Obesity as a Novel Risk Factor for Influenza

Section:

ChooseTop of pageAbstractObesity as a Novel Risk F... <<Obesity and Influenza: Ke...Obesity and Influenza: Tr...ReferencesCITING ARTICLES

Obesity has long been associated with higher risks of chronic diseases; however, recent data highlight obesity’s association with a greater risk of infectious diseases (11, 12). Following the first pandemic influenza outbreak of the 21st century, the 2009 H1N1 swine flu, obesity (body mass index [BMI], ≥30.0 kg/m²) was identified as an independent risk factor for increased morbidity and mortality resulting from pandemic H1N1 (pH1N1) infection (13). Louie and colleagues identified 51% of 534 adult cases of influenza in California during the 2009 H1N1 pandemic outbreak occurring in obese individuals, with 61% of influenza mortality cases happening in obese adults (13). Additionally, compared with healthy-weight adults, obese adults were found to have a higher risk of hospitalization for respiratory illness during seasonal influenza, with 1.45 times the odds of contracting seasonal influenza for adults with BMIs ranging from 30.0 to 34.9 kg/m² and 2.12 times the odds for adults with BMIs greater than or equal to 35.0 kg/m² (14).

This identification of obesity as a high-risk group for influenza infection presents a serious public health problem, given the exponential rise in obesity over the past few decades. Recently, for the first time in recorded human history, obese adults were found to outnumber underweight adults worldwide, suggesting that increases in the prevalence of obesity are not isolated to one particular region but reflective of an overall global trend (15). This alarming rise in the prevalence of obesity, coupled with its identification as a risk factor for influenza, increases the threat of severe infection for the nearly 500 million obese individuals worldwide (16). This observation begs several questions: How does obesity increase the risk of influenza infection? What mechanistic aspects of obesity cause greater lung pathology, complications, and/or mortality? How can data be used to better inform measures of influenza prevention, such as vaccination or therapeutic intervention?

Obesity and Influenza: Key Insights Gleaned from Animal Models

Section:

ChooseTop of pageAbstractObesity as a Novel Risk F...Obesity and Influenza: Ke... <<Obesity and Influenza: Tr...ReferencesCITING ARTICLES

Recent findings using models of obesity have elucidated key insights into possible mechanisms of influenza infection in the obese. Murine models of obesity provide a unique translational option to study influenza’s impact in vivo (17). Similar to epidemiological observations in obese adults, compared with lean mice, mice with diet-induced obesity infected with influenza virus have higher mortality rates (18). Obese mice developed greater lung inflammation and damage, higher numbers of cytotoxic CD8⁺ T cells, and fewer suppressive T-regulatory cells (18, 19). Additionally, impairments in immune responses of obese mice occurred upon secondary influenza infection, whereby a primary sublethal influenza infection stimulated immunological memory much like vaccination. In these studies, compared with lean mice, obese mice infected with pH1N1 showed decreased memory CD8⁺ T-cell production of IFN-γ, a key cytokine involved in influenza clearance (20).

Other studies using mice with diet-induced obesity infected with influenza have demonstrated decreased populations of bone marrow–resident B cells, the primary memory cells responsible for antibody production (21). This lack of memory B-cell development is further supported by the finding that influenza-specific antibodies were absent in obese mice at 35 days postinfection (19). Furthermore, Karlsson and coworkers found that obese mice had lower influenza-specific antibody production than lean mice despite increased production of neutralizing and nonneutralizing influenza-specific antibodies following adjuvant vaccination (22). Furthermore, obese mice had higher mortality even after adjuvant vaccine–stimulated production of influenza-specific antibodies, thus suggesting that obesity-impaired cellular immune responses are responsible for higher morbidity and mortality resulting from influenza (22).

These models of mice with obesity induced by a high-fat diet mimic observations seen in clinical settings. However, the question as to whether obesity or diet influences the outcome of infection remains an inherent limitation of these types of models. In other models, researchers have used global leptin receptor–knockout mice (db/db) to study the effects of obesity in response to influenza infection. Leptin, a hormone produced by adipocytes and responsible for regulating satiety, binds its receptor in the hypothalamus and thus signals a state of fullness. This type of model eliminates diet as a potential confounder because db/db mice become obese when fed a standard chow diet, due to a lack of leptin-stimulated satiety signaling. However, global depletion of leptin receptors also affects other cell types that use leptin signaling.

Compared with wild-type lean mice, leptin receptor–deficient obese mice (db/db) displayed greater mortality, higher measures of lung inflammation, and decreased viral clearance when infected with the pH1N1 influenza virus (23). Interestingly, selectively knocking out leptin receptors by crossing transgenic Cre and fully floxed (fl) mice for macrophages (LysM-Cre^+/+/LepR^fl/fl) and lung epithelial cells (SP-C-Cre^+/+/LepR^fl/fl) of influenza-infected lean mice did not alter viral clearance, lung damage, or mortality compared with wild-type mice (23). These data suggest that leptin signaling in other immune cell types may be critical in the adaptive immune response to influenza virus. Other studies support evidence suggesting that leptin plays a critical role in the immune response of T cells to pathogens through promoting the glycolytic activity of effector T cells (24).

To confirm whether obesity independent of diet accounts for the observed impairments in response to influenza, our laboratory used a hypothalamic leptin receptor–knockout (LepR^H−/−) model in mice. After crossing a fully floxed leptin receptor mouse with a Cre transgenic mouse under control of the Nkx2.1 promoter [C57BL/6J-Tg(Nkx2-1-cre)2S], mice lacking hypothalamic leptin receptors became obese as a result of hyperphagia while consuming the same chow diet as their lean controls (LepR^HFlox/Flox) (18). In this model, hypothalamic leptin–deficient obese mice (LepR^H−/−), compared with lean mice (LepR^HFlox/Flox) fed identical diets, were found to have increased mortality following infection with pH1N1 influenza. Additionally, obese LepR^H−/− mice had fewer CD4⁺ and CD8⁺ T cells as well as reduced numbers and activity of bronchoalveolar lavage T-regulatory cells (18). Interestingly, compared with lean controls, both mice with diet-induced obesity and obese LepR^H−/− mice had altered metabolic profiles in lung tissue following pH1N1 infection (18).

Further investigations revealed that, following influenza infection, obese mice displayed altered metabolic profiles in lung, liver, mesenteric white adipose tissue, serum, urine, and feces (25). These studies demonstrate impairments in the metabolic profile as well as the immune response of obese mice compared with wild-type lean mice in response to influenza infection. Furthermore, leptin may play a critical role in the immune response of specific cell types in response to influenza virus. Obesity is inherently a metabolic condition in which prolonged caloric intake results in hormone and nutrient dysregulation and a proinflammatory environment. This altered metabolic milieu suggests that metabolic factors may account for higher rates of influenza infection and mortality.

Obesity and Influenza: Translational Insights into Possible Mechanisms

Section:

ChooseTop of pageAbstractObesity as a Novel Risk F...Obesity and Influenza: Ke...Obesity and Influenza: Tr... <<ReferencesCITING ARTICLES

In addition to model studies using mice, clinical research studies with human subjects have also yielded great insight into how obesity alters the immune response to influenza. In 2011, our group established an observational clinical study in which participants received the influenza vaccine and underwent pre- and postvaccination venous blood draws to isolate serum and peripheral blood mononuclear cells. We found that at 30 days postvaccination, there were no significant differences in influenza-specific serological responses to the vaccine between healthy-weight, overweight, and obese individuals. Interestingly, however, overweight and obese adults had a greater decline in influenza-specific antibody titers at 1 year postvaccination (26).

In addition, peripheral blood mononuclear cells from influenza-vaccinated healthy-weight, overweight, and obese adults were stimulated with H1N1 influenza virus in vitro. We found that CD4⁺ and CD8⁺ T cells from obese and overweight adults expressed fewer activation and functional markers than those from healthy-weight adults (27). These impairments included less expression of activation markers CD28, CD40 ligand, CD69, and IL-12R as well as reduced expression of IFN-γ and granzyme B, critical cytokines produced by effector T cells involved in influenza clearance (25). Additionally, there were no differences in dendritic cell activation or function, suggesting that obesity affects T-cell activation and function independently of antigen presentation (25).

In the 2013–2014 and 2014–2015 influenza seasons, our group examined the influenza-specific antibody responses of 1,022 study participants monitored weekly for laboratory confirmed influenza or influenza-like illness. We found that, compared with vaccinated healthy-weight adults, vaccinated obese adults had twice the risk of influenza or influenza-like illness despite equivalent influenza-specific antibody responses to the vaccine (28). This finding suggests that impairments in the cellular immune response, namely CD4⁺ and CD⁺ effector T cells, are responsible for the higher observed risk of obese adults for influenza. This finding challenges the current standard of protection for influenza vaccination. This suggests that obese adults may need alternative approaches to achieve protection from influenza, much like the elderly and immunocompromised.

Obesity, as a metabolic condition, often leads to hyperinsulinemia, hyperleptinemia, and nutrient dysregulation. Furthermore, how T-cell metabolism drives cell homeostasis, proliferation, and function is well established (29, 30). Given impairments of T cells in murine models of influenza infection coinciding with alterations in the metabolic milieu of obese mice, it is plausible that alterations in the metabolic profile of T cells stemming from obesity may drive functional impairments. Recent studies have demonstrated how insulin and leptin signaling in T cells can drive glycolytic profiles of effector T cells, supporting cell proliferation and function (24, 31). Other factors, such as inflammatory cytokines and adipocyte activation of T cells, have been implicated in the skewing of T-cell populations, thus promoting a proinflammatory microenvironment and impairing the immune response to influenza (32–34). However, how excess insulin or leptin signaling, along with other obesogenic factors, alters the metabolic profile and thus the function of these critical immune cells remains unknown.