Journal Article

Host inflammatory dynamics reveal placental immune modulation by Group B Streptococcus during pregnancy

Dammann, Allison N, Kuperwaser, Felicia, Ratner, Adam J, Noble, Kristen N, Randis, Tara M, Avital, Gal, Aronoff, David M, Yanai, Itai, Vaz, Michelle J

2023

Overview

Group B Streptococcus (GBS) is a pathobiont that can ascend to the placenta and cause adverse pregnancy outcomes, in part through production of the toxin β‐hemolysin/cytolysin (β‐h/c). Innate immune cells have been implicated in the response to GBS infection, but the impact of β‐h/c on their response is poorly defined. We show that GBS modulates innate immune cell states by subversion of host inflammation through β‐h/c, allowing worse outcomes. We used an ascending mouse model of GBS infection to measure placental cell state changes over time following infection with a β‐h/c‐deficient and isogenic wild type GBS strain. Transcriptomic analysis suggests that β‐h/c‐producing GBS elicit a worse phenotype through suppression of host inflammatory signaling in placental macrophages and neutrophils, and comparison of human placental macrophages infected with the same strains recapitulates these results. Our findings have implications for identification of new targets in GBS disease to support host defense against pathogenic challenge. Synopsis Analyses of placental responses in an ascending infection model show that mice infected with a Group B Streptococcus (GBS) toxin knockout strain show a milder tissue‐level phenotype but their innate immune cells exhibit more inflammation than wild type GBS‐infected counterparts. Comparison of infection with β‐h/c knockout (KO) and wild type (WT) GBS in an ascending model of infection reveals more severe tissue‐level phenotype over time in the WT‐infected group. Transcriptomic analysis reveals a large shift in innate immune cell expression in response to infection. Despite the milder tissue‐level phenotype, β‐h/c KO GBS elicited a more inflammatory phenotype in innate immune cells. Infection of human placental macrophages with the same two strains recapitulated these results on the transcript and protein level and highlighted expression of immunomodulatory genes in β‐h/c KO GBS‐infected cells. Graphical Abstract Analyses of placental responses in an ascending infection model show that mice infected with a Group B Streptococcus (GBS) toxin knockout strain show a milder tissue‐level phenotype but their innate immune cells exhibit more inflammation than WT GBS‐infected counterparts.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Animals / bacterial infection / EMBO19 / EMBO23 / Female / Fetuses / Genotype & phenotype / group B Streptococcus (GBS) / host–pathogen interactions / Humans / Immune system / Immunomodulation / Inflammation / innate immunity / Leukocytes (neutrophilic) / Macrophages / Mice / Pathogens / Phenotypes / Placenta / Placenta - metabolism / Pregnancy / Premature birth / Strain analysis / Streptococcal Infections - metabolism / Streptococcus / Streptococcus agalactiae - genetics / Streptococcus agalactiae - metabolism / Streptococcus infections / Toxins / Transcriptomics