The Cardiovascular Consequences of Influenza A Virus Infection: Mechanisms and Therapies for High-risk Groups

Influenza (IAV) is a significant global respiratory virus, responsible for 1 billion infections every year. Although infection in healthy individuals is often self-limiting, in high-risk populations, such as pregnant women and those with underlying cardiovascular disease (CVD), influenza poses a significant health concern. Clinically, pregnant women have an elevated risk of preterm birth, intrauterine growth restriction (IUGR) and miscarriage, while the long-term effects of maternal infection have been associated with neurodevelopmental disorders in children, such as autism and schizophrenia. Preclinical models have shown that IAV infection during pregnancy results in a ‘vascular storm’, with viral dissemination into the cardiovascular system triggering significant endothelial dysfunction and inflammation. Aspirin is a currently approved therapeutic for use in pregnancy to treat preeclampsia (PE), a hypertensive disease of pregnancy, and therefore may lend itself to use during maternal IAV infection. Similarly, in people with underlying cardiovascular disease, such as those with atherosclerosis, infection has been linked with adverse vascular outcomes, however the mechanisms are not well understood. Atherosclerosis is a chronic inflammatory disorder characterised by the development of atherosclerotic lesions throughout major blood vessels which contribute to arterial stiffening and reductions in blood flow. In people with atherosclerosis, infection has been linked with plaque destabilisation and myocardial infarction. Despite vaccination significantly reducing the incidence of these adverse events, vaccination uptake remains low. Throughout this thesis, we investigated the cardiovascular consequences of IAV infection in high-risk groups to identify the potential mechanisms underpinning adverse outcomes as a result of infection and identify therapeutic opportunities using pre-clinical mouse models. To begin, we hypothesised that currently approved therapeutic aspirin (ASA) and its novel nitric oxide derivative NCX4016 (NCX) would promote cardiovascular health in pregnant IAV infected dams. Accordingly, IAV infection caused local lung inflammation, with viral dissemination into the maternal aorta resulting in the ‘vascular storm’, with significant aortic inflammation and endothelial dysfunction. Treatment with either ASA or NCX significantly reduced viral dissemination into the maternal cardiovascular system, with reduced aortic inflammation and improved endothelial function. Further, we found that treatment with either ASA or NCX promoted the development of the pregnancy and improved survival rates of pups born to IAV infected dams. Upon establishing that IAV has profound effects on the cardiovascular system, we decided to investigate the effects of IAV infection in models of cardiovascular disease, such as atherosclerosis. To begin, we hypothesised that influenza infection in atherosclerotic mice would cause vascular inflammation, like what we observed during IAV infection in pregnancy, and that this would result in the increased progression of atherosclerosis. Surprisingly, influenza significantly reduced atherosclerotic lesion coverage throughout the aorta. However, the functional capacity of the aorta was significant reduced, with reductions in total vascular relaxation to smooth muscle dilator, sodium nitroprusside (SNP) and the thinning of the aortic intima and media. Not only this, but infected mice showed cardiac hypertrophy and reduced natural killer cell populations, which may be indicative of the development of pulmonary hypertension. To continue our investigations in preclinical models of atherosclerosis, we interrogated the effects of IAV on the respiratory system of atherosclerotic mice. We found that acutely, IAV infection caused local lung inflammation and bodyweight loss. Chronically, IAV infection caused significant reductions in lung functional capacity such as inspiratory capacity (IC) and FEV0.1/FVC ratios. Further, mice showed significant structural damage with increased distance between alveolar walls (Lm), and the chronic elevation in expression of cytokines TNFα, IL-6 and IL17, while there were no changes in MMP expression. This combined work in this thesis highlights the impacts of IAV infection on the cardiovascular system in high-risk populations and shows for the first time that the vascular storm can be therapeutically targeted to protect the cardiovascular system during infection. We provide strong evidence to improve the current clinical management of patients not only in the acute phases of IAV infection, but chronically to monitor the development of future lung and cardiovascular diseases. As well, we suggest that future therapeutics for these patients should not only focus on the respiratory system but should be broadened to include combination therapies that treat subsequent cardiovascular inflammation as well.<p></p>