Macrophage renewal in the small intestine governs early-life control of streptococci

Group B Streptococcus (GBS) is both a common intestinal colonizer that is transferred intergenerationally, and a primary cause of neonatal sepsis and meningitis worldwide. Circumstantial evidence suggests that GBS invasive disease can be a colonization accident. However, the innate immune properties that contain the pathogen at the intestinal barrier at the beginning of life are largely unclear. In an enteral GBS colonization model in infant mice, we found that lamina propria (LP) macrophages controlled both GBS colonization densities and invasion in an age-dependent fashion. Notably, LP macrophages turnover and differentiation characteristics were strongly impacted by topology. In the small intestine, monocytes infiltrated the LP from the first day on in response to perinatally acquired microbiota whereas a similar reaction in the colon was driven by the weaning reaction around three weeks of life. Moreover, small intestine macrophages responded to enteral GBS with activation of inflammatory genes, whereas colon macrophages remained largely unaffected. Finally, the response to GBS was dependent on MyD88 as its absence in macrophages led to failure in controlling GBS colonization in both the neonatal and adult intestine. In summary, bona fide resident and bone marrow-derived LP macrophages are driven by distinct cues in small intestine versus colon early in life, and these dynamics directly affect the outcome in the face of virulent streptococci on their way of becoming adapted colonizers.