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，表现为感染雾化结核分枝杆菌(Mtb) 的一部分个体。与人类结核病不同，小鼠感染会导致肺部细菌负荷普遍较高和组织不良的肉芽肿。为了开发更接近人类疾病的结核病模型，我们用 1-3 种创始细菌的超低剂量 (ULD) 感染小鼠，反映了生理接种。感染 ULD 的小鼠表现出高度异质性的细菌负荷、与人类肉芽肿具有共同特征的界限清楚的肉芽肿，以及一些小鼠单侧肺部感染的结核分枝杆菌抑制时间延长。我们确定了感染 ULD 或常规 Mtb 剂量 (50-100 CFU) 的小鼠的血液 RNA 特征，这些特征与肺部细菌负荷相关，并预测了跨物种的 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，这些发现凸显了小鼠结核病模型的潜力，并表明 ULD 感染概括了人类结核病的主要特征。