The Influence of Programmed Cell Death in Myeloid Cells on Host Resilience to Infection with Legionella pneumophila or Streptococcus pyogenes

PLoS Pathogens

Yun Xu¹  Sandra Högler²  Pavel Kovarik³  Amanda M. Jamieson³  Kellyanne Duncan⁴  Nina Gratz⁵  Pia Gamradt⁶  Thomas Decker⁶  Lester Kobzik⁷ 

[1] CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France;CNRS, UMR 5308, Lyon, France;Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, United States;Ecole Normale Supérieure de Lyon, Lyon, France;Inserm U111, Lyon, France;Max F. Perutz Laboratories, University of Vienna, Vienna, Austria;Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France

关键词: Apoptosis;    Bone marrow cells;    Legionella pneumophila;    Streptococcus pyogenes;    Macrophages;    Cell death;    Mouse models;    Bacterial pathogens;   

DOI  :  10.1371/journal.ppat.1006032

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Pathogen clearance and host resilience/tolerance to infection are both important factors in surviving an infection. Cells of the myeloid lineage play important roles in both of these processes. Neutrophils, monocytes, macrophages, and dendritic cells all have important roles in initiation of the immune response and clearance of bacterial pathogens. If these cells are not properly regulated they can result in excessive inflammation and immunopathology leading to decreased host resilience. Programmed cell death (PCD) is one possible mechanism that myeloid cells may use to prevent excessive inflammation. Myeloid cell subsets play roles in tissue repair, immune response resolution, and maintenance of homeostasis, so excessive PCD may also influence host resilience in this way. In addition, myeloid cell death is one mechanism used to control pathogen replication and dissemination. Many of these functions for PCD have been well defined in vitro, but the role in vivo is less well understood. We created a mouse that constitutively expresses the pro-survival B-cell lymphoma (bcl)-2 protein in myeloid cells (CD68(bcl2tg), thus decreasing PCD specifically in myeloid cells. Using this mouse model we explored the impact that decreased cell death of these cells has on infection with two different bacterial pathogens, Legionella pneumophila and Streptococcus pyogenes. Both of these pathogens target multiple cell death pathways in myeloid cells, and the expression of bcl2 resulted in decreased PCD after infection. We examined both pathogen clearance and host resilience and found that myeloid cell death was crucial for host resilience. Surprisingly, the decreased myeloid PCD had minimal impact on pathogen clearance. These data indicate that the most important role of PCD during infection with these bacteria is to minimize inflammation and increase host resilience, not to aid in the clearance or prevent the spread of the pathogen.

【 授权许可】

CC BY