Abstract
Newborns suffer high rates of mortality due to infectious disease—this has been generally regarded to be the result of an “immature” immune system with a diminished disease-fighting capacity. However, the immaturity dogma fails to explain (i) greater pro-inflammatory responses than adults in vivo and (ii) the ability of neonates to survive a significantly higher blood pathogen burden than of adults. To reconcile the apparent contradiction of clinical susceptibility to disease and the host immune response findings when contrasting newborn to adult, it will be essential to capture the entirety of available host-defense strategies at the newborn’s disposal. Adults focus heavily on the disease resistance approach: pathogen reduction and elimination. Newborn hyperactive innate immunity, sensitivity to immunopathology, and the energetic requirements of growth and development (immune and energy costs), however, preclude them from having an adult-like resistance response. Instead, newborns also may avail themselves of disease tolerance (minimizing immunopathology without reducing pathogen load), as a disease tolerance approach provides a counterbalance to the dangers of a heightened innate immunity and has lower-associated immune costs. Further, disease tolerance allows for the establishment of a commensal bacterial community without mounting an unnecessarily dangerous immune resistance response. Since disease tolerance has its own associated costs (immune suppression leading to unchecked pathogen proliferation), it is the maintenance of homeostasis between disease tolerance and disease resistance that is critical to safe and effective defense against infections in early life. This paradigm is consistent with nearly all of the existing evidence.
Highlights
The world has seen under-five mortality greatly reduced over the last two decades but this progress has least benefited those in the first 28 days of life—the neonatal period—which accounts for nearly half of all under-five deaths [1]
Exogenous supplementations of pro-inflammatory cytokines have been shown to greatly increase mortality in a polymicrobial model of sepsis in neonatal mice [53, 54]. This increased mortality of neonatal sepsis does not relate to a decreased bacterial clearance, as neonatal mice suffer a much greater mortality than adults when challenged with purified toll-like receptor (TLR) agonists in the absence of an infection [24, 26]
The paradigm that neonates are more susceptible to infectious disease than adults is well known, well documented, yet poorly understood
Summary
The world has seen under-five mortality greatly reduced over the last two decades but this progress has least benefited those in the first 28 days of life—the neonatal period—which accounts for nearly half of all under-five deaths [1]. It is not surprising that evolution has selected for a higher threshold that needs to be overcome in early life before a fullfledged immune response can be unleashed [12] This leaves the newborn with a conundrum; a disease avoidance approach has clear limitations [indiscriminately avoiding bacterial colonization is impossible, but would be harmful as the first few days of life are extremely important for establishing a healthy and diverse community of commensal enteric bacteria [25]], while a disease resistance approach carries substantial risk for immunemediated damage [11, 13, 24, 26]. The host microbiota has increasingly been recognized as key to host defense, impacting all aspects of from avoidance (colonization resistance) to immune development; its role and relation to disease tolerance is significant and unexplored, as the tolerance to a range of microbial commensals is essential for a healthy human host [28]
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