The Relevance of a Physical Active Lifestyle and Physical Fitness on Immune Defense: Mitigating Disease Burden, With Focus on COVID-19 Consequences

Abstract

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a fast spreading virus leading to the development of Coronavirus Disease-2019 (COVID-19). Severe and critical cases are characterized by damage to the respiratory system, endothelial inflammation, and multiple organ failure triggered by an excessive production of proinflammatory cytokines, culminating in the high number of deaths all over the world. Sedentarism induces worse, continuous, and progressive consequences to health. On the other hand, physical activity provides benefits to health and improves low-grade systemic inflammation. The aim of this review is to elucidate the effects of physical activity in physical fitness, immune defense, and its contribution to mitigate the severe inflammatory response mediated by SARS-CoV-2. Physical exercise is an effective therapeutic strategy to mitigate the consequences of SARS-CoV-2 infection. In this sense, studies have shown that acute physical exercise induces the production of myokines that are secreted in tissues and into the bloodstream, supporting its systemic modulatory effect. Therefore, maintaining physical activity influence balance the immune system and increases immune vigilance, and also might promote potent effects against the consequences of infectious diseases and chronic diseases associated with the development of severe forms of COVID-19. Protocols to maintain exercise practice are suggested and have been strongly established, such as home-based exercise (HBE) and outdoor-based exercise (OBE). In this regard, HBE might help to reduce levels of physical inactivity, bed rest, and sitting time, impacting on adherence to physical activity, promoting all the benefits related to exercise, and attracting patients in different stages of treatment for COVID-19. In parallel, OBE must improve health, but also prevent and mitigate COVID-19 severe outcomes in all populations. In conclusion, HBE or OBE models can be a potent strategy to mitigate the progress of infection, and a coadjutant therapy for COVID-19 at all ages and different chronic conditions.

Keywords: COVID-19; home-based exercise; immune system; sedentarism; social isolation.

Figure 1

Inflammatory responses during SARS-CoV-2 infection. (A) Virus entry – nasal epithelial cells and alveolar type II epithelial cells: (1) when SARS-CoV-2 infects cells expressing the surface receptors ACE2 and TMPRSS2, (2) the active replication and (3) release of the virus induces (4) the death of host cells. (5) These cells will then release DAMPs, including ATP and viral RNA which will be (6) recognized by neighboring epithelial cells, endothelial cells, and alveolar macrophages. (7) Proinflammatory cytokines and chemokines (including IL-6, TNF, IL-1β, IP-10, MIP1α, MIP1β, and MCP1), will be generated by those cells. (8) These proteins attract monocytes, macrophages, T cells, and NK cells (which will secrete IFNγ) to the site of infection, promoting further inflammation. (B) Lung/alveolar immune response: in a healthy immune response (left side), alveolar macrophages recognize neutralized viruses and apoptotic cells and clear them by phagocytosis. The initial inflammation attracts virus-specific T and NK cells to the site of infection, where they can eliminate the infected cells before the virus spreads. In addition, neutralizing antibodies can block viral infection and CD4 T cells mediate efficient immune response. Altogether, these processes lead to clearance of the virus and minimal lung damage, resulting in recovery and maintaining vascular integrity. In a dysfunctional immune response (right side), this may lead to further accumulation of immune cells (massive infiltration of monocytes, T cells, NK cells macrophages, and neutrophils in the lungs) causing overproduction of proinflammatory cytokines, which eventually damages the lung structure leading to pulmonary edema and pneumonia. Moreover, the NLRP3 inflammasome is induced by SARS-CoV-2 in monocytes and epithelial cells, which will result in cell death and the release of IL-18, IL-1β, and Casp1p20. The resulting cytokine storm circulates to other organs, leading to multi-organ damage and defective systemic immune response, with decreases CD8 T cells and NK cells as well as decreases cytotoxic capacity. Moreover, SARS-CoV-2 affects vascular epithelial cells leading to endotheliitis development, and consequent dysfunction and death of endothelial cells. In addition, accumulation of immune cells and inflammatory cytokines might lead to loss of inter-endothelial junctions which contribute to increased vascular permeability and vascular leakage. The increased vascular leakage leads to pulmonary edema. Moreover, activation of the coagulation pathway with the accumulation of D-dimers and secretion of inflammatory cytokines by both epithelial cells and immune cells contribute to the systemic inflammatory response observed in severe/critical COVID-19 patients. ACE2, angiotensin-converting enzyme 2; DAMPs, damage-associated molecular patterns; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony stimulating factor; IP-10, interferon gamma-induced protein-10; MIP1, macrophage inflammatory protein 1; TNF, tumor necrosis factor; NLRP3, NLR family pyrin domain containing 3; NK, natural killer cell; Casp1p20, Caspase-1 subunit p20.

Figure 2

Mechanisms by which SARS-CoV-2 promotes muscle wasting and sarcopenia. A proposed mechanism is attributed to the direct viral infection, given that ACE receptors are widely expressed in skeletal muscle, especially in satellite cells. Another mechanism is attributed to the interaction between SARS-CoV-2 and the ACE2 receptor in respiratory epithelial cells that diminishes the biodisponibility of the ACE2 receptor. This promotes a deregulation in the renin-angiotensin-system with elevation in Ang II and decreasing in Ang 1-7. Ang II leads to increased levels of myostatin and IL-6 and decreased IGF-1 expression. Myostatin modulates the intracellular signaling molecules SMAD2/SMAD3, leading to increased expression of atrogens, such as MuRF-1 and atrogin-1, and inhibits PI3K/Akt/mTOR signaling. Moreover, increased IL-6 expression plays a role through SOCS3 which also inhibits the IGF1-R signaling pathway. Together, these activities promote increased protein breakdown and decrease protein synthesis in muscle, which leads to muscle wasting and disability. Ang, angiotensin; MuRF-1, muscle ring finger 1; IGF1, insulin-like growth factor 1; IGF1-R, insulin-like growth factor 1 receptor; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; SOCS, suppressor of cytokine signaling.

Figure 3

Effects of exercise and inactivity on physical health and the risk of severe disease upon viral infections. Inactivity is described as a risk factor for sarcopenia, reduced muscle function and functionality, cardiovascular and metabolic diseases, impaired immune function and immunosenescence, but also it has been associated with impairing energy expenditure, increasing total body and abdominal fat. On the other hand, physically active individuals have improved T cell responses, decreased levels of lung inflammation and bacterial pneumonia, improved lung function, stronger and long-lasting antibody responses to the influenza vaccine, decreased immunosenescence, increased anti-inflammatory capacity, and decreased upper respiratory tract infection (URTI) incidence and symptoms.