Does hypometabolism constrain innate immune defense?

Many animals routinely make energetic trade-offs to adjust to environmental demands and these trade-offs often have significant implications for survival. For example, environmental hypoxia is commonly experienced by many organisms and is an energetically challenging condition because reduced oxygen availability constrains aerobic energy production, which can be lethal. Many hypoxia-tolerant species downregulate metabolic demands when oxygen is limited; however, certain physiological functions are obligatory and must be maintained despite the need to conserve energy in hypoxia. Of particular interest is immunity (including both constitutive and induced immune functions) because mounting an immune response is among the most energetically expensive physiological processes but maintaining immune function is critical for survival in most environments. Intriguingly, physiological responses to hypoxia and pathogens share key molecular regulators such as hypoxia-inducible factor-1α, through which hypoxia can directly activate an immune response. This raises an interesting question: do hypoxia-tolerant species mount an immune response during periods of hypoxia-induced hypometabolism? Unfortunately, surprisingly few studies have examined interactions between immunity and hypometabolism in such species. Therefore, in this review, we consider mechanistic interactions between metabolism and immunity, as well as energetic trade-offs between these two systems, in hypoxia-tolerant animals but also in other models of hypometabolism, including neonates and hibernators. Specifically, we explore the hypothesis that such species have blunted immune responses in hypometabolic conditions and/or use alternative immune pathways when in a hypometabolic state. Evidence to date suggests that hypoxia-tolerant animals do maintain immunity in low oxygen conditions, but that the sensitivity of immune responses may be blunted.