Influenza infection exacerbates high-fat diet-induced atherosclerosis in apolipoprotein gene-deficient mice

Influenza is a significant public health and economic threat around the world. Although pneumonia is the most common complication associated with influenza, there are several clinical reports showing an increased risk for cardiovascular disease. Studies have shown that influenza infection correlates with increased incidence of myocardial infarction. Atherosclerosis is a common cause of coronary artery disease including myocardial infarction, stroke, and heart failure. Here, we analyzed the effect of influenza infection in high-fat diet-induced atherosclerosis in Apoe-/- mice. We found increased weight loss and decreased survival, increased numbers of CD11b+Ly6C+ cells (inflammatory monocytes) and CD11b+Ly6G+ cells (neutrophils), increased levels of CCL3, CCL4, and CCL5, increased lung pathology, and increased atherosclerotic lesions in the aorta in influenza-infected Apoe-/- mice when compared to influenza-infected wild-type (WT) and control (PBS-treated) Apoe-/- mice. An increased percentage of RORγt+ and IL-17+ cells were identified in influenza-infected Apoe-/- mice compared with influenza-infected WT mice and PBS-treated Apoe-/- mice. Bone marrow macrophages from influenza-infected Apoe-/- mice showed increased expression of Th17 polarizing cytokines. Influenza-infected Color-flu (Venus)-positive cells were identified in inflammatory monocytes and neutrophils in the lungs, spleen, blood, aorta, and vascular endothelial cells. These results suggest that influenza infection increases arterial inflammation by directly infecting endothelial cells, and indirectly through recruitment of inflammatory monocytes and neutrophils. Increased Th17 responses in influenza-infected Apoe-/- mice may be a possible mechanism involved in increased lung pathology and exacerbation of high-fat diet-induced atherosclerosis.