Ectopic Expression of Human Thymosin β4 Confers Resistance to Legionella pneumophila during Pulmonary and Systemic Infection in Mice

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, CD4+, and CD8+ 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-1β) and tumor necrosis factor alpha (TNF-α), which primarily originate from lung macrophages, in Tβ4-Tg mice after pulmonary infection. Upon L. pneumophila challenge of bone marrow-derived macrophages (BMDM) in vitro, secretion of IL-1β and TNF-α 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.

Construction of a prediction model for pulmonary infection and its risk factors in Intensive Care Unit patients

“…Most patients with diabetes have abnormal protein and fat metabolism, which can lead to increased body consumption, decreased muscle strength, respiratory muscle atrophy, reduced deep breathing function and cough ability, thus increasing the risk of lung infection. 21 Mechanical ventilation duration was an independent risk factor of pulmonary infection in our study. Similarly, Zhang et al 22 showed that mechanical ventilation time ≥3 days in ICU patients is a risk factor for pulmonary infection.…”

“…Most patients with diabetes have abnormal protein and fat metabolism, which can lead to increased body consumption, decreased muscle strength, respiratory muscle atrophy, reduced deep breathing function and cough ability, thus increasing the risk of lung infection. 21 …”

Association Between Plasma Redox State/Mitochondria Function and a Flu-Like Syndrome/COVID-19 in the Elderly Admitted to a Long-Term Care Unit

“…The problem that could arise is how to simply measure the mitochondrial function in people. About this issue, it should be highlighted that in our study the correlation analysis showed positive relation between mitochondrial membrane potential and the levels of plasma Thymosin β4, which is an anti-inflammatory hormone that can down-regulate chemokines and cytokines, as well as increase fibrinolysis ( Park et al, 2021 ).…”

Recombinant human thymosin beta‐4 (rhTβ4) improved scalp condition and microbiome homeostasis in seborrheic dermatitis

“…Thymosin beta‐4 (Tβ4), a 43‐amino acid peptide, is involved in multiple cellular responses and plays dual roles in antimicrobial and immune modulation (Park et al ., 2021). Tβ4 has shown potential antimicrobial effects against various bacteria, including E. coli, Staphylococcus aureus , Pseudomonas aeruginosa, and Staphylococcus epidermidis (Tang et al ., 2002; Huang et al ., 2007; Schillaci et al ., 2016; Carion et al ., 2020) and downregulates inflammation.…”