The quantitative and qualitative differences between the immune systems of infants and adults have been extensively investigated in the context of adaptive immunity. Here, we demonstrate that the infantile innate immune system is immature and weak against bacterial infections. Upon infection by Escherichia coli, macrophages from infantile mice showed a lower performance in killing the bacteria. In infant macrophages, bacteria were taken Lip relatively normally and delivered into lysosomal compartments, but not efficiently digested. The inefficient bacterial killing in infant macrophages was correlated with impaired acidification of the lysosomal compartments and reduced lysosomal recruitment of Rab7, an essential component of the acidification process. The acidification defect was not intrinsic to the cells, and was rescued by pretreatment with interferon-gamma. Thus, we propose that the limited capacity of phagosome Maturation is one of the major causes of the high sensitivity to infectious microorganisms during infancy and that the specific cytokine milieu shapes the nature of infantile innate immunity. (C) 2008 Elsevier Inc. All rights reserved.