fbpx

Exercise: The Powerful Intervention Needed to Boost Immunity & Fight COVID-19

According to the New England Journal of Medicine, “As the U.S. health care system defines the new normal in the Covid-19 era, it needs a new approach to providing routine preventive care for adults and children [1].” What should this care entail? A vaccine will help our bodies develop immunity to the SARS-CoV-2 virus that causes Covid-19, but it does not eliminate the virus. Stopping a pandemic requires comprehensive prevention strategies. Dr. John J. Ratey, Associate Clinical Professor of Psychiatry at Harvard Medical School and author of Spark: The Revolutionary New Science of Exercise and the Brain, states, “As our human brains evolved, we also became better movers. When we move, we not only treat the body; we transform the mind [2].” In other words, exercise is power. As more research emerges during the pandemic, results point to exercise as a clinical intervention needed to mitigate the symptoms of, and even help prevent, Covid-19. In the following review, we discuss how physical activity reduces the symptoms of Covid-19 and accelerates recovery. We also reveal how exercise can strengthen the immune system to fight the virus right from the start.

Exercise & the Immune System

To understand how exercise helps mitigate or prevent Covid-19, we need to look at how inactivity impacts our immune system. From obesity and diabetes to cardiovascular issues and inflammation, inactivity causes a myriad of negative health issues and comorbidities [3]. Chronic inflammation lowers the immune system, increasing the risk of health issues such as:

  • Excessive lipid accumulation

  • Impaired metabolism

  • Infectious diseases

Fortunately, research continues to discover that exercise has powerful impacts throughout the immune system and beyond. According to one study [3], aerobic activity increases insulin resistance reduction and anti-inflammatory proteins. Research [4] also reveals during and after exercise, pro and anti-inflammatory cytokines release, and lymphocyte circulation and cell recruitment increase. Such practice reduces the incidence, symptom intensity, and mortality in viral infections. These studies suggest exercise boosts immunity and lowers chronic inflammation, but can it protect the body against Covid-19? To answer this question, we need to understand how SARS-CoV-2 attacks the immune system. When our cells sense pathogens, they produce cytokines. Cytokines activate white blood cells (T cells) that begin fighting the virus by blasting them with deadly chemicals and releasing more cytokines. T cells activate B cells that produce antibodies that neutralize the pieces of virus left behind. Covid-19 is intelligent because it understands how the adaptive immune system reacts when foreign bodies appear. The virus takes this tactical knowledge and uses it to invade the body long before it knows it is under attack. Covid-19’s covert operation begins with the angiotensin-converting enzyme-2 or ACE2 receptor.

The Role of ACE2 in Covid-19

ACE2 is present in many tissues, including the lungs, blood vessels, and kidneys. This enzyme is a vital factor in the pathway called the renin-angiotensin-aldosterone system (RAAS). RAAS plays a role in orchestrating two key pathways:

·       Vasoconstriction – narrowing blood vessels, increasing blood pressure, and tissue inflammation.

·       Vasodilator – widening blood vessels, lowering blood pressure, anti-inflammation, and protective actions in the lung, kidney, and heart tissues [5].

ACE2 converts Ang-II to Ang-(1-7), which acts on the Mas receptor. This action lowers/controls blood pressure and tissue inflammation. These effects directly oppose those induced by ACE-Ang-II signaling, where ACE converts Ang-I into Ang-II, acting at the AT1 receptor [6]. This action increases blood pressure and oxidative stress, promoting inflammation. Factors such as smoking and obesity cause the downregulation of the ACE2 receptor axis and an increase in the ACE receptor axis – primarily the rise of Ang-II. Chronic dysregulation can result in conditions such as heart disease. Unfortunately, ACE2 is also a receptor for the SARS-CoV-2 spike protein, through which the virus gains entry to host cells [7]. The binding of the virus to the ACE2 site downregulates the receptor axis. With less ACE2 available to convert Ang-II to Ang-(1-7), Ang-II signaling accelerates. Without the ability for ACE2 to put the brakes on Ang-II, injury and inflammation to tissues occur in Covid-19 patients, especially in the lungs [8].

The Insidious Nature of SARS-CoV-2

After SARS-CoV-2 binds to the ACE2 receptor, the virus subverts the immune system, propagates, and creates several proteins. This is the moment where Covid-19 mounts a hidden and strategic battle. Out of the many proteins created by SARS-CoV-2, the nucleocapsid protein, or N-protein, is one of the virus’ secret weapon. The N-protein blocks interferon (IFN) production, which is critical to preventing cell replication. This hidden feature allows the virus to subvert the host’s initial innate immune response – enabling it to replicate without being noticed by the body [9]. During this sneaky and aggressive operation, the virus activates the dreaded cytokine storm – causing massive inflammation throughout the body. Around a week after the onset of initial symptoms is the decisive moment where the immune system eliminates the virus giving rise to the patient’s recovery – or advances into the lungs [9]. If it makes it into the lungs, an innate response cytokine may be predictive of patients’ clinical course.

How Exercise May Prove a Worthy Adversary to COVID-19

Factors such as obesity can cause the downregulation of the ACE2 receptor axis. This causes problems such as uncontrolled blood pressure, resulting in chronic inflammation and dysregulation of the immune system. What happens to the individual that develops pulmonary issues during Covid-19 and has a co-morbidity like obesity? It creates a perfect storm – increasing the risk of worse outcomes of the virus, such as respiratory failure from acute respiratory distress syndrome (ARDS) – a major cause of death in Covid-19 patients. We know exercise is the most readily available tool to help boost the immune system. However, is it powerful enough to reduce the complications of the virus? One study [10] reports that exercise may lower the risk of Covid-19 infection and minimize the cardiopulmonary sequela during recovery. Exercise increases ACE2, and ACE2 via the production of Ang-(1-7) has anti-inflammatory and anti-fibrotic effects. This action inhibits Ang-II, reducing cytokine release and hindering the signaling of tissue fibrosis pathways. By increasing ACE2, exercise may help reduce pulmonary fibrosis and prevent acute respiratory issues like ARDS.

Physical Activity Boosts Killer Cells & Interferon

When it comes to the immune system, exercise may prove a worthy opponent to Covid-19. Evidence from previous studies [9] suggests that physical activity may help reduce the frequency of upper-respiratory-tract infections (URTIs), especially in those 65 or older. During intense exercise, transient lymphocytosis occurs, followed by a sudden influx of both NK (Natural Killer) and T cells. This outcome is governed by the stimulation of beta-2-adrenergic receptors (stemming from adrenaline released during exercise). This activation boosts T cells and B cells and causes the expansion of bronchial air passages. This action also produces IgM (antibodies) that may help ward off the virus at the pass. Notably, this reduction has been recognized by older individuals whose URTIs incidence per year has been inversely proportional to the amount of energy expenditure utilized during exercise [9].

We know that SARS-CoV-2 produces proteins that block interferon production. This action subverts the host’s immune response – allowing it to replicate undetected. Research shows that physical activity may have a targeted impact on INF and cytokine responses in the bloodstream. One study [9] revealed that post-exercise, peripheral blood mononuclear cell (PBMC) cultures showed a significant increase of IFN-γ and IL-12 compared to their pre-exercise samples.

An Antioxidant with a One-Two Punch

Extracellular Superoxide Dismutase (EcSOD), a powerful antioxidant released during physical activity, can serve as another weapon in reducing inflammation during Covid-19. A review [11] by Zhen Yan of the UVA School of Medicine revealed that research findings strongly support the idea that exercise and boosting EcSOD can prevent or reduce the severity of ARDS in the lungs. The review showed that aerobic and strength training improves muscle action, causing a rise in EcSOD, a potent antioxidant that protects the lung and kidney tissue and reduces inflammation. EcSOD hunts down free radicals and prevents oxidative stress and endothelial damage, fundamental in disease pathologies, including SARS-CoV-2. Research suggests that even a single session of exercise boosts the production of the antioxidant.

Fighting Senescent Cells to Reduce Inflammation

Research also [12] points to fighting Senescent cells to strengthen the immune system and decrease inflammation. Senescent cells secrete a mix of signals known as a senescence-associated secretory phenotype (SASP). These signals spur chronic inflammation, destroy tissues, and encourage nearby cells to become senescent. Exercise, especially muscle toning, can help clear out these cells, making way for healthy new ones. It does this by maintaining immune balance through bone marrow homing and increasing the death of senescent T-cells, thus stimulating the production and release of new cells (i.e., IFN-producing CD8+ T-cells) [9].  Another anti-inflammatory effect of exercise is its capacity to temper the activation of TLRs (toll-like receptors) signaling. TLRs play a role in the innate immune response during SARS-CoV infection. These receptors recognize pathogen-associated molecular patterns derived from microbes [13]. Research [9] finds that physical inactivity correlates with augmented TLRs activation. Conversely, regular exercise decreases the cell-surface expression of TLRs on immune cells. Studies [9] show that moderate exercise can reduce the activation of the NLRP3 inflammasome and IL-1β, a cytokine processed by the inflammasome.

A Future of Promise

In terms of long-term prevention strategies in fighting Covid-19, vaccination is a critical element in this battle – especially in the elderly. A study [14] out of The Journals of Gerontology reports that exercise may enhance an elderly patient’s response to vaccinations. Decreases in immune response with age contribute to the increased frequency of infectious disease among elderly adults. The immune response to vaccines also declines with age. One of the study’s objectives was to identify a connection between physical activity and the immune response to the flu vaccine. The results showed that anti-influenza immunoglobulins IgG and IgM were greater in active subjects than moderately active or sedentary participants. Though these findings are preliminary, the promising takeaway is that practicing healthy behaviors, such as exercise, may minimize the age-related decline of immune function and enhance an older patient’s response to Covid-19 vaccinations.

Recently, physicians Kemar Brown and Hanna Gaggin shared how to manage hypertension and prevent Covid-19. They state, “We strongly encourage taking medications as directed and following healthy lifestyle practices like regular exercise, maintaining a healthy weight, reducing stress, and practicing mindfulness [15].” The pandemic is a prime opportunity for clinicians and the healthcare community to review and improve current infectious disease management protocols and interventions – this includes adding exercise. Mounting research suggests that physical activity is not just a benefit or “alternative” measure, but a powerful clinical tool in fighting the battle against Covid-19.

References:

  1. Horn DM & Hass JS. Covid-19 and the mandate to redefine preventive care. N Engl J Med, 2020. 383:1505-1507.

  2. Ratey JJ (2008). Spark: The Revolutionary New Science of Exercise and the Brain. Little, Brown, and Company.

  3. Inoue DS, et al. Pathophysiological features of obesity and its impact on cognition: Exercise training as a non-pharmacological approach. Curr Pharm Des, 2020. 26(9):916-931.

  4. da Silveira MP, et al. Physical exercise as a tool to help the immune system against COVID-19: An integrative review of the current literature. Clin Exp Med, 2020. 29:1–14.

  5. Tikellis C & Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin-angiotensin system in health and disease. International Journal of Peptides, 2012.

  6. South AM, et al. Controversies of renin-angiotensin system inhibition during the Covid-19 pandemic. Nat Rev Nephrol, 2020. 16: 305–307.

  7. Chowdhury MA, et al. Immune response in Covid-19: A review. Journal of Infection and Public Health, 2020. 13(11): 1619-1629.

  8. Sriram K & Insel P. A hypothesis for pathobiology and treatment of Covid-19: The centrality of ACE1/ACE2 imbalance. Authorea, 2020.

  9. Larenas-Linnemann D, et al. Enhancing innate immunity against virus in times of Covid-19: Trying to untangle facts from fictions. World Allergy Organization Journal, 2020. 13(11).

  10. Heffernan KS & Jae SY. Exercise as medicine for Covid-19: An ACE in the hole? Medical Hypotheses, 2020. 142.

  11. Yan Z & Spaulding HR. Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise. Redox Biol, 2020. 32.

  12. Xu, M et al. Senolytics improve physical function and increase lifespan in old age, 2018. Nat Med. 24:1246–1256.

  13. Kawasaki T & Kawai T. Toll-like receptor signaling pathways. Front. Immunol, 2014. 5:461.

  14. Kohut ML, et al. Exercise and psychosocial factors modulate immunity to influenza vaccine in elderly individuals. The Journals of Gerontology: Series A, 2002. 57(9):557–562.

  15. Gaggin H & Brown K (2020, November 18). Hypertension, health inequities, and implications for Covid-19. Harvard Health. Retrieved from https://www.health.harvard.edu/blog/hypertension-health-inequities-and-implications-for-covid-19-2020111821348.