Chronic Exercise Reduces Illness Severity, Decreases Viral Load, and Results in Greater Anti-Inflammatory Effects than Acute Exercise during Influenza Infection

Epidemiological evidence suggests that moderate exercise may reduce the risk or severity of infection, whereas exhaustive exercise may increase that risk or severity [1–4]. With respect to animal models of respiratory viral infection, moderate exercise tends to decrease morbidity and mortality, whereas prolonged, strenuous exercise increases mortality [5–8]. The modulation of immune responsiveness that occurs as a result of exercise was well studied and was the subject of a number of review articles [9–11]. However, relatively few studies were conducted in the context of infection to determine which immunological changes may be responsible for improved protection from infection. The early response to respiratory viral infection involves production of type I interferons by plasmacytoid dendritic cells, alveolar macrophages, and infected epithelial cells [12–14]. Type I interferons (IFNs) have potent antiviral activity [15] and have more recently been shown to modulate adaptive immune responses [16]. Moreover, monocytes, macrophages, and neutrophils accumulate in the lungs and produce inflammatory cytokines that may contribute to immunopathologic responses [17, 18]. Lung natural killer (NK) cells can be detected 48 h after infection; they respond by producing interferom γ (IFN-γ) and lysing virus-infected cells [19]. Respiratory dendritic cells bridge the innate adaptive response by acquiring viral antigen in the lungs, migrating to regional lymph nodes, and activating CD8+ cells that act to lyse virally infected cells [20, 21]. The potential effect of exercise on each of these parameters in the context of infection remains largely unexplored. Moderate exercise is associated with enhanced activity of several immune parameters that could be important in limiting or clearing viral infection. For example, levels of antigen-specific IFN-γ and interleukin 2 (IL-2) were enhanced by moderate exercise [22], although no effect on immunoglobulin M was found. It was recently found that moderate exercise performed during the early phase of infection is associated with reduced cellular infiltration of the lungs and a shift from a Th1 to a Th2 profile [23]. To our knowledge, that is the only published study to date that has examined the effect of exercise on the immune response at the local site of infection. It remains to be determined whether exercise before infection may have a preventive role in reducing virus load or altering local immune response, given that exercise during infection could potentially have detrimental consequences. It is also unknown whether a single session of exercise, as opposed to regular exercise, may affect the severity of infection. The purpose of the current study was therefore to evaluate the extent to which acute versus regular moderate exercise could alter the severity of influenza infection and the degree of immune responsiveness at the site of infection. With respect to moderate exercise, the aim was to determine whether repeated, moderate exercise confers a protective effect that persists at rest (24 h after the last exercise session, ie, a “training effect”). To test this aim, exercise-trained mice were infected 24 h after exercise. To examine the possibility that a single session of exercise may have a short-term protective effect for a brief period, other mice were infected 15 min after a single session of exercise. Epidemiological studies support the concept that moderate exercise may improve resistance to infection, but the potential mechanisms involved are unknown. It is also unclear how any benefits from repeated single sessions of acute exercise compare with the potential benefits of the trained but rested state. Therefore, we evaluated the effects of acute as well as chronic exercise in our experiments to address this question.