Genome-Wide Transcriptomics Uncovers a Lung-to-Aorta Inflammatory Program Driving Influenza-Induced Atherosclerosis Exacerbation

Influenza infection increases cardiovascular risk in individuals with pre-existing atherosclerosis, yet the genome-wide transcriptional basis of this association remains undefined. We performed bulk RNA sequencing of aorta and lung tissues from high-fat diet-fed Apoe -/- mice infected with influenza A/PR/8/34 versus PBS-treated controls at day 15 post-infection, identifying 6,828 differentially expressed genes across both tissues (5,694 in the lung and 1,134 in the aorta; adjusted p < 0.05). In the lung, influenza sustained a CXCR3-driven chemokine storm, comprehensive Th1, Th17, and exhaustion T-cell activation programs, coordinated monocyte recruitment through Ccl2 , Ccl7 , Ccl8 , and Ccl12 , a broad acute phase response including Saa3 and A2m , alveolar identity collapse through loss of Nkx2-1 and surfactant proteins, and broad metabolic dysregulation involving suppression of fatty acid oxidation, mitochondrial function, and circadian metabolic regulators. In the aorta, influenza drove macrophage and DAMP activation through Trem1 , Fpr2 , and S100a8 , cytotoxic T-cell engagement, smooth muscle cell dedifferentiation through Myocd loss, convergent bioenergetic failure, and an ectopic lung-identity gene signature representing a previously undescribed cross-organ communication mechanism. Circadian clock and Hippo/YAP pathway suppression were shared across both tissues, identifying systemic vulnerabilities connecting pulmonary infection to vascular structural compromise. Consistent with the in vivo findings, influenza-infected Apoe -/- bone marrow-derived macrophages exhibited inflammasome activation, DAMP amplification, M1 polarization, and suppression of prostaglandin-mediated inflammatory resolution. Together these findings define a lung-to-aorta inflammatory and metabolic axis driving atherosclerotic plaque destabilization during the post-infection recovery period and identify CCR2/CXCR3 antagonism, NLRP3 inhibition, and YAP pathway activation as candidate therapeutic interventions.

Influenza infection drives atherosclerotic plaque destabilization.