因为大多数人类抵抗结核分枝杆菌感染,需要研究的肺样本很少。为了解决这个差距,我们用结核分枝杆菌感染了多样性近交小鼠,并研究了不同疾病状态下小鼠的肺部。低剂量气雾剂感染后,进展者死于急性,60天内炎症性肺病,而控制者保持无症状感染至少60天,然后发展为慢性肺结核(TB)持续数月至1年以上。这里,我们通过对多模式数据集应用计算和统计方法,确定了无症状结核分枝杆菌感染的特征.细胞因子和抗M.结核细胞壁抗体可区分患有慢性肺结核的进展者和控制者,但无法对无症状感染的小鼠进行分类。然而,一种在肺肉芽肿图像上训练的新型深度学习神经网络能够准确地对进展者中的无症状感染肺、急性肺结核和控制者中的慢性肺结核进行分类,和区分是基于血管周围和细支气管周围淋巴细胞。由于辨别性病变富含淋巴细胞,并且需要CD4T细胞介导的免疫来抵抗,我们预计无症状感染时CD4T细胞基因会升高.然而,显著的不同,高表达的基因来自B细胞途径(例如,Bank1,Cd19,Cd79,Fcmr,Ms4a1、Pax5和H2-Ob),CD20+B细胞富集在无症状结核分枝杆菌感染小鼠的血管周围和细支气管周围区域。一起,这些结果表明,基因控制的B细胞反应对于建立无症状的结核分枝杆菌肺部感染很重要.
Because most humans resist Mycobacterium tuberculosis infection, there is a paucity of lung samples to study. To address this gap, we infected Diversity Outbred mice with M. tuberculosis and studied the lungs of mice in different disease states. After a low-dose aerosol infection, progressors succumbed to acute, inflammatory lung disease within 60 days, while controllers maintained asymptomatic infection for at least 60 days, and then developed chronic pulmonary tuberculosis (TB) lasting months to more than 1 year. Here, we identified features of asymptomatic M. tuberculosis infection by applying computational and statistical approaches to multimodal data sets. Cytokines and anti-M. tuberculosis cell wall antibodies discriminated progressors vs controllers with chronic pulmonary TB but could not classify mice with asymptomatic infection. However, a novel deep-learning neural network trained on lung granuloma images was able to accurately classify asymptomatically infected lungs vs acute pulmonary TB in progressors vs chronic pulmonary TB in controllers, and discrimination was based on perivascular and peribronchiolar lymphocytes. Because the discriminatory lesion was rich in lymphocytes and CD4 T cell-mediated immunity is required for resistance, we expected CD4 T-cell genes would be elevated in asymptomatic infection. However, the significantly different, highly expressed genes were from B-cell pathways (e.g., Bank1, Cd19, Cd79, Fcmr, Ms4a1, Pax5, and H2-Ob), and CD20+ B cells were enriched in the perivascular and peribronchiolar regions of mice with asymptomatic M. tuberculosis infection. Together, these results indicate that genetically controlled B-cell responses are important for establishing asymptomatic M. tuberculosis lung infection.