Dynamic regulation of cardiolipin by the lipid pump, ATP8b1, determines the severity of lung injury in experimental bacterial pneumonia

Pneumonia remains the leading cause of infectious deaths and yet fundamentally new conceptual models underlying its pathogenesis have not emerged. Patients and mice with bacterial pneumonia have marked elevations of cardiolipin in lung fluid, a rare, mitochondrial-specific phospholipid that potently disrupts surfactant function. Intratracheal cardiolipin in mice recapitulates the clinical phenotype of pneumonia including impaired lung mechanics, modulation of cell survival and cytokine networks, and lobar consolidation. We have identified and characterized the activity of a novel cardiolipin transporter, ATP8b1, a mutant version of which is associated with severe pneumonia in humans and mice. ATP8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of cardiolipin binding motif peptide or ATP8b1 gene transfer in mice lessened lung injury and improved survival. The results unveil a new paradigm whereby ATP8b1 is a cardiolipin importer but its capacity to remove cardiolipin from lung fluid is exceeded during inflammation or ATP8b1 inefficiency. This discovery opens the door for new therapeutic strategies directed at modulating cardiolipin levels or its molecular interactions in pneumonia.