Cytidine 5'-Diphosphocholine Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice

Area of Science:

• Cell Biology
• Virology
• Biochemistry

Background:

• Influenza A virus (IAV) infection causes acute respiratory distress syndrome (ARDS) linked to impaired alveolar type II (ATII) cell phosphatidylcholine synthesis.
• Cytidine 5'-diphosphocholine (CDP-choline), a phosphatidylcholine precursor, mitigates IAV-induced ARDS in mice.

Purpose of the Study:

• To investigate the impact of inhibited phosphatidylcholine synthesis on ATII cell mitochondrial function during IAV infection.
• To determine if CDP-choline administration can ameliorate IAV-induced mitochondrial dysfunction.

Main Methods:

• Adult C57BL/6 mice were infected with IAV (A/WSN/33) or mock-infected.
• Mice received daily intraperitoneal injections of saline vehicle or CDP-choline from 1 to 5 days post-inoculation.
• ATII cells were isolated at 6 days post-inoculation for mitochondrial function analysis, including glucose analog uptake, ATP synthesis pathways, mitochondrial membrane potential, and protein expression.

Main Results:

• IAV infection led to increased lung glucose analog uptake and a metabolic shift from oxidative phosphorylation to aerobic glycolysis in ATII cells.
• Mitochondrial dysfunction was evident, characterized by depolarization, shrinkage, PGC-1α upregulation, decreased cardiolipin, and reduced expression of key mitochondrial proteins and enzymes.
• CDP-choline treatment preserved oxidative phosphorylation, mitochondrial membrane potential, and cardiolipin synthesis but did not fully reverse the glycolytic shift or prevent all protein expression changes.

Conclusions:

• IAV-induced ATII cell mitochondrial dysfunction is primarily driven by impaired de novo phospholipid synthesis.
• CDP-choline shows therapeutic potential by protecting mitochondrial function against IAV infection, although it does not fully normalize all cellular metabolic and protein alterations.