Metabolic Syndrome and Viral Pathogenesis: Lessons from Influenza and Coronaviruses

Abstract

Metabolic syndrome increases the risk of severe disease due to viral infection. Yet few studies have assessed the pathogenesis of respiratory viruses in high-risk populations. Here, we summarize how metabolic dysregulation impairs immune responses, and we define the role of metabolism during influenza virus and coronavirus infections. We also discuss the use of various in vitro, in vivo, and ex vivo models to elucidate the contributions of host factors to viral susceptibility, immunity, and disease severity.

Keywords: COVID-19; SARS-CoV-2; diabetes; influenza; metabolic syndrome; models of metabolic syndrome; obesity; type 2 diabetes mellitus; viral pathogenesis.

FIG 1

Obesity and T2DM impair host immunity and enhance the severity of influenza virus infection. During IAV infection in healthy hosts, surfactant protein D (SP-D) binds to IAV surface glycoproteins to inhibit IAV binding to the sialic acid receptors on the surfaces of the lung epithelia. Also, IAV particles that arrive at the bronchial epithelial cell surface are trapped in the mucus and transported out of the respiratory tract via the rhythmic movement of cilia. Circulating CD4⁺ and CD8⁺ T cells can migrate from the blood vessels to the lung tissue to target IAV and prevent damage to the lung epithelial-endothelial barrier. In contrast, excess glucose in the obese and T2DM microenvironments binds to SP-D and restricts the neutralization of IAV. IAV infection also leads to the loss of cilia on the bronchial epithelial cells of obese individuals and hence promotes IAV binding to the sialic acid receptors. Additionally, glycolytic efflux leads to glucose intolerance and insulin resistance, which alter the cytokine milieu and contribute to a chronic state of metainflammation. As IAV infection progresses, this significantly upregulates proinflammatory cytokines, such as IL-6 and IFN-γ, that potentiate inflammation, further damaging the epithelial layer. Obesity is also associated with upregulated neutrophil extravasation during IAV infection, whereby neutrophils attach to blood vessels, migrate to the epithelial cell layer, and release reactive oxygen species (ROS) that induce alveolar damage. Damage to type 2 pneumocytes results in severe influenza virus infection, increased barrier permeability, and the development of acute lung injury, which can result in viral pneumonia. Furthermore, obesity can result in upregulated lipid synthesis and increased production of lipid rafts, which can be exploited by IAV for viral entry, replication, and the release of progeny virions. Accelerated glycolysis increases ATP sources that are used for assembling V-ATPase and for transporting protons into the endosome. This results in the acidification of endosomes and the upregulation of IAV M2 activity, which collectively promote the uncoating and release of viral genomic material to facilitate viral replication.