Preterm newborns are highly susceptible to
bacterial infections. This susceptibility is regarded as being due to immaturity of multiple pathways of the immune system. However, it is unclear whether a mechanism that unifies these different, suppressed pathways exists. Here, we argue that the immune vulnerability of the preterm neonate is critically related to
arginine depletion.
Arginine, a "conditionally
essential" amino acid, is depleted in acute catabolic states, including
sepsis. Its metabolism is highly compartmentalized and regulated, including by
arginase-mediated hydrolysis. Recent data suggest that
arginase II-mediated
arginine depletion is essential for the innate immune suppression that occurs in newborn models of bacterial challenge, impairing pathways critical for the immune response. Evidence that
arginine depletion mediates protection from immune activation during first gut colonization suggests a regulatory role in controlling gut-derived pathogens. Clinical studies show that plasma
arginine is depleted during
sepsis. In keeping with animal studies, small clinical trials of
L-arginine supplementation have shown benefit in reducing
necrotizing enterocolitis in premature neonates. We propose a novel, broader hypothesis that
arginine depletion during bacterial challenge is a key factor limiting the neonate's ability to mount an adequate immune response, contributing to the increased susceptibility to
infections, particularly with respect to gut-derived
sepsis.