Mitochondrial Dysfunction in Aged Macrophages and Lung during Primary Streptococcus pneumoniae Infection is Improved
Maria Plataki1, Soo Jung Cho1, Rebecca M Harris1
1Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, NY, USA.
Abstract:
Pneumococcal infections remain a leading cause of death in older adults, with the most serious cases occurring in persons ≥65 years of age. There is an urgent need to investigate molecular pathways underlying these impairments and devise new therapeutics to modulate innate immunity. The goal of our current study is to understand the impact of chronological aging on mitochondrial function in response to Streptococcus pneumoniae, a causative agent of bacterial pneumonia. Using chronologically aged murine models, our findings demonstrate that decreased ATP production is associated with dysregulated mitochondrial complex expression, enhanced oxidative stress, diminished antioxidant responses, and decreased numbers of healthy mitochondria in aged adult macrophages and lung in response to S. pneumoniae. Pre-treatment of aged macrophages with pirfenidone, an anti-fibrotic drug with antioxidant and anti-inflammatory properties, improved mitochondrial function and decreased cellular oxidative stress responses. In vivo administration of pirfenidone decreased superoxide formation, increased healthy mitochondria number, improved ATP production, and decreased inflammatory cell recruitment and pulmonary oedema in aged mouse lung during infection. Taken together, our data shed light on the susceptibility of older persons to S. pneumoniae and provide a possible therapeutic to improve mitochondrial responses in this population.
Insights
Aging impairs mitochondrial function during pneumococcal infections. Pirfenidone treatment improved mitochondrial health and reduced infection severity in aged mice, offering a potential therapy for older adults.
Area of Science:
- Immunology
- Gerontology
- Mitochondrial Biology
Background:
- Pneumococcal infections pose a significant threat to older adults, leading to high mortality rates.
- Understanding the molecular mechanisms of aging-related immune dysfunction is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the impact of chronological aging on mitochondrial function during Streptococcus pneumoniae infection.
- To explore pirfenidone as a potential therapeutic agent to restore mitochondrial health in aged individuals.
Main Methods:
- Utilized chronologically aged murine models to study lung and macrophage responses to S. pneumoniae.
- Assessed mitochondrial function, oxidative stress, ATP production, and inflammatory markers.
- Evaluated the effects of pirfenidone pre-treatment in aged macrophages and in vivo administration.
Main Results:
- Aged mice exhibited decreased ATP production, impaired mitochondrial complex expression, increased oxidative stress, and fewer healthy mitochondria in response to S. pneumoniae.
- Pirfenidone treatment improved mitochondrial function and reduced oxidative stress in aged macrophages.
- In vivo pirfenidone administration enhanced ATP production, increased healthy mitochondria, and reduced inflammation and edema in aged mouse lungs during infection.
Conclusions:
- Chronological aging significantly compromises mitochondrial function in response to pneumococcal infection.
- Pirfenidone demonstrates therapeutic potential by improving mitochondrial responses and mitigating infection severity in aged populations.
- These findings highlight a promising strategy to combat pneumococcal infections in older adults.
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