al., 2004; Reglinski & Sriskandan, 2014)) only have activity against humans cells and proteins. The second issue reflects S. pyogenes’ remarkable versatility as a pathogen, as it is capable of causing diseases that result from very different pathogenic mechanisms. Most of these fall into one of three broad classes (Reglinski & Sriskandan, 2014; Cunningham, 2000; Ralph & Carapetis, 2013; Wong & Stevens, 2013; Cunningham, 2012): first, local, lesional diseases in soft tissue characterized by inflammation, which can result in considerable damage to tissue in more severe manifestations; second, both local and systemic diseases that arise from damage caused by secreted streptococcal toxins; and third, immune dysfunction that results from an inappropriate immune response to streptococcal antigens. The third challenge to model development arises from the range of different tissue compartments that S. pyogenes can damage, which ranges from skin and soft tissue to internal organs like the heart and kidneys and to any number of different sites in the skin and other soft tissues. A final major challenge to model development is the population of S. pyogenes itself, which has proven to have extensive strain diversity despite its restriction to a human habitat (Bessen, 2009). This means that there is no single strain of S. pyogenes that can be considered representative of the population as a whole and also, that relatively few strains have been shown to be virulent in any given animal model.
Despite these challenges, the prior 15 years has seen the development of an impressive number of in vivo models in a diversity of animal species, ranging from invertebrates to primates, that have proven useful in the dissection of S. pyogenes gene/pathogenesis relationships (Figure 1). In considering these models, it is important to note that there is no single comprehensive model of S. pyogenes infection. In fact, there is no single model that can accurately reproduce the authentic pathogenesis of any specific S. pyogenes disease. Instead, various models have been developed to model different aspects of various pathogenic mechanisms, and as a result, a thorough understanding of any particular model’s strengths and weaknesses is an important consideration for experimental design, for interpretation of results as they apply to understanding pathogenesis in that model system, and for extrapolation to the mechanism by which any S. pyogenes gene may contribute to human disease. In the following sections, we will review the salient features of the animal models that have proven particularly useful in modern analyses of S. pyogenes pathogenesis, including their utility, strengths, and limitations, as well as some examples of the types of strains and mutants whose pathogenic mechanism a given model has been shown to resolve. For purposes of organization, the various models will be grouped together with the host animal upon which they are based.
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