Summary Maternal infection during pregnancy is associated with adverse outcomes for the fetus, including postnatal cognitive disorders. However, the underlying mechanisms are obscure. We find that bacterial cell wall peptidoglycan (CW), a universal PAMP for TLR2, traverses across the murine placenta into the developing fetal brain. In contrast to adults, CW-exposed fetal brains did not show any signs of inflammation or neuronal death. Instead, the neuronal transcription factor FoxG1 was induced and neuroproliferation leading to a 50% greater density of neurons in the cortical plate was observed. Bacterial infection of pregnant dams followed by antibiotic treatment, which releases CW, yielded the same result. Neuroproliferation required TLR2 and was recapitulated in vitro with fetal neuronal precursor cells and TLR2/6, but not TLR2/1 ligands. The fetal neuroproliferative response correlated with abnormal cognitive behavior in CW-exposed pups following birth. Thus, the bacterial CW-TLR2 signaling axis affects fetal neurodevelopment and may underlie postnatal cognitive disorders.

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Streptococcus pneumoniae encounters a variety of unique cellular situations during colonization of the nasopharynx or invasion into the lungs, the bloodstream, or the central nervous system. The ligand/receptor pairings that enable this progression of disease appear to be shared by many respiratory pathogens suggesting that a primitive “innate invasion” mechanism may underlie the well-known species-specific mechanisms of pathogenesis. That the acute phase of the innate immune response includes elements to interrupt this path supports this concept. However, it also appears that each cell type or organ responds differently to activation of this innate invasion pathway leaving some organs, such as the lung, intact post-infection but others, such as the brain, largely destroyed. This review posits a concept of innate invasion but cautions that organ-specific responses complicate opportunities for a simple approach to protect from organ damage.