Outgrowing the Immaturity Myth: The Cost of Defending From Neonatal Infectious Disease

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.

Keywords: defense; infection; neonate; sepsis; tolerance.

Figure 1

The cost of host-defense strategies in newborn infection. The immune response must be suppressed to a degree in order to allow healthy commensal colonization of the gut, though unchecked suppression can result in gut “leakiness” and lead to infection. Upon infection, newborns must balance the potential self-inflicted harm associated with the pro-inflammatory/antimicrobial response (immunopathology) with the dangers of unencumbered pathogen proliferation and ensuing virulence. A disease tolerance strategy reduces immunopathology and supports microbiome development at the cost of pathogen load, while a disease resistance strategy reduces pathogen load at the cost of microbiome development and immunopathology.

Figure 2

Difference in energy demands of the newborn and adult as it relates to infectious disease. Newborns must devote a large amount of energy toward growth and development which adults are able to spend on maintaining homeostasis. When healthy (A), these differences in energetic demands may not be important, though when fighting infectious disease (B), the newborn is unable to expend the resources required to employ a strategy of disease resistance and must therefore rely more heavily on disease tolerance.