Pisu Davide, Johnston Luana, Mattila Joshua T, Russell David G
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
Nat Commun. 2024 Oct 2;15(1):8522. doi: 10.1038/s41467-024-52846-w.
Tuberculosis, caused by Mycobacterium tuberculosis, remains an enduring global health challenge due to the limited efficacy of existing treatments. Although much research has focused on immune failure, the role of host macrophage biology in controlling the disease remains underappreciated. Here we show, through multi-modal single-cell RNA sequencing in a murine model, that different alveolar macrophage subsets play distinct roles in either advancing or controlling the disease. Initially, alveolar macrophages that are negative for the CD38 marker are the main infected population. As the infection progresses, CD38 monocyte-derived and tissue-resident alveolar macrophages emerge as significant controllers of bacterial growth. These macrophages display a unique chromatin organization pre-infection, indicative of epigenetic priming for pro-inflammatory responses. Moreover, intranasal BCG immunization increases the numbers of CD38 macrophages, enhancing their capability to restrict Mycobacterium tuberculosis growth. Our findings highlight the dynamic roles of alveolar macrophages in tuberculosis and open pathways for improved vaccines and therapies.
由结核分枝杆菌引起的结核病，由于现有治疗方法的疗效有限，仍然是一个持久的全球健康挑战。尽管许多研究都集中在免疫失败上，但宿主巨噬细胞生物学在控制该疾病中的作用仍未得到充分认识。在这里，我们通过在小鼠模型中进行多模态单细胞RNA测序表明，不同的肺泡巨噬细胞亚群在疾病的进展或控制中发挥着不同的作用。最初，CD38标记阴性的肺泡巨噬细胞是主要的感染群体。随着感染的进展，CD38单核细胞衍生的和组织驻留的肺泡巨噬细胞成为细菌生长的重要控制者。这些巨噬细胞在感染前表现出独特的染色质组织，表明其对促炎反应进行了表观遗传预激活。此外，鼻内卡介苗免疫增加了CD38巨噬细胞的数量，增强了它们限制结核分枝杆菌生长的能力。我们的研究结果突出了肺泡巨噬细胞在结核病中的动态作用，并为改进疫苗和治疗方法开辟了途径。
