Metabolic syndrome and aberrant immune responses to viral infection and vaccination: Insights from small animal models

Abstract

This review outlines the propensity for metabolic syndrome (MetS) to induce elevated disease severity, higher mortality rates post-infection, and poor vaccination outcomes for viral pathogens. MetS is a cluster of conditions including high blood glucose, an increase in circulating low-density lipoproteins and triglycerides, abdominal obesity, and elevated blood pressure which often overlap in their occurrence. MetS diagnoses are on the rise, as reported cases have increased by greater than 35% since 1988, resulting in one-third of United States adults currently diagnosed as MetS patients. In the aftermath of the 2009 H1N1 pandemic, a link between MetS and disease severity was established. Since then, numerous studies have been conducted to illuminate the impact of MetS on enhancing virally induced morbidity and dysregulation of the host immune response. These correlative studies have emphasized the need for elucidating the mechanisms by which these alterations occur, and animal studies conducted as early as the 1940s have linked the conditions associated with MetS with enhanced viral disease severity and poor vaccine outcomes. In this review, we provide an overview of the importance of considering overall metabolic health in terms of cholesterolemia, glycemia, triglyceridemia, insulin and other metabolic molecules, along with blood pressure levels and obesity when studying the impact of metabolism-related malignancies on immune function. We highlight the novel insights that small animal models have provided for MetS-associated immune dysfunction following viral infection. Such animal models of aberrant metabolism have paved the way for our current understanding of MetS and its impact on viral disease severity, dysregulated immune responses to viral pathogens, poor vaccination outcomes, and contributions to the emergence of viral variants.

Keywords: dyslipidemia; hypertension; metabolic syndrome; obesity; type 2 diabetes; vaccination; vaccine efficacy; viral infection.

Figure 1

Diagnostic criteria for metabolic syndrome (MetS). Pictorial representation of the diagnostic criteria used to diagnose metabolic syndrome (MetS). MetS is diagnosed when an individual displays at least three of the following pathophysiological conditions: high blood glucose, high cholesterol, high triglycerides, abdominal obesity, and high blood pressure (conditions depicted in blue). In addition to these conditions, MetS patients often experience nonalcoholic fatty liver disease (NAFLD), chronic inflammation, and insulin resistance (conditions depicted in green).

Figure 2

Insights gained from small animal models of the impact of MetS on viral immunity. Several small animal models have been utilized to interrogate the impact of MetS on viral immunity. The main animal models employed thus far are those that model dyslipidemia, obesity, hyperglycemia, and hypertension. Studies done utilizing these animal models have revealed that MetS-associated conditions lead to enhanced viral disease severity, blunted type I interferon responses, elevated viral titers, impaired macrophage infiltration to sites of infection, impaired T cell effector responses, generation of poorly neutralizing antibodies, poor antibody maintenance, and impaired maintenance of memory T cells.

Figure 3

Impact of hypercholesterolemia on viral immunity. In a state of normal cholesterol levels, an invading virus hijacks host cell machinery to replicate and produce progeny virions that are released from the infected cell. A macrophage recruited to the infection site can engulf viral progeny and contribute to the anti-viral state by transcribing genes that stimulate the innate immune response, like pro-inflammatory cytokine-encoding genes. In a state of hypercholesterolemia, there is a defect in macrophage recruitment to infection sites. Consequently, there are fewer macrophages found at infection sites, blunting this arm of the immune response.

Figure 4

Obesity promotes accumulation of M1 macrophages. In the non-obese state, adipocytes secrete adiponectin, an adipokine that promotes macrophage polarization to the M2 phenotype. Within the obese state, adipocytes enlarge to store excess nutrients from overnutrition, which results in hypoxia and macrophage recruitment into adipose tissue. In the hypoxic state, less adiponectin is secreted, thus inducing macrophage polarization to the M1 phenotype, contributing to a state of chronic inflammation as these macrophages secrete high levels of inflammatory cytokines. This chronic inflammation is also believed to underlie and link the conditions that encompass MetS.

Figure 5

Obesity blunts anti-viral type I IFN responses. In the non-obese state, a lung epithelial cell produces type I interferons (type I IFNs) in response to infection by a respiratory pathogen. In turn, these proteins mediate the induction of an antiviral state through tasks such as enhancing barriers, signaling infected cells to die, and recruiting immune cells to infection sites. In the obese state, mRNA transcripts of type I IFNs are decreased at infection sites, thus blunting the induction of an antiviral state and allowing the invading virus to persist.

Figure 6

Impact of hyperglycemia on viral immunity. In a state of normal glycemia levels, lung cells can become infected by a respiratory virus, which may result in moderate damage to bronchial tissue. However, in the hyperglycemic state, severe damage of bronchioles following viral pathogen infection is more likely due to an impairment in lung barriers, thus enhancing their permeability and increasing the incidence of lung edema.

Figure 7

Impact of hypertension on viral immunity. In a state of normal blood pressure levels, T cells can be activated and proliferate to respond to virally infected cells following antigen presentation by a dendritic cell. However, in the hypertensive state, angiotensin II levels are higher, and this protein can bind to its receptor present on activated T cells. Upon binding, angiotensin II promotes the T cell contraction phase at the expense of sustaining a robust effector response. This phenomenon can result in delayed viral clearance due to a lack of T cells counteracting virally infected cells.