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

Abstract

In early life, susceptibility to invasive infection skews toward a small subset of microbes, whereas other pathogens 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 efferocytosis, which also resulted in more CD11b^hi "aged" neutrophils in peripheral blood. Dampened efferocytosis during early life could be attributed to the lack of CD169⁺ macrophages in neonates and reduced systemic expressions of multiple efferocytic mediators, including MerTK. On experimentally impairing efferocytosis later in life, CD11b^hi 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.

Keywords: CD11b; complement; early-life immunity; efferocytosis; invasive infection; macrophages; myeloid development; neutrophils; opsonophagocytosis; streptococci.