With the rising prevalence of obesity has come an increasing awareness of its impact on communicable disease. As a consequence of the 2009 H1N1 influenza A virus pandemic, obesity was identified for the first time as a risk factor for increased disease severity and mortality in infected individuals. Over-nutrition that results in obesity causes a chronic state of meta-inflammation with systemic implications for immunity. Obese hosts exhibit delayed and blunted antiviral responses to influenza virus infection, and they experience poor recovery from the disease. Furthermore, the efficacy of antivirals and vaccines is reduced in this population and obesity may also play a role in altering the viral life cycle, thus complementing the already weakened immune response and leading to severe pathogenesis. Case studies and basic research in human cohorts and animal models have highlighted the prolonged viral shed in the obese host, as well as a microenvironment that permits the emergence of virulent minor variants. This review focuses on influenza A virus pathogenesis in the obese host, and on the impact of obesity on the antiviral response, viral shed, and viral evolution. We comprehensively analyze the recent literature on how and why viral pathogenesis is altered in the obese host along with the impact of the altered host and pathogenic state on viral evolutionary dynamics in multiple models. Finally, we summarized the effectiveness of current vaccines and antivirals in this populations and the questions that remain to be answered. If current trends continue, nearly 50% of the worldwide population is projected to be obese by 2050. This population will have a growing impact on both non-communicable and communicable diseases and may affect global evolutionary trends of influenza virus.

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.

A B S T R A C TAstroviruses are small, non-enveloped, positive-sense, single-stranded RNA viruses that belong to the Astroviridae family. Astroviruses infect diverse hosts and are typically associated with gastrointestinal illness; although disease can range from asymptomatic to encephalitis depending on the host and viral genotype. Astroviruses have high genetic variability due to an error prone polymerase and frequent recombination events between strains. Once thought to be species specific, recent evidence suggests astroviruses can spread between different host species, although the frequency with which this occurs and the restrictions that regulate the process are unknown. Recombination events can lead to drastic evolutionary changes and contribute to cross-species transmission events. This work reviews the current state of research on astrovirus evolution and emergence, especially as it relates to cross-species transmission and recombination of astroviruses.

Sialic acids (Sia) are the primary receptors for influenza viruses and are widely displayed on cell surfaces and in secreted mucus. Sia may be present in variant forms that include O-acetyl modifications at C-4, C-7, C-8, and C-9 positions and N-acetyl or N-glycolyl at C-5. They can also vary in their linkages, including α2-3 or α2-6 linkages. Here, we analyze the distribution of modified Sia in cells and tissues of wild-type mice or in mice lacking CMP-N-acetylneuraminic acid hydroxylase (CMAH) enzyme, which synthesizes N-glycolyl (Neu5Gc) modifications. We also examined the variation of Sia forms on erythrocytes and in saliva from different animals. To determine the effect of Sia modifications on influenza A virus (IAV) infection, we tested for effects on hemagglutinin (HA) binding and neuraminidase (NA) cleavage. We confirmed that 9-O-acetyl, 7,9-O-acetyl, 4-O-acetyl, and Neu5Gc modifications are widely but variably expressed in mouse tissues, with the highest levels detected in the respiratory and gastrointestinal (GI) tracts. Secreted mucins in saliva and surface proteins of erythrocytes showed a high degree of variability in display of modified Sia between different species. IAV HAs from different virus strains showed consistently reduced binding to both Neu5Gc- and O-acetyl-modified Sia; however, while IAV NAs were inhibited by Neu5Gc and O-acetyl modifications, there was significant variability between NA types. The modifications of Sia in mucus may therefore have potent effects on the functions of IAV and may affect both pathogens and the normal flora of different mucosal sites. IMPORTANCE Sialic acids (Sia) are involved in numerous different cellular functions and are receptors for many pathogens. Sia come in chemically modified forms, but we lack a clear understanding of how they alter interactions with microbes. Here, we examine the expression of modified Sia in mouse tissues, on secreted mucus in saliva, and on erythrocytes, including those from IAV host species and animals used in IAV research. These Sia forms varied considerably among different animals, and their inhibitory effects on IAV NA and HA activities and on bacterial sialidases (neuraminidases) suggest a host-variable protective role in secreted mucus.

Metabolic syndrome increases the risk of severe disease due to viral infection. Yet, few6 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 and coronavirus infections. We also discuss the use of various in vitro, in vivo, and ex vivo models to elucidate the contribution of host factors to viral susceptibility, immunity, and disease severity.

Obese individuals are considered a high-risk group for developing severe influenza virus infection. While the exact mechanisms for increased disease severity remain under investigation, obese-mouse models suggest that increased acute lung injury (ALI), potentially due to enhanced viral spread and decreased wound repair, is likely involved. We previously demonstrated that upregulation of the lung epithelial cell β6 integrin during influenza virus infection was involved in disease severity. Knocking out β6 (β6 KO) resulted in improved survival. Of interest, obese mice have increased lung β6 integrin levels at homeostasis. Thus, we hypothesized that the protective effect seen in β6 KO mice would extend to the highly susceptible obese-mouse model. In the current study, we show that crossing β6 KO mice with genetically obese (ob/ob) mice (OBKO) resulted in reduced ALI and impaired viral spread, like their lean counterparts. Mechanistically, OBKO alveolar macrophages and epithelial cells had increased type I interferon (IFN) signaling, potentially through upregulated type I IFN receptor expression, which was important for the enhanced protection during infection. Taken together, our results indicate that the absence of an epithelial integrin can beneficially alter the pulmonary microenvironment by increasing protective type I IFN responses even in a highly susceptible obese-mouse model. These studies increase our understanding of influenza virus pathogenesis in high-risk populations and may lead to the development of novel therapies. IMPORTANCE Obesity is a risk factor for developing severe influenza virus infection. However, the reasons for this are unknown. We found that the lungs of obese mice have increased expression of the epithelial integrin β6, a host factor associated with increased disease severity. Knocking out integrin β6 in obese mice favorably altered the pulmonary environment by increasing type I IFN signaling, resulting in decreased viral spread, reduced lung injury, and increased survival. This study furthers our understanding of influenza virus pathogenesis in the high-risk obese population and may potentially lead to the development of novel therapies for influenza virus infection.

Transmission of influenza A viruses (IAV) between hosts is subject to numerous physical and biological barriers that impose genetic bottlenecks, constraining viral diversity and adaptation. The bottlenecks within hosts and their potential impacts on evolutionary pathways taken during infection are poorly understood. To address this, we created highly diverse IAV libraries bearing molecular barcodes on two gene segments, enabling high-resolution tracking and quantification of unique virus lineages within hosts. Here we show that IAV infection in lungs is characterized by multiple within-host bottlenecks that result in “islands” of infection in lung lobes, each with genetically distinct populations. We perform site-specific inoculation of barcoded IAV in the upper respiratory tract of ferrets and track viral diversity as infection spreads to the trachea and lungs. We detect extensive compartmentalization of discrete populations within lung lobes. Bottleneck events and localized replication stochastically sample individual viruses from the upper respiratory tract or the trachea that become the dominant genotype in a particular lobe. These populations are shaped strongly by founder effects, with limited evidence for positive selection. The segregated sites of replication highlight the jackpot-style events that contribute to within-host influenza virus evolution and may account for low rates of intrahost adaptation.

Factoring significantly into the global burden of influenza disease are high-risk populations that suffer the bulk of infections. Classically, the very young, very old, and pregnant women have been identified as high-risk populations; however, recent research has uncovered several other conditions that contribute to severe infection. By using varied animal models, researchers have identified molecular mechanisms underpinning the increased likelihood for infection due to obesity and malnourishment, as well as insight into the role sex hormones play in antiviral immunity in males, in females, and across the life span. Additionally, novel comorbidity models have helped elucidate the role of chronic infectious and genetic diseases in influenza virus pathogenesis. Animal models play a vital role in understanding the contribution of host factors to influenza severity and immunity. An in-depth understanding of these host factors represents an important step in reducing the burden of influenza among the growing number of people living with one or more chronic medical conditions.