Journal
MBIO
Volume 13, Issue 6, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/mbio.02870-22
Keywords
Streptococcus; infection; innate immunity; reactive oxygen species; ROS
Categories
Funding
- National Institutes of Health [NICHD R01 HD090061]
- NIH [T32 HL007411-36S1, 2T32AI112541-06, K08AI151100, K12HD087023, R01AI134036, P30DK058404, CA68485, DK20593, DK58404, DK59637, EY08126]
- Office of Medical Research, Department of Veterans Affairs [I01 BX005352-01]
- NSF [1847804]
- Vanderbilt Faculty Research Scholars award
- Global Alliance To Prevent Prematurity and Stillbirth project [N015615]
- March of Dimes
- National Center for Research Resources [UL1 RR024975-01]
- National Center for Advancing Translational Sciences [2 UL1 TR000445-06]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1847804] Funding Source: National Science Foundation
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This study reveals how group B Streptococcus (GBS) defends itself against oxidative stress in the infected host. The enzyme encoded by the GBS gene npx is an NADH peroxidase that provides defense against macrophage-derived reactive oxygen stress and facilitates infections of the uterus during pregnancy. This enzyme could represent a tractable target for future treatment strategies against invasive GBS infections.
Streptococcus agalactiae, also known as group B Streptococcus (GBS), is a Gram-positive encapsulated bacterium that colonizes the gastrointestinal tract of 30 to 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 the expression of the gene npx, which encodes an NADH peroxidase. GBS mutants with an npx deletion (Delta npx) 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 invading reproductive tissues and is critical for inducing disease progression, including PPROM and preterm birth. Reproductive tissue cytokine production was also significantly diminished in Delta npx mutant-infected animals compared to that in animals infected with wild-type (WT) GBS. Complementation in trans reversed this phenotype, indicating that npx is critical for GBS survival and the initiation of proinflammatory signaling in the gravid host.IMPORTANCE This study sheds new light on the way that group B Streptococcus (GBS) defends itself against oxidative stress in the infected host. The enzyme encoded by the GBS gene npx is an NADH peroxidase that, our study reveals, provides defense against macrophage-derived reactive oxygen stress and facilitates infections of the uterus during pregnancy. This enzyme could represent a tractable target for future treatment strategies against invasive GBS infections. This study sheds new light on the way that group B Streptococcus (GBS) defends itself against oxidative stress in the infected host. The enzyme encoded by the GBS gene npx is an NADH peroxidase that, our study reveals, provides defense against macrophage-derived reactive oxygen stress and facilitates infections of the uterus during pregnancy. This enzyme could represent a tractable target for future treatment strategies against invasive GBS infections.
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