Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109, USA.
Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA 98109, USA; Department of Pediatrics, University of Washington, Seattle, WA 98109, USA.
Cell Host Microbe. 2021 Jan 13;29(1):68-82.e5. doi: 10.1016/j.chom.2020.10.003. Epub 2020 Nov 2.
Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1-3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the murine TB model and show that ULD infection recapitulates key features of human TB.
结核病（TB）是一种异质性疾病，仅在感染分枝杆菌（Mtb）气溶胶的个体亚群中表现出来。与人类结核病不同，鼠类感染导致肺部细菌负荷均匀升高，且肉芽肿组织发育不良。为了开发更接近人类疾病的结核病模型，我们用超低剂量（ULD）（1-3 个创始细菌）感染小鼠，反映生理接种量。ULD 感染的小鼠表现出高度异质的细菌负荷，边界清楚的肉芽肿与人类肉芽肿具有相似特征，并且在一些小鼠中单侧肺部感染时能够长期控制 Mtb。我们在感染 ULD 或常规 Mtb 剂量（50-100 CFU）的小鼠中鉴定出血液 RNA 特征，这些特征与肺部细菌负荷相关，并可预测跨物种的 Mtb 感染结果，包括人类进展为活动性结核病的风险。总体而言，这些发现突出了鼠类结核病模型的潜力，并表明 ULD 感染重现了人类结核病的关键特征。
