Age-dependent differences in efferocytosis determine the outcome of opsonophagocytic protection from invasive pathogens

In early life, susceptibility to invasive infection skews toward a small subset of microbes, whereas other path-ogens associated with diseases later in life, including Streptococcus pneumoniae (Spn), are uncommon among neonates. To delineate mechanisms behind age-dependent susceptibility, we compared age-specific mouse models of invasive Spn infection. We show enhanced CD11b-dependent opsonophagocytosis by neonatal neutrophils improved protection against Spn during early life. The augmented function of neonatal neutrophils was mediated by higher CD11b surface expression at the population level due to dampened ef-ferocytosis, which also resulted in more CD11bhi "aged"neutrophils in peripheral blood. Dampened effero-cytosis during early life could be attributed to the lack of CD169+ macrophages in neonates and reduced sys-temic expressions of multiple efferocytic mediators, including MerTK. On experimentally impairing efferocytosis later in life, CD11bhi neutrophils increased and protection against Spn improved. Our findings reveal how age-dependent differences in efferocytosis determine infection outcome through the modulation of CD11b-driven opsonophagocytosis and immunity.