Impact of Obesity on Influenza A Virus Pathogenesis, Immune Response, and Evolution

Abstract

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.

Keywords: evolution; immunity; influenza; obesity; pathogenesis.

Figures

Figure 1

Alterations to the host response to IAV in the lung epithelium due to the obese state. The effects of obesity on antiviral processes are summarized by a green + symbol indicating and increased number or process; a red—sign indicating a decreased number or process; a blue ellipses (…) indicating a delayed response; and a yellow interrogation mark (?) indicating conflicting or scarce literature. IFN, interferon; ISGs, interferon-stimulated genes; Ab, antibody; Ag, antigen; Adapted and updated from references (28, 60).

Figure 2

Obesity alters within-host viral population dynamics. Both the amount of viral RNA shed and well as the duration of positive samples for H1N1 virus, as determined by RT-PCR, are increased in obese adults (blue, solid line) as compared to average-weight counterparts (gold, dashed line). Furthermore, our lab determined through experimental evolution of H1N1 virus in OB and DIO mice that serial passaging through an obese host results in the emergence of minor variants that influence pathogenicity and in increased overall viral population diversity. The model is compiled from results in references (124, 125).

Figure 3

Vaccine-elicited responses are diminished in the obese host, leaving the obese population vulnerable to infection. Hemagglutination inhibition titers, the current standard correlate of protection, are equal in obese and lean hosts measured immediately after vaccination but decline more rapidly in the obese population than in the lean population. A greater breadth of HA-specific responses is elicited in lean hosts than in obese hosts, and class switching IgM to IgG may be impaired. Furthermore, the cellular immune responses to vaccination in obese hosts displays reduced activation and maintenance of memory T cells. Ab, antibody; TMEM, T memory cell. The figure is compiled from information in references (44, 47, 78, 110).