Host obesity impacts genetic variation in influenza A viral populations

Abstract

Obesity is a chronic health condition characterized by excess adiposity leading to a systemic increase in inflammation and dysregulation of metabolic hormones and immune cell populations. Obesity is well established as a risk factor for many noncommunicable diseases; however, its consequences for infectious disease are poorly understood. Influenza A virus (IAV) is a highly infectious pathogen responsible for seasonal and pandemic influenza. Host risk factors, including compromised immunity and pre-existing health conditions, can contribute to increased infection susceptibility and disease severity. During viral replication in a host, the negative sense single stranded RNA genome of IAV accumulates genetic diversity that may have important consequences for viral evolution and transmission. Here, we investigated the impact of host obesity on IAV genetic variation using a diet induced obesity ferret model. We infected obese and lean male ferrets with the A/Hong Kong/1073/1999 (H9N2) IAV strain. Using a co-caging study design, we investigated the maintenance, generation, and transmission of intrahost IAV genetic variation by sequencing viral genomic RNA obtained from nasal wash samples over multiple days of infection. We found evidence for an enhanced role of positive selection acting on de novo mutations in obese hosts that led to nonsynonymous changes that rose to high frequency. In addition, we identified numerous cases of recurrent low-frequency mutations throughout the genome that were specific to obese hosts. Despite these obese-specific variants, overall viral genetic diversity did not differ significantly between obese and lean hosts. This is likely due to the high supply rate of de novo variation and common evolutionary adaptations to the ferret host regardless of obesity status, which we show are mediated by variation in the hemagglutinin (HA) and polymerase genes (PB2 and PB1). As with single nucleotide variants, we identified a class of defective viral genomes (DVGs) that were found uniquely in either obese or lean hosts, but overall DVG diversity and dynamics did not differ between the two groups. Our study provides the first insight into the consequences of host obesity on viral genetic diversity and adaptation, suggesting that host factors associated with obesity alter the selective environment experienced by a viral population, thereby impacting the spectrum of genetic variation.

The Impact of Obesity on the Host–Pathogen Interaction with Influenza Viruses – Novel Insights: Narrative Review

“…When vaccinated, they were more likely to have other chronic conditions, particularly diabetes, cardiovascular disease, or chronic lung disease. 62 Similarly, among the pediatric population, Karachaliou et al recently demonstrated that obese children had significantly lower rates of influenza vaccination compared to the general pediatric population; by the age of 4, only 13.3% of obese children were vaccinated compared to 37% of the general population, and by the age of 10, only 2.9% of obese children were vaccinated compared to 40% of the general population. 66 For these reasons, it is important to study the determinants of vaccine uptake for each specific risk group, in order to better address each gap in vaccination coverage with a targeted and tailored approach.…”

“…61 Other recent research on avian variants of the influenza virus (H9N2) has identified increased positive selection on de novo mutations in obese murine subjects, resulting in a variety of non-synonymous changes. 62 The analysis of the efficacy of antiviral treatment revealed that the use of oseltamivir did not positively impact virus clearance in obese mice, and no resistance mutations were identified. However, it led to phenotypic resistance in vitro.…”