1) Respiratory viruses invade respiratory mucosal epithelial cells and residential innate immune cells, where they activate Toll-like receptors (TLR) and induce the innate immune response. 2) Activated macrophages (Mφ) and plasmacytoid dendritic cells (pDC) produce IFN-α/β, which prevents viral replication in host cells 3) Additionally, macrophages secrete pro-inflammatory cytokines (IL-6, TNF-α, and IL-1) which stimulate the acute phase inflammatory response. 4) Secretion of IL-12 by pDCs differentiates naïve T_helper (Th0) cells into 5) Th₁ cells, which secrete IL-2 and IFN-γ. 6) IL-2 promotes maturation of T_cytotoxic cells, which recognize antigen presented through MHC 1 on infected cells, and promote apoptosis. 7) IFN-γ stimulates natural killer cells (NK) activity, also leading to increased apoptosis. 8) Apoptotic cells are phagocytized by Mφ, pDCs, and myeloid dendritic cells (mDCs) and the intracellular antigen is cross presented to T_cytotoxic cells. To counter-regulate the inflammatory Th₁ response, naïve Th0 cells differentiate into 9) Th₂ cells which secrete anti-inflammatory cytokines IL-10 and IL-4. 10) IL-10 down regulates the acute phase response, while IL-4 promotes differentiation of B cell into plasma and memory B lymphocytes. 11) Plasma B cells secrete antibodies, particularly IgA, which block viral entry and opsonize infected cells for antibody dependent cellular cytotoxicity.

Influence of exercise on mortality due to influenza (H1N1 Puerto Rico A/8/34) in male 20–24 wk old Balb/c mice. Mean survival was 14 ± 1, 17 ± 2, and 16 ± 3 days for control, moderate and prolonged exercise, respectively. There was a statistically significant difference between control and moderate exercise (log rank = 7.3; p = 0.007), but not between control and prolonged exercise (log rank = 1.1; p = 0.29). (Reprinted from Lowder T, Padgett DA, Woods JA. Moderate exercise protects mice from death due to influenza virus. Brain Behav Immun. 2005;19(5):377–80. Copyright © 2005 Elsevier. Used with permission.)

“J-shaped” model depicting dose-dependent effect of exercise on risk and severity of respiratory tract infections. Sedentary persons are considered to be at normal risk of URTI. Exercise of low-to-moderate intensity or frequency is associated with reduced risk of URTI (3,18,23,25,34) while high-intensity exercise is associated with an increased risk of infection (8,11,24). [Adapted from Nieman DC, Johanssen LM, Lee JW. Infectious episodes in runners before and after a roadrace. J Sports Med Phys Fitness. 1989;29(3):289–96. Copyright © 1989 BMJ Publishing Group Ltd. Used with permission.]

Hypothetical model describing the exercise dose-response effect on Th1 and Th2 immune responses to respiratory viral infection. Moderate exercise transiently increases glucocorticoids, catecholamines and IL-6 to moderate levels resulting in a subtle skewing away from Th1 and towards Th2 while either not affecting or increasing key effector cell functions and allowing for development of an appropriate adaptive immune response. Conversely, intense, prolonged exercise results in a greater, longer lasting increase in glucocorticoids, catecholamines and IL-6 resulting in severe skewing away from Th1 towards Th2, decreased effector cell function and failure to develop appropriate adaptive immune responses.