Accumulation of Quinolinic Acid Modulates the Pulmonary Immune Response During Influenza Infection

Influenza viruses cause a highly contagious, acute pulmonary disease that results in significant mortality each year. These infections trigger the production of interferons, known to induce the expression of the rate-limiting enzyme in the kynurenine degradation pathway in the lungs. As some kynurenine pathway metabolites are biologically active, we aimed to gain a better understanding of their role in influenza A virus infection. The expression of kynurenine pathway enzymes and the levels of their metabolites were quantified in the lungs of C57BL/6 mice 7 days after infection with an H3N2 influenza A virus (IAV). Furthermore, the impact of quinolinic acid supplementation was evaluated on IAV-infected mice and in vitro, in human monocyte-derived macrophages. The expression of key enzymes (IDO1, KMO, and KYNU) increased in mice in the airways of IAV infected mice. High levels of quinolinic acid were produced in the lungs, as revealed by immunohistochemistry in both epithelial cells and immune cells. Oral quinolinic acid supplementation resulted in higher levels of viral mRNA in the lungs and modulated cytokine production, leading to an increased number of neutrophils and interstitial macrophages in lung tissue. In IAV-infected macrophages, the addition of quinolinic acid was associated with higher levels of viral RNA and protein and in increased antiviral and proinflammatory responses (IFN-β, CXCL-1, and TNF-α). These increases were further reduced by memantine, an NMDA receptor antagonist, suggesting that quinolinic acid may modulate the macrophage immune response via NMDA receptors. A deeper understanding of these mechanisms could lead to new therapeutic strategies for influenza infections.