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

Abstract

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.