Phagosome-lysosome fusion in innate immune cells like macrophages and neutrophils marshal an essential role in eliminating intracellular microorganisms. In microbe-challenged macrophages, phagosome-lysosome fusion occurs 4 to 6 h after the phagocytic uptake of the microbe. However, live pathogenic mycobacteria hinder the transfer of phagosomes to lysosomes, up to 20 h post-phagocytic uptake. This period is required to evade pro-inflammatory response and upregulate the acid-stress tolerant proteins. The exact sequence of events through which mycobacteria retards phagolysosome formation remains an enigma. The macrophage coat protein Coronin1(Cor1) is recruited and retained by mycobacteria on the phagosome membrane to retard its maturation by hindering the access of phagosome maturation factors. Mycobacteria-infected macrophages exhibit an increased cAMP level, and based on receptor stimulus, Cor1 expressing cells show a higher level of cAMP than non-Cor1 expressing cells. Here we have shown that infection of bone marrow-derived macrophages with H37Rv causes a Cor1 dependent rise of intracellular cAMP levels at the vicinity of the phagosomes. This increased cAMP fuels cytoskeletal protein Cofilin1 to depolymerize F-actin around the mycobacteria-containing phagosome. Owing to reduced F-actin levels, the movement of the phagosome toward the lysosomes is hindered, thus contributing to the retarded phagosome maturation process. Additionally, Cor1 mediated upregulation of Cofilin1 also contributes to the prevention of phagosomal acidification, which further aids in the retardation of phagosome maturation. Overall, our study provides first-hand information on Cor1 mediated retardation of phagosome maturation, which can be utilized in developing novel peptidomimetics as part of host-directed therapeutics against tuberculosis.

巨噬细胞和中性粒细胞等先天免疫细胞中的吞噬体-溶酶体融合在消除细胞内微生物方面发挥着重要作用。在微生物攻击的巨噬细胞中，吞噬体-溶酶体融合在微生物被吞噬后 4 至 6 小时发生。然而，活的致病性分枝杆菌会阻碍吞噬体向溶酶体的转移，直至吞噬后 20 小时。这段时间是逃避促炎反应和上调酸胁迫耐受蛋白所必需的。分枝杆菌阻碍吞噬溶酶体形成的确切事件顺序仍然是一个谜。巨噬细胞外壳蛋白 Coronin1(Cor1) 被吞噬体膜上的分枝杆菌募集和保留，通过阻碍吞噬体成熟因子的进入来延缓其成熟。分枝杆菌感染的巨噬细胞表现出增加的 cAMP 水平，并且基于受体刺激，表达 Cor1 的细胞比不表达 Cor1 的细胞表现出更高的 cAMP 水平。在这里，我们已经表明，用 H37Rv 感染骨髓来源的巨噬细胞会导致吞噬体附近的细胞内 cAMP 水平的 Cor1 依赖性升高。这种增加的 cAMP 为细胞骨架蛋白 Cofilin1 提供燃料，以解聚含有分枝杆菌的吞噬体周围的 F-肌动蛋白。由于 F-肌动蛋白水平降低，吞噬体向溶酶体的运动受到阻碍，从而导致吞噬体成熟过程延迟。此外，Cor1 介导的 Cofilin1 上调也有助于防止吞噬体酸化，这进一步有助于延缓吞噬体成熟。总体，