Streptococcus agalactiae npxis required for survival in human placental macrophages and full virulence in a model of ascending vaginal infection during pregnancy

Abstract

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a Gram-positive encapsulated bacterium that colonizes the gastrointestinal tract of 30-50% of humans. GBS causes invasive infection during pregnancy that can lead to chorioamnionitis, funisitis, preterm prelabor rupture of membranes (PPROM), preterm birth, neonatal sepsis, and maternal and fetal demise. Upon infecting the host, GBS encounters sentinel innate immune cells, such as macrophages, within reproductive tissues. Once phagocytosed by macrophages, GBS upregulates expression of the gene, npx, which encodes a NADH peroxidase. GBS mutants with a npx deletion (Δnpx) are exquisitely sensitive to reactive oxygen stress. Furthermore, we have shown that npx is required for GBS survival in both THP-1 and placental macrophages. In an in vivo murine model of ascending GBS vaginal infection during pregnancy, npx is required for invasion of reproductive tissues and is critical for inducing disease progression including PPROM and preterm birth. Reproductive tissue cytokine production was also significantly diminished in Δnpx infected animals compared to those infected with wild type (WT)-GBS. Complementation in trans reversed this phenotype, indicating npx is critical for GBS survival and initiation of proinflammatory signaling in the gravid host.