Abstract
Mouse models are invaluable resources for studying the pathogenesis and preclinical evaluation of therapeutics and vaccines against many human pathogens. Infections caused by group A streptococcus (GAS, Streptococcus pyogenes) are heterogeneous ranging from mild pharyngitis to severe invasive necrotizing fasciitis, a subgroup of necrotizing soft-tissue infections (NSTIs). While several strains of mice including BALB/c, C3H/HeN, CBA/J, and C57BL/10 offered significant insights, the human specificity and the interindividual variations on susceptibility or resistance to GAS infections limit their ability to mirror responses as seen in humans. In this chapter, we discuss the advanced recombinant inbred (ARI) BXD mouse model that mimics the genetic diversity as seen in humans and underpins the feasibility to map multiple genes (genetic loci) modulating GAS NSTI. GAS produces a myriad of virulence factors, including superantigens (SAg). Superantigens are potent immune toxins that activate T cells by cross-linking T cell receptors with human leukocyte antigen class-II (HLA-II) molecules expressed on antigen-presenting cells. This leads to a pro-inflammatory cytokine storm and the subsequent multiple organ damage and shock. Inbred mice are innately refractive to SAg-mediated responses. In this chapter, we discuss the versatility of the HLA-II transgenic mouse model that allowed the biological validation of known genetic associations to GAS NSTI. The combined utility of ARI-BXD and HLA-II mice as complementary approaches that offer clinically translatable insights into pathomechanisms driven by complex traits and host genetic context and novel means to evaluate the in vivo efficiency of therapies to improve outcomes of GAS NSTI are also discussed.
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Acknowledgements
The work presented was supported by the grants from the European Union (FP7/2012–2017) under the grant agreement 305340 (MK), grants from the Swedish Research Council under grant number 20150338 (MK), UND CoBRE Host–Pathogen Interactions Pilot Award (SN), and UND Genomics Core funded through grant support from the National Institutes of Health grants P20GM104360 (SN) and by the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P20GM103442, U54GM128729, and P20GM113123. We thank John Lee, Graphic Design Specialist, at Information Resources of the University of North Dakota School of Medicine & Health Sciences, for his assistance with the figure illustrations.
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Nookala, S., Krishnan, K.C., Mukundan, S., Kotb, M. (2020). Systems Genetics Approaches in Mouse Models of Group A Streptococcal Necrotizing Soft-Tissue Infections. In: Norrby-Teglund, A., Svensson, M., Skrede, S. (eds) Necrotizing Soft Tissue Infections. Advances in Experimental Medicine and Biology, vol 1294. Springer, Cham. https://doi.org/10.1007/978-3-030-57616-5_10
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