Does High Cardiorespiratory Fitness Confer Some Protection Against Proinflammatory Responses After Infection by SARS-CoV-2?

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in China in late 2019 and has since spread rapidly to every continent in the world. This pandemic continues to cause widespread personal suffering, along with severe pressure on medical and health care providers. The symptoms of SARS-CoV-2 and the subsequent prognosis are worsened in individuals who have preexisting comorbidities prior to infection by the virus. Individuals with obesity or overweight, insulin resistance, and diabetes typically have chronic low-grade inflammation characterized by increased levels of several proinflammatory cytokines and the inflammasome; this state predisposes to greater risk for infection along with more adverse outcomes. Here, we consider whether a high level of cardiorespiratory fitness induced by prior exercise training may confer some innate immune protection against COVID-19 by attenuating the "cytokine storm syndrome" often experienced by "at risk" individuals.

Figure 1

Proposed model for the protective effects of high levels of cardiorespiratory fitness on proinflammatory responses after infection by SARS‐CoV‐2. Binding of the virus SARS‐CoV‐2 to the angiotensin converting enzyme 2 (ACE2) receptor activates the inflammasome, causing the symptomatology in the lungs characteristic of the COVID‐19. Lipopolysaccharide (LPS), and possibly SARS‐CoV‐2, bind to the Toll‐like receptors (TLR) to activate the inflammation pathway. Myeloid differentiation primary response 88 (MyD88) or TIR domain‐containing adapter‐inducing interferon‐β (TRIF) activates tumor necrosis factor receptor associated factor 6 (TRAF6), which in turn stimulates caspase 1, inducing the activation of the inflammasomes as well as tumor growth factor‐β–activated kinase (TAK) and I kappa B kinase (IKK). This cascade ultimately initiates the activation of nuclear factor‐kappa B (NF‐κB) in the nucleus. Subsequently, proinflammatory cytokines, such as tumor necrosis factor‐alpha (TNFα), IL‐6, and IL‐1β, initiate the inflammatory processes in the lung, giving rise to the classic COVID‐19 symptoms. A high level of cardiorespiratory fitness at the onset of symptoms may reduce the susceptibility to infection and be beneficial for host immune defense against a proinflammatory state. Exercise training may act to reduce inflammatory pathways via the following three putative mechanisms: (1) by reducing the expression of the TLRs; (2) by increasing the levels of anti‐inflammatory cytokines such as IL‐10 and IL‐37, which in turn will inhibit the TLR‐inflammation pathway and counteract the inflammatory response induced by the inflammasomes; and (3) by activating the AMPK‐activated protein kinase (AMPK) in the lung, reducing the inflammatory processes by allowing for the transformation of Ang II to Ang 1‐7. [Color figure can be viewed at wileyonlinelibrary.com]