Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA.
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Adv Exp Med Biol. 2020;1294:151-166. doi: 10.1007/978-3-030-57616-5_10.
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.
小鼠模型是研究多种人类病原体的发病机制和临床前评估的宝贵资源。A 组链球菌（GAS，化脓性链球菌）引起的感染具有异质性，从轻度咽炎到严重的侵袭性坏死性筋膜炎，后者是坏死性软组织感染（NSTI）的一个亚组。虽然包括 BALB/c、C3H/HeN、CBA/J 和 C57BL/10 在内的几种小鼠株提供了重要的见解，但 GAS 感染的人类特异性和个体间易感性或抗性的差异限制了它们模拟人类反应的能力。在本章中，我们讨论了高级重组近交（ARI）BXD 小鼠模型，该模型模拟了人类所见的遗传多样性，并为绘制调节 GAS NSTI 的多个基因（遗传基因座）提供了可行性。GAS 产生了许多毒力因子，包括超抗原（SAg）。超抗原是一种强大的免疫毒素，通过与抗原呈递细胞上表达的人类白细胞抗原 II 类（HLA-II）分子交联 T 细胞受体来激活 T 细胞。这导致促炎细胞因子风暴，随后发生多器官损伤和休克。近交系小鼠天生对 SAg 介导的反应有抵抗力。在本章中，我们讨论了 HLA-II 转基因小鼠模型的多功能性，该模型允许对已知与 GAS NSTI 相关的遗传关联进行生物学验证。ARI-BXD 和 HLA-II 小鼠的联合使用作为互补方法，提供了与复杂特征和宿主遗传背景驱动的发病机制相关的临床可转化见解，以及评估改善 GAS NSTI 治疗效果的治疗方法体内效率的新方法。
