Abstract:
Pulmonary Mycobacterium tuberculosis (Mtb) infection results in highly heterogeneous lesions ranging from granulomas with central necrosis to those primarily comprised of alveolitis. While alveolitis has been associated with prior immunity in human post-mortem studies, the drivers of these distinct pathologic outcomes are poorly understood. Here, we show that these divergent lesion structures can be modeled in C3HeB/FeJ mice and are regulated by prior immunity. Using quantitative imaging, scRNAseq, and flow cytometry, we demonstrate that Mtb infection in the absence of prior immunity elicits dysregulated neutrophil recruitment and necrotic granulomas. In contrast, prior immunity induces rapid recruitment and activation of T cells, local macrophage activation, and diminished late neutrophil responses. Depletion studies at distinct infection stages demonstrated that neutrophils are required for early necrosis initiation and necrosis propagation at chronic stages, whereas early CD4 T cell responses prevent neutrophil feedforward circuits and necrosis. Together, these studies reveal fundamental determinants of tuberculosis lesion structure and pathogenesis, which have important implications for new strategies to prevent or treat tuberculosis.
摘要:
肺结核分枝杆菌(Mtb)感染会导致高度异质性的病变,从具有中央坏死的肉芽肿到主要由肺泡炎组成的肉芽肿。虽然在人类验尸研究中肺泡炎与先前的免疫力有关,对这些不同病理结局的驱动因素知之甚少.这里,我们表明,这些不同的病变结构可以在C3HeB/FeJ小鼠中建模,并受先前免疫的调节。使用定量成像,scRNAseq,和流式细胞术,我们证明,在没有既往免疫的情况下,Mtb感染会导致中性粒细胞募集失调和坏死性肉芽肿.相比之下,先前的免疫诱导T细胞的快速募集和激活,局部巨噬细胞活化,和减少晚期中性粒细胞反应。不同感染阶段的耗竭研究表明,慢性阶段早期坏死开始和坏死传播需要中性粒细胞。而早期CD4T细胞反应阻止中性粒细胞前馈回路和坏死。一起,这些研究揭示了结核病病变结构和发病机理的基本决定因素,这对预防或治疗结核病的新策略具有重要意义。