Obesity-Related Microenvironment Promotes Emergence of Virulent Influenza Virus Strains

Abstract

Obesity is associated with increased disease severity, elevated viral titers in exhaled breath, and significantly prolonged viral shed during influenza A virus infection. Due to the mutable nature of RNA viruses, we questioned whether obesity could also influence influenza virus population diversity. Here, we show that minor variants rapidly emerge in obese mice. The variants exhibit increased viral replication, resulting in enhanced virulence in wild-type mice. The increased diversity of the viral population correlated with decreased type I interferon responses, and treatment of obese mice with recombinant interferon reduced viral diversity, suggesting that the delayed antiviral response exhibited in obesity permits the emergence of a more virulent influenza virus population. This is not unique to obese mice. Obesity-derived normal human bronchial epithelial (NHBE) cells also showed decreased interferon responses and increased viral replication, suggesting that viral diversity also was impacted in this increasing population. IMPORTANCE Currently, 50% of the adult population worldwide is overweight or obese. In these studies, we demonstrate that obesity not only enhances the severity of influenza infection but also impacts viral diversity. The altered microenvironment associated with obesity supports a more diverse viral quasispecies and affords the emergence of potentially pathogenic variants capable of inducing greater disease severity in lean hosts. This is likely due to the impaired interferon response, which is seen in both obese mice and obesity-derived human bronchial epithelial cells, suggesting that obesity, aside from its impact on influenza virus pathogenesis, permits the stochastic accumulation of potentially pathogenic viral variants, raising concerns about its public health impact as the prevalence of obesity continues to rise.

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic

“…These findings are not limited by viral subtype and are also found in human studies. Diminished INF response and an increased influenza virus replication were found in normal bronchial epithelial (NHBE) cells derived from obese subjects [16][17][18].…”

“…Secondly, the obese microenvironment favors the emergence of novel more virulent virus strains. This is due mainly to the reduced and delayed capacity to produce interferons by obese individuals and animals [17,18]. The delay in producing interferon to contrast viral replication allows more viral RNA replication increasing the chances of the appearance of novel, more virulent viral strains [18].…”

“…This is due mainly to the reduced and delayed capacity to produce interferons by obese individuals and animals [17,18]. The delay in producing interferon to contrast viral replication allows more viral RNA replication increasing the chances of the appearance of novel, more virulent viral strains [18]. Thirdly, body mass index correlates positively with infectious virus in exhaled breath [23].…”

Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

“…infection. Comorbidities (such as hypertension, diabetes mellitus, overweight) are risk factors for severe Covid-19 and could negatively impact IFN production as well as exacerbate inflammatory responses [28][29][30] . Genetic host susceptibility can be also suspected since inherited monogenic disorders in children 31,32 or susceptibility variants in adults 33 , each involving the type I IFN pathway, have been associated with life-threatening influenza infections.…”

SARS-CoV-2 and Obesity: “CoVesity” - A Pandemic Within A Pandemic

“…The obesity microenvironment may also be conducive to the development of more virulent viral strains. For example, obese mice models infected with in uenza were observed to have a decreased type I interferon response, and had increased viral replication as compared to non-obese mice (44). There is a paucity of evidence on the infectivity of obese individuals in the COVID-19 pandemic, but extrapolations can be made from investigations on other viruses.…”