Putting Together the Pieces: A Metabolic Model of Viral Infection and the Subsequent Development of Asthma

Introduction

The presence of chronic airway inflammation in asthma has been documented for over a century. Allergic disease has continued to markedly increase in prevalence over the past half century associated with urbanization, although this pattern is now starting to level off in some areas (14).Wheezing illnesses in young children are almost exclusively (up to 95%) associated with viral infections (1). Despite the increasing evidence base and understanding the full picture as to the cause of atopic disease, the step between a healthy immune system and that of asthma and atopic disease remains elusive.

The traditionally described pathological mechanism for inhaled allergen sensitization is that inhaled allergens stimulate T helper type 2 (Th2) lymphocyte proliferation, and then subsequently Th2 cytokines, interleukin (IL)-4, IL-5, and IL-13 production and consequent release. IL levels are significantly increased in asthma sufferers (34). These immune changes induce serum immunoglobulin E (IgE) production by B lymphocytes (13).

When an atopic sufferer is exposed to subsequent allergens, increased levels of IgE are then proposed to prime the IgE-mediated allergic response by binding to Fc receptors found on the surface of mast cells and basophils, among others (5). This causes a shift in calcium ions leading to degranulation and the release of proinflammatory mediators by mast cells (24). Strategies to suppress Th2 activity are not successful for all patients. It has been found that other effector lymphocytes, such as Th17 and Th9 cell subtypes, also contribute to the development of asthma, making the full picture more complicated than previously believed (12).

Immune Metabolism and Asthma

T lymphocytes are an important subtype of white blood cell in the cell-mediated immune response to foreign antigens. They have been found to have a dysfunctional role in the development of many autoimmune conditions. T lymphocytes found in asthma sufferers have abnormal function, as they have been noted to have upregulated cell aerobic glycolysis with a high glycolytic activity, resulting in dysfunctional cell metabolism. This change continues to drive inappropriate lymphocyte activation and the resulting increase of proinflammatory mediators (23).

To protect their host, immune cells need to be able to respond promptly to any foreign antigen. To accomplish this, lymphocytes must go through swift energy changes to meet the increased energy demands needed for continued proliferation (15). Further failure to increase glucose consumption by lymphocytes reduces continued sustained cell proliferation (11). Normally, in their resting state, lymphocytes sustain their low energy demand with the metabolic process of oxidative phosphorylation. Ordinarily on activation, lymphocytes meet the now increased energy demands by switching their metabolic state to aerobic glycolysis (8). Aerobic glycolysis is the process of conversion of glucose to lactate in the presence of oxygen in the cell mitochondria. Glycolysis is less energy efficient than oxidative phosphorylation, but it creates energy at a much faster rate (38).

The regulatory T cells are a subpopulation of T cells that modulate the immune system and maintain the resting immune state once an infection is cleared, by suppressing activated immune cells. These regulatory cells have a much smaller metabolic demand than effector cells, much like the metabolic profile of resting effector T cells, and rely predominantly on oxidative phosphorylation (21).

Increased extracellular glucose availability promotes lymphocyte differentiation to effector T cells. Th (effector) cells, which have been implicated in several conditions, have a high glycolytic capacity and can efficiently increase their glycolytic rates with the addition of glucose (9). Metabolic environments have been seen in investigation to control T lymphocyte cell fate and differentiation (6).

The effect of raised glucose levels on lymphocyte function and its mechanism is, however, still to be fully established. It is widely accepted that chronic hyperglycemia disrupts T cell function. A number of articles have reported increased levels of T cell activation in hyperglycemic conditions (17,31,37). Authors investigating T cell function in diabetic patients also found that high glucose levels increased levels of proinflammatory mediators and the number of activated lymphocytes (32). High glucose concentrations may induce macrophage production of IL-12, which can stimulate CD4 cell production of IFN-γ (36). Conversely, to challenge these findings, another study has suggested that ongoing hyperglycemia may reduce T cell activation levels by disruption of calcium signaling (3).

Although recent evidence points chronic immune activation to be a significant aspect in hyperglycemic conditions and type 2 diabetes pathogenesis, this is not conclusive. A systematic review is currently underway to further explore the evidence in this area and the effect of glucose-lowering drugs on T cell function, which may help to address this question (22).

In respect of this article, one study found that blocking aerobic glycolysis inhibits asthmatic T cell proliferation and downregulates cytokine production in vitro, as well as airway inflammation in vivo (23). Lymphocyte metabolism dysfunction therefore could be a key process in the development and maintenance of asthma.

The viral hypothesis of asthma development has been previously proposed and widely debated, particularly the notion of the role of childhood RNA viral infections as the cause of asthma. Many studies have found associations between viral lower respiratory tract infections and the future development of allergic sensitization in children. These discussions are well summarized elsewhere (29). The extent of the involvement of viral infection in the development and persistence of asthma has yet to be fully established. The full pathological mechanism behind the development of asthma in a previously healthy individual has continued to remain elusive, leaving this viral hypothesis open for debate. Recently, authors of a randomized control study concluded that respiratory syncytial virus (RSV) was not a significant predictor of childhood asthma, which challenges this hypothesis, although there was still a clear link to recurrent wheeze in infected patients (28). It has also been shown that RSV infection in infancy may alter subsequent Th1/Th2 immune responses, and thus induce the development of an asthmatic phenotype (19).

The Proposed Metabolic Step Between Health and Asthma

A new pathway was previously proposed for disease characterization, suggesting a mechanism for the development of autoimmune, malignant, and atopic disease from lymphocyte metabolic dysfunction, as a result of different types of viral infection (7). With respect to acute viral infection in asthma, many viruses induce high rates of aerobic glycolysis in infected cells, which induces a rapid intracellular glucose flux to support the evolving viral spread in the host. These findings include viruses proposed to trigger asthma and atopic disease. To support this statement, Rhinovirus, the cause of the common cold and a virus that has also been previously proposed as a factor in asthma development, has recently been found to significantly upregulate glucose intake in infected cells (10).

In relation to this article and this model, two lymphocyte outcomes are proposed after an acute viral infection. First, after an infection, ideally the virus is cleared and the host's immune cells are deactivated by regulatory T cells. Extracellular glucose levels return to normal and the host's lymphocytes are deactivated by the circulating regulatory T cells. The immune system then returns to a normal healthy resting state. Any further environmental allergens will be met with a normal IgE response, which will resolve after clearance of the allergen.

In asthma development, I suggest there is a second host lymphocyte metabolic outcome after viral infection. After clearance of a persisting infection, there is some evidence to suggest there is a significant increase in extracellular glucose availability for effector lymphocytes to metabolize. Mild stress hyperglycemia is common in acute infection and is multifactorial (18,25).

While the extracellular glucose conditions following viral infection have not been widely studied, there have been several recent articles aiming to further investigate this. A recent article by Sestan et al. found transient postinfective extracellular hyperglycemia in skeletal muscle after viral infection (30). In obese patients, this metabolic change was amplified and the patients were more likely to develop prolonged glucose intolerance. Another study exploring herpes simplex virus infection noted persisting local hyperglycemia in inflamed lesions, well after the virus had been cleared by the host's immune system (33).

The longer an infection persists, the higher the local glucose demand is with increased intercellular glucose levels in infected cells (26). Considering the increased oxidative stress, proinflammatory mediators, and glucose demand of prolonged or more severe infection, it would suggest that the level of hyperglycemia would be directly linked to whether an infection persists or can be quickly cleared by the host's immune response. Although this would seem to be an obvious point, this is however a hypothetical statement, given the limited data in postinfective glucose states in mild viral illness, as most of the investigation in this area has been done in patients with sepsis or severe illness, not in isolated respiratory illness.

Despite this, it is worth noting that stress hyperglycemia has been linked to illness severity. In the case of viral infections, elevated fasting plasma glucose induced by H1N1 pneumonia has been proposed as an independent predictor for the severity of infection (35). This is more likely to be related to the high levels of physiological stress associated with this type of infection, rather than the type of respiratory infection linked with asthma development. Further exploration of postinfective metabolic status in infections linked to asthma development would be helpful to strengthen this understanding.

The reason why an infection would be more severe or persist in an individual to cause this model of asthma development is complex. The main factor to consider is the concept of disease tolerance in viral infection. This roughly means that some people are more tolerant to specific viruses and can be infected with a larger number of pathogens without displaying severe illness from the infection. In combination with this, there is resilience to infection, whether an individual can recover promptly from infection. These are both dependent on a number of factors, including host and pathogen genetics, previous pathogen exposure, and environmental factors (20).

Thus, in patients who have reduced immune tolerance to a virus and as a result have a prolonged infection, the current body of evidence could propose that there is increased extracellular glucose availability after the infection has cleared. In an older study, the authors recognized that insulin resistance and the restoration of glycemic control take longer than the immediate recovery period from infection, so this short-term glucose shift would persist after infection (27). This metabolic shift increases glucose availability to local lymphocytes; therefore, by our understanding of lymphocyte function, they could enter a hyperactive state with a high rate of aerobic glycolysis. This is a process of cell dysfunction that we have discussed, which has been found in states of hyperglycemia.

Due to the shift in glucose, T cell differentiation would move away from regulatory T cell types toward effector cell types and further prevent the resolution of the proinflammatory state. The new step proposed by this pathway is the link between the short-term postinfective transient hyperglycemia triggering the known lymphocyte metabolism and immune disturbance seen in asthmatics. Obviously, this step hinges on the assumption in the current evidence of the effect of hyperglycemia on lymphocyte function. Although the current evidence is pointing toward increased activation as we have already discussed, it is not conclusive, and as a result leaves this open for further debate with future investigation.

It would be tempting at this point to discuss the link between asthma development and obesity to these features, but this is likely to be multifactorial (2). It is an interesting topic, given the role of impaired glucose tolerance in postinfective hyperglycemia in the limited evidence we do have available.

Due to their hyperactive state, local effector T lymphocytes will have an overactive response when stimulated by new antigen-presenting cells, subsequently triggering an overproduction of ILs. This would continue the notion of reduced immune tolerance to allergens in asthmatics, as the increased levels of ILs would induce B Cells to increase to an abnormal level of IgE production to the antigen. Thus, if an individual is exposed to an antigen, for example, pollen during this phase of immune dysfunction, larger levels of IgE to the allergen will be produced and continue the known pathway of asthma, thereby leading to a greatly increased reaction on further allergen exposure in the individual (Fig. 1).

OPEN IN VIEWER

FIG. 1.

Represents the proposed metabolic pathway for asthma development from viral infection. (1) Host T lymphocytes and infected cells both increase metabolism of extracellular glucose. (2) The viral infection persists due to host and pathogen factors. (3) The infection is cleared; there is a transient increase in extracellular glucose, which is metabolized by local T lymphocytes. This hyperglycemia results in a dysfunction state of overactivation. (4) When a further allergic antigen is presented to these cells, lymphocytes have an overactive response resulting in increased interleukin and proinflammatory mediator production. (5) This induces B cells to increase IgE production to the allergen. IgE is primed for further allergen exposure resulting in mast cell degranulation and resulting airway inflammation seen in asthma. IgE, immunoglobulin E.

Obviously, further viral infections could repeat this local metabolic dysfunction and lymphocyte overactivation. Hence, this may be why viral infections can trigger further exacerbations and relapses once asthma resolves. Sufferers would be caught in a cycle of increased IgE production to antigens and nonresolving inflammation.

This pathway of infection offers another potential step into the growing understanding of asthma development. Reviewing the current literature base exploring metabolic changes in the immune system in asthma, infection, and health, we can clearly see a pattern emerging. From this, a new metabolic connection in the phase between a healthy immune response and that of atopic disease has been proposed. This further strengthens the role of metabolic dysfunction due to acute viral infection in atopic disease as a therapeutic target.

Conclusion

It is well established that changes in an individual's immune response to viral infections in the genetically predisposed is likely to be the main factor involved in the link between viral infection and subsequent asthma and exacerbations. The mechanism for this is still poorly understood, but the role of metabolic dysfunction has started to be elicited.

This article considers the development of asthma as a condition that may be triggered by short-term disturbed local glucose metabolism following persisting viral infection in those with reduced immune tolerance to the infection. This results in increased lymphocyte aerobic glycolysis and continuing the pathway of known asthma pathophysiology. While these metabolic and lymphocyte changes are not a new concept, it does put forward a step to how this links the lymphocyte metabolic disturbance seen in asthma and the metabolic disturbance seen in a preceding viral illness.

Targeting this step of the pathway once asthma is established would likely not be curative as the IgE response from the resultant lymphocyte dysfunction would already be well established. However, it may have a role in reducing future relapses and symptoms, and this is where current investigation of immunotherapy fits in. This aims to try to recover lymphocyte dysfunction and the lymphocyte population imbalance. An interesting consideration is the role of short-term impaired glucose tolerance in asthma development put forward by this model, how this could be targeted and how significant is this in the role of obesity in asthma?

Considering the severity of preceding infection, this does continue the historic debate about the role of vaccination in preventing asthma development by improving immune tolerance to infection. Several vaccine strategies have been previously tested and the lack of success has been attributed to the complexity of the disease, which includes genetic, viral, and environmental interactions. However, recent advances in rhinovirus immunity and vaccine possibilities may lead to some further progress in this area (16).

There is a lack of data for lymphocyte metabolism in a number of atopic conditions that may further strengthen this understanding, although increased lymphocyte aerobic glycolysis has been seen in rhinitis sufferers (4). Asthma is a complex multifactorial condition and only a relatively small number of atopic conditions, along with viral infections, have been discussed in this article to further build this model. Lymphocyte metabolism has not been widely targeted in the management of asthma and this has been identified as a promising area for further research and development.