Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA.
Bacterial Physiology and Metabolism Unit, Laboratory of Bacteriology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA.
Nat Commun. 2024 Sep 8;15(1):7848. doi: 10.1038/s41467-024-52184-x.
The accidental human pathogen Legionella pneumophila (Lp) is the etiological agent for a severe atypical pneumonia known as Legionnaires' disease. In human infections and animal models of disease alveolar macrophages are the primary cellular niche that supports bacterial replication within a unique intracellular membrane-bound organelle. The Dot/Icm apparatus-a type IV secretion system that translocates ~300 bacterial proteins within the cytosol of the infected cell-is a central virulence factor required for intracellular growth. Mutant strains lacking functional Dot/Icm apparatus are transported to and degraded within the lysosomes of infected macrophages. The early foundational work from Dr. Horwitz's group unequivocally established that Legionella does not replicate extracellularly during infection-a phenomenon well supported by experimental evidence for four decades. Our data challenges this paradigm by demonstrating that macrophages and monocytes provide the necessary nutrients and support robust Legionella extracellular replication. We show that the previously reported lack of Lp extracellular replication is not a bacteria intrinsic feature but rather a result of robust restriction by serum-derived nutritional immunity factors. Specifically, the host iron-sequestering protein Transferrin is identified here as a critical suppressor of Lp extracellular replication in an iron-dependent manner. In iron-overload conditions or in the absence of Transferrin, Lp bypasses growth restriction by IFNγ-primed macrophages though extracellular replication. It is well established that certain risk factors associated with development of Legionnaires' disease, such as smoking, produce a chronic pulmonary environment of iron-overload. Our work indicates that iron-overload could be an important determinant of severe infection by allowing Lp to overcome nutritional immunity and replicate extracellularly, which in turn would circumvent intracellular cell intrinsic host defenses. Thus, we provide evidence for nutritional immunity as a key underappreciated host defense mechanism in Legionella pathogenesis.
偶然的人类病原体嗜肺军团菌（Lp）是一种严重非典型肺炎的病原体，称为军团病。在人类感染和疾病动物模型中，肺泡巨噬细胞是主要的细胞生态位，支持细菌在独特的细胞内膜结合细胞器内复制。Dot/Icm 装置是一种 IV 型分泌系统，可在感染细胞的细胞质内转运约 300 种细菌蛋白，是细胞内生长所必需的主要毒力因子。缺乏功能 Dot/Icm 装置的突变株被转运到感染巨噬细胞的溶酶体中并被降解。霍维茨博士小组的早期基础工作明确证实，军团菌在感染过程中不会在细胞外复制——这一现象得到了 40 年来实验证据的充分支持。我们的数据通过证明巨噬细胞和单核细胞提供必要的营养物质并支持强大的军团菌细胞外复制，挑战了这一范例。我们表明，以前报道的 Lp 缺乏细胞外复制并不是细菌内在特征，而是由于血清衍生的营养免疫因子的强烈限制所致。具体来说，这里发现宿主铁螯合蛋白转铁蛋白以铁依赖性方式作为一种关键的 Lp 细胞外复制抑制剂。在铁过载条件下或转铁蛋白缺乏时，Lp 通过 IFNγ 引发的巨噬细胞的细胞外复制绕过生长限制。众所周知，与军团病发展相关的某些危险因素，如吸烟，会产生铁过载的慢性肺部环境。我们的工作表明，铁过载可能是严重感染的一个重要决定因素，因为它允许 Lp 克服营养免疫并进行细胞外复制，从而规避细胞内固有宿主防御。因此，我们为营养免疫作为军团菌发病机制中一个重要但未被充分认识的宿主防御机制提供了证据。
