Streptococcus agalactiae npx Is 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 to 50% of humans. GBS causes invasive infection during pregnancy that can lead to chorioamnionitis, funisitis, preterm prelabor rupt...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02870-22 |
| _version_ | 1828114614311714816 |
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| author | Jacky Lu Rebecca E. Moore Sabrina K. Spicer Ryan S. Doster Miriam A. Guevara Jamisha D. Francis Kristen N. Noble Lisa M. Rogers Julie A. Talbert Michelle L. Korir Steven D. Townsend David M. Aronoff Shannon D. Manning Jennifer A. Gaddy |
| author_facet | Jacky Lu Rebecca E. Moore Sabrina K. Spicer Ryan S. Doster Miriam A. Guevara Jamisha D. Francis Kristen N. Noble Lisa M. Rogers Julie A. Talbert Michelle L. Korir Steven D. Townsend David M. Aronoff Shannon D. Manning Jennifer A. Gaddy |
| author_sort | Jacky Lu |
| collection | DOAJ |
| description | ABSTRACT 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 (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 invading reproductive tissues and is critical for inducing disease progression, including PPROM and preterm birth. Reproductive tissue cytokine production was also significantly diminished in Δnpx 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. |
| first_indexed | 2024-04-11T12:28:16Z |
| format | Article |
| id | doaj.art-a4dcbca43151424ab3662c888ebec53d |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-11T12:28:16Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-a4dcbca43151424ab3662c888ebec53d2022-12-22T04:23:52ZengAmerican Society for MicrobiologymBio2150-75112022-12-0113610.1128/mbio.02870-22Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during PregnancyJacky Lu0Rebecca E. Moore1Sabrina K. Spicer2Ryan S. Doster3Miriam A. Guevara4Jamisha D. Francis5Kristen N. Noble6Lisa M. Rogers7Julie A. Talbert8Michelle L. Korir9Steven D. Townsend10David M. Aronoff11Shannon D. Manning12Jennifer A. Gaddy13Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Chemistry, Vanderbilt University, Nashville, Tennessee, USADepartment of Chemistry, Vanderbilt University, Nashville, Tennessee, USADepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Medicine, Indiana University, Indianapolis, Indiana, USADepartment of Chemistry, Vanderbilt University, Nashville, Tennessee, USADepartment of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USADepartment of Chemistry, Vanderbilt University, Nashville, Tennessee, USADepartment of Medicine, Indiana University, Indianapolis, Indiana, USADepartment of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USADepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USAABSTRACT 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 (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 invading reproductive tissues and is critical for inducing disease progression, including PPROM and preterm birth. Reproductive tissue cytokine production was also significantly diminished in Δnpx 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.https://journals.asm.org/doi/10.1128/mbio.02870-22Streptococcusinfectioninnate immunityreactive oxygen speciesROS |
| spellingShingle | Jacky Lu Rebecca E. Moore Sabrina K. Spicer Ryan S. Doster Miriam A. Guevara Jamisha D. Francis Kristen N. Noble Lisa M. Rogers Julie A. Talbert Michelle L. Korir Steven D. Townsend David M. Aronoff Shannon D. Manning Jennifer A. Gaddy Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy mBio Streptococcus infection innate immunity reactive oxygen species ROS |
| title | Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy |
| title_full | Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy |
| title_fullStr | Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy |
| title_full_unstemmed | Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy |
| title_short | Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy |
| title_sort | streptococcus agalactiae npx is required for survival in human placental macrophages and full virulence in a model of ascending vaginal infection during pregnancy |
| topic | Streptococcus infection innate immunity reactive oxygen species ROS |
| url | https://journals.asm.org/doi/10.1128/mbio.02870-22 |
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