Streptococcus agalactiae cadD alleviates metal stress and promotes intracellular survival in macrophages and ascending infection during pregnancy

Abstract

Perinatal infection with Streptococcus agalactiae, or Group B Streptococcus (GBS), is associated with preterm birth, neonatal sepsis, and stillbirth. Here, we study the interactions of GBS with macrophages, essential sentinel immune cells that defend the gravid reproductive tract. Transcriptional analyses of GBS-macrophage co-cultures reveal enhanced expression of a gene encoding a putative metal resistance determinant, cadD. Deletion of cadD reduces GBS survival in macrophages, metal efflux, and resistance to metal toxicity. In a mouse model of ascending infection during pregnancy, the ΔcadD strain displays attenuated bacterial burden, inflammation, and cytokine production in gestational tissues. Furthermore, depletion of host macrophages alters cytokine expression and decreases GBS invasion in a cadD-dependent fashion. Our results indicate that GBS cadD plays an important role in metal detoxification, which promotes immune evasion and bacterial proliferation in the pregnant host.

Streptococcus agalactiae cadD Is Critical for Pathogenesis in the Invertebrate Galleria mellonella Model

“…In response to GBS infections, the host innate immune system deploys a repertoire of antimicrobial strategies to control bacterial burden. Our previous work has shown that the cadD locus, which encodes a putative divalent metal cation resistance determinant, is critical for GBS survival in host phagocytes . We demonstrate here that GBS virulence in the invertebrate Galleria mellonella model requires expression of the cadD locus to survive and replicate in the invertebrate host and contribute to disease progression (such as melanin induction and death) (Figure ).…”

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

“…While GBS has been identified as a perinatal pathogen since the 1930s, there are still major gaps in the knowledge of the pathophysiology of infection and disease outcomes by this bacterium. We have previously observed that GBS interacts with gestational tissue macrophages, and that GBS can invade the reproductive tract in a mouse model of ascending vaginal infection during pregnancy (17, 29, 47). We sought to understand the importance of individual GBS virulence factors that influence the outcome of GBS-macrophage interactions and might also have significance in clinical outcomes during pregnancy.…”

“…Furthermore, macrophages have been implicated as a potential Trojan Horse aiding in dissemination of a variety of microbial pathogens including Candida albicans (58), Mycobacterium tuberculosis (59), Toxoplasma gondii (60), Staphylococcus aureus (61), Cryptococcus neoformans (62), and Chlamydia trachomatis (63). Depletion of host macrophages impedes Chlamydia and GBS dissemination in the reproductive tract (47, 64), demonstrating the important role that intracellular bacterial survival within macrophages plays in bacterial invasion of the reproductive tract. Our previous results indicate that GBS utilizes cadD , a metal resistance determinant, to circumnavigate metal stress within placental macrophages, and enhance bacterial ascension and invasion of the gravid reproductive tract (47).…”

“…Depletion of host macrophages impedes Chlamydia and GBS dissemination in the reproductive tract (47, 64), demonstrating the important role that intracellular bacterial survival within macrophages plays in bacterial invasion of the reproductive tract. Our previous results indicate that GBS utilizes cadD , a metal resistance determinant, to circumnavigate metal stress within placental macrophages, and enhance bacterial ascension and invasion of the gravid reproductive tract (47). Similarly, our current work demonstrates that GBS utilizes npx , a peroxide resistance determinant, to circumnavigate peroxide stress within placental macrophages, and to aid in ascending infection and disease progression during pregnancy.…”

“…Depletion of host macrophages impedes Chlamydia and GBS dissemination in the reproductive tract (47,64), demonstrating the important role that intracellular bacterial survival within macrophages plays in bacterial invasion of the reproductive tract. Our previous results indicate that GBS utilizes cadD, a metal resistance determinant, to circumnavigate metal stress within placental macrophages, and enhance bacterial ascension and invasion of the gravid reproductive tract (47).…”