Recent insights into why obesity puts individuals in danger for severe influenza

In a recent study published within the journal Nature Communications, researchers used blood and airway sampling of morbidly obese individuals and murine models to elucidate the mechanisms underpinning severe cases of influenza among the many obese population.

Study: Obesity dysregulates the pulmonary antiviral immune response. Image Credit: Jarun Ontakrai/Shutterstock.com

Background

Their findings reveal that obesity induces deficits in pulmonary antiviral responses and airway metabolomes, thereby increasing leptin concentrations.

The overexpression of leptin incapacitates antiviral type 1 interferon, increasing severe influenza risk. This study may provide insights into therapeutic interventions, resembling leptin manipulation, which will profit higher-risk obese individuals in the long run.

Obesity and severe influenza

Obese and obesity present a few of the world’s biggest clinical and economic burdens today. Over 13% of the world’s adult human population and over 1 billion persons are estimated to suffer from obesity, problems which today’s sedentary lifestyle and overconsumption of the Western weight loss program are compounding.

The 2009 swine flu (H1N1) pandemic highlights obese individuals’ heightened risk of developing severe respiratory tract infections, contributing to increased hospitalizations and mortalities.  

Seasonal influenza research has corroborated these findings, with the continuing coronavirus disease 2019 (COVID-19) pandemic providing the ultimate evidence that obesity is related to opposed viral outcomes.

Scientists have hypothesized that obesity may function via altered lung mechanics, heart problems and other comorbidities, and immunometabolic effects. Nevertheless, studies haven’t confirmed the mechanical influences of abnormal body weight on viral susceptibility.

Concerning the study

In the current study, researchers employ a multi-compartment sampling strategy of the peripheral blood and airways of morbidly obese patients with ongoing bariatric surgery.

The cross-disciplinary approach combines in vitro metabolomic investigations with in vivo functional murine models and clinical case-control human studies to elucidate the association between obesity and perturbed viral immunity in these patients.

The study’s participants (N = 30; 15 cases and 15 controls) were recruited from the Imperial College Healthcare NHS Trust. Morbidly obese patients with body mass index (BMI) greater than 35 kg/m² and normal body weight controls (BMI = 20-25 kg/m²) were age, gender, and ethnicity matched and underwent anthropometric characterization.

Clinical sampling involving blood, nasal synthetic absorptive matrix (SAM) sampling, and bronchoscopy were conducted.

For ex vivo virus infection experiments, bronchoalveolar lavage (BAL), bronchial epithelial cells (BECs), or plasmacytoid dendritic cells (DCs) were infected with select influenza virus strains – A/Eng/195, A/Eng/691/10 or B/Florida, following which RNA extraction and protein quantification were carried out.

In vivo, experiments were conducted on 6-8 week-old female BALB/c mice and comprised intranasal administration of recombinant mouse leptin followed by intranasal infection with influenza virus strain X31.

In vitro experiments included protein assays, RNA and quantitative polymerase chain response (PCR), flow cytometry, and metabolomics.

Statistic analyses used Mann-Whitney U tests, Kruskal-Wallis tests, and Dunn’s multiple correction test for evaluating human obesity data retrieved from the Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study. Evaluation of variance (ANOVA) tests were used to match case-control data across human and animal evaluations.

Study findings

Initial creator hypotheses regarding bronchial epithelial cell responses altered by obesity-mediated effects were proven incorrect, as findings revealed no statistically significant differences between case and control participants.

Interleukin (IL) response experiments corroborated these findings in airway inflammation experiments – pro-inflammatory cytokine responses were found to be uniform between obese cases and normal controls, suggesting unaltered epithelial inflammation during influenza infection of chubby individuals.

In contrast, BAL macrophages did show significant perturbations of their antiviral responses. BAL cells infected with H1N1/09, H3N2, and B/Florida influenza strains depicted reduced interferon-alpha (IFN-α) induction in obese patients in comparison with their control counterparts.

Similarly, IFN-β and IFN-λ induction was severely hampered in obese individuals, impairing type I and III IFN antiviral protection. BAL cell pro-inflammatory cytokine production of IL-6, IL-8, and TNF also showed reduced efficiency in obese versus normal adults.

Evaluations of BECs revealed that these cells are usually not affected by obesity, with no differences in cell activation patterns between normal and obese individuals.

Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) analyses of BAL fluid metabolite abundances presented that 15 metabolites were significantly downregulated in obese patients, and two – adenosine monophosphate (AMP) and glycerol – were upregulated on this cohort.

“…bronchosorption concentrations of leptin negatively correlated with the magnitude of BAL cell IFN-β responses to all three influenza strains tested in our ex vivo experiments, with greater concentrations of leptin being significantly related to weaker induction of IFN-β by each virus strain. This indicated a possible causal link between raised leptin concentrations and impaired antiviral immunity in obesity, potentially through perturbed fatty acid metabolism.”

In vivo, exogenous leptin administration experiments in mice revealed that the obese mice models presented upregulated suppressors of cytokine signaling 3 (Socs3) mRNA.

SOCS-3 is a known negative modulator of type I IFN signaling, severely impacting obese individuals’ early response to viral infection. These results were corroborated when analyzing results from each whole lung expression and BAL macrophages.

Analyses of MOSAIC cohort data elucidate that immune dysregulation in obese patients is restricted to the upper airway mucosa with none significant perturbation throughout the systemic circulatory system.

Conclusions

The current study utilizes ex vivo experiments and in vivo murine models to elucidate the mechanisms underlying the increased susceptibility of obese individuals to severe influenza infections.

The outcomes of those cross-disciplinary analyses comprising metabolomics, RNA sequencing, HPLC, and flow cytometry reveal that obesity significantly alters the upper airway mucosa of chubby individuals versus their normal BMI counterparts.

This leads to upregulated SOCS-2 production and correspondingly attenuated IFN production. Type I and III IFN regulation perturbs normal early infection responses, allowing influenza to present more severe infections in obese individuals.

“In conclusion, our study uncovers insight into mechanisms driving susceptibility to severe influenza infections in obese individuals. Future work should concentrate on whether sustained weight reduction results in a restitution of this impaired antiviral immunity, especially on condition that epidemiological evidence indicates that the clinical risk of influenza infection diminishes following bariatric surger and impaired mononuclear cell type II IFN responses in obese individuals could be corrected by weight reduction.”

These findings may form the premise for research into leptin manipulation or IFN administration interventions that help obese individuals higher address influenza and other viral respiratory tract infections in the long run.