Ectopic expression of human thymosin β4 confers resistance to Legionella pneumophila during pulmonary and systemic infection in mice

Bonggoo Park, Min Hwa Shin, Jiyoung Kim, Gayoung Park, Yun Kyoung Ryu, Jae Wook Lee, Tae Jin Kim, Eun Yi Moon, Kyung Mi Lee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Thymosin beta-4 (Tβ4) is an actin-sequestering peptide that plays important roles in regeneration and remodeling of injured tissues. However, its function in a naturally occurring pathogenic bacterial infection model has remained elusive. We adopted Tβ4-overexpressing transgenic (Tg) mice to investigate the role of Tβ4 in acute pulmonary infection and systemic sepsis caused by Legionella pneumophila. Upon infection, Tβ4-Tg mice demonstrated significantly lower bacterial loads in the lung, less hyaline membranes and necrotic abscess, with lower interstitial infiltration of neutrophils, CD41, and CD81 T cells. Bronchoalveolar lavage fluid of Tβ4-Tg mice possessed higher bactericidal activity against exogenously added L. pneumophila, suggesting that constitutive expression of Tβ4 could efficiently control L. pneumophila. Furthermore, qPCR analysis of lung homogenates demonstrated significant reduction of interleukin 1 beta (IL-1b) and tumor necrosis factor alpha (TNF-a), which primarily originate from lung macrophages, in Tβ4-Tg mice after pulmonary infection. Upon L. pneumophila challenge of bone marrowderived macrophages (BMDM) in vitro, secretion of IL-1b and TNF-a proteins was also reduced in Tβ4-Tg macrophages, without affecting their survival. The anti-inflammatory effects of BMDM in Tβ4-Tg mice on each cytokine were affected when triggering with tlr2, tlr4, tlr5, or tlr9 ligands, suggesting that anti-inflammatory effects of Tβ4 are likely mediated by the reduced activation of Toll-like receptors (TLR). Finally, Tβ4-Tg mice in a systemic sepsis model were protected from L. pneumophila-induced lethality compared to wild-type controls. Therefore, Tβ4 confers effective resistance against L. pneumophila via two pathways, a bactericidal and an anti-inflammatory pathway, which can be harnessed to treat acute pneumonia and septic conditions caused by L. pneumophila in humans.

Original languageEnglish
Article numbere00735
JournalInfection and Immunity
Volume89
Issue number4
DOIs
Publication statusPublished - 2021 Apr

Keywords

  • Anti-inflammatory
  • Bactericidal
  • Legionella pneumophila
  • Pulmonary infection
  • Sepsis
  • Thymosin β4

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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