Browsing by Author "Doster, Ryan S."

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    Antibacterial and Anti-biofilm Activity of the Human Breast Milk Glycoprotein Lactoferrin against Group B Streptococcus
    (Wiley, 2021) Lu, Jacky; Francis, Jamisha D.; Guevara, Miriam A.; Doster, Ryan S.; Eastman, Alison J.; Rogers, Lisa M.; Noble, Kristin N.; Manning, Shannon D.; Damo, Steven M.; Aronoff, David M.; Townsend, Steven D.; Gaddy, Jennifer A.; Medicine, School of Medicine
    Group B Streptococcus (GBS) is an encapsulated Gram-positive human pathogen that causes invasive infections in pregnant hosts and neonates, as well as immunocompromised individuals. Colonization of the human host requires the ability to adhere to mucosal surfaces and circumnavigate the nutritional challenges and antimicrobial defenses associated with the innate immune response. Biofilm formation is a critical process to facilitate GBS survival and establishment of a replicative niche in the vertebrate host. Previous work has shown that the host responds to GBS infection by producing the innate antimicrobial glycoprotein lactoferrin, which has been implicated in repressing bacterial growth and biofilm formation. Additionally, lactoferrin is highly abundant in human breast milk and could serve a protective role against invasive microbial pathogens. This study demonstrates that human breast milk lactoferrin has antimicrobial and anti-biofilm activity against GBS and inhibits its adherence to human gestational membranes. Together, these results indicate that human milk lactoferrin could be used as a prebiotic chemotherapeutic strategy to limit the impact of bacterial adherence and biofilm formation on GBS-associated disease outcomes.
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    Group B streptococcal infection of the genitourinary tract in pregnant and non-pregnant patients with diabetes mellitus: an immunocompromised host or something more?
    (Wiley, 2021) Nguyen, Lynsa M.; Omage, Joel I.; Noble, Kristen; McNew, Kelsey L.; Moore, Daniel J.; Aronoff, David M.; Doster, Ryan S.; Pediatrics, School of Medicine
    Group B Streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive bacterium commonly encountered as part of the microbiota within the human gastrointestinal tract. A common cause of infections during pregnancy, GBS is responsible for invasive diseases ranging from urinary tract infections to chorioamnionitis and neonatal sepsis. Diabetes mellitus (DM) is a chronic disease resulting from impaired regulation of blood glucose levels. The incidence of DM has steadily increased worldwide to affecting over 450 million people. Poorly controlled DM is associated with multiple health comorbidities including an increased risk for infection. Epidemiologic studies have clearly demonstrated that DM correlates with an increased risk for invasive GBS infections, including skin and soft tissue infections and sepsis in non-pregnant adults. However, the impact of DM on risk for invasive GBS urogenital infections, particularly during the already vulnerable time of pregnancy, is less clear. We review the evolving epidemiology, immunology, and pathophysiology of GBS urogenital infections including rectovaginal colonization during pregnancy, neonatal infections of infants exposed to DM in utero, and urinary tract infections in pregnant and non-pregnant adults in the context of DM and highlight in vitro studies examining why DM might increase risk for GBS urogenital infection.
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    Group B Streptococcus cpsE is required for serotype V capsule production and aids in biofilm formation and ascending infection of the reproductive tract during pregnancy
    (American Chemical Society, 2021) Noble, Kristen; Lu, Jacky; Guevara, Miriam A.; Doster, Ryan S.; Chambers, Schuyler A.; Rogers, Lisa M.; Moore, Rebecca E.; Spicer, Sabrina K.; Eastman, Alison J.; Francis, Jamisha D.; Manning, Shannon D.; Rajagopal, Lakshmi; Aronoff, David M.; Townsend, Steven D.; Gaddy, Jennifer A.; Pediatrics, School of Medicine
    Group B Streptococcus (GBS) is an encapsulated Gram-positive pathogen that causes ascending infections of the reproductive tract during pregnancy. The capsule of this organism is a critical virulence factor that has been implicated in a variety of cellular processes to promote pathogenesis. Primarily comprised of carbohydrates, the GBS capsule and its synthesis is driven by the capsule polysaccharide synthesis (cps) operon. The cpsE gene within this operon encodes a putative glycosyltransferase that is responsible for the transfer of a Glc-1-P from UDP-Glc to an undecaprenyl lipid molecule. We hypothesized that the cpsE gene product is important for GBS virulence and ascending infection during pregnancy. Our work demonstrates that a GBS cpsE mutant secretes fewer carbohydrates, has a reduced capsule, and forms less biofilm than the wild-type parental strain. We show that, compared to the parental strain, the ΔcpsE deletion mutant is more readily taken up by human placental macrophages and has a significantly attenuated ability to invade and proliferate in the mouse reproductive tract. Taken together, these results demonstrate that the cpsE gene product is an important virulence factor that aids in GBS colonization and invasion of the gravid reproductive tract.
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    Streptococcus agalactiae cadD alleviates metal stress and promotes intracellular survival in macrophages and ascending infection during pregnancy
    (Springer Nature, 2022-09-14) Korir, Michelle L.; Doster, Ryan S.; Lu, Jacky; Guevara, Miriam A.; Spicer, Sabrina K.; Moore, Rebecca E.; Francis, Jamisha D.; Rogers, Lisa M.; Haley, Kathryn P.; Blackman, Amondrea; Noble, Kristen N.; Eastman, Alison J.; Williams, Janice A.; Damo, Steven M.; Boyd, Kelli L.; Townsend, Steven D.; Serezani, C. Henrique; Aronoff, David M.; Manning, Shannon D.; Gaddy, Jennifer A.; Medicine, School of Medicine
    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.
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    Streptococcus agalactiae npx Is Required for Survival in Human Placental Macrophages and Full Virulence in a Model of Ascending Vaginal Infection during Pregnancy
    (American Society for Microbiology, 2022-11-21) Lu, Jacky; Moore, Rebecca E.; Spice, Sabrina K.; Doster, Ryan S.; Guevara, Miriam A.; Francis, Jamisha D.; Noble, Kristen N.; Rogers, Lisa M.; Talbert, Julie A.; Korir, Michelle L.; Townsend, Steven D.; Aronoff, David M.; Manning, Shannon D.; Gaddy, Jennifer A.; Medicine, School of Medicine
    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.
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    Walk before you run: feasibility challenges and lessons learned from the PROCLAIM Study, a multicenter randomized controlled trial of misoprostol for prevention of recurrent C. difficile during COVID-19
    (Elsevier, 2023) Lavieri, Robert R.; Dubberke, Erik R.; McGill, Sarah K.; Bartelt, Luther; Smith, Stephanie A.; Pandur, Balint K.; Phillips, Sharon E.; Vermillion, Krista; Shirey-Rice, Jana; Pulley, Jill; Xu, Yaomin; Lindsell, Christopher J.; Zaleski, Nicole; Jerome, Rebecca; Doster, Ryan S.; Aronoff, David M.; Medicine, School of Medicine
    We analyzed our challenging experience with a randomized controlled trial of misoprostol for prevention of recurrent C. difficile. Despite careful prescreening and thoughtful protocol modifications to facilitate enrollment, we closed the study early after enrolling just 7 participants over 3 years. We share lessons learned, noting the importance of feasibility studies, inclusion of biomarker outcomes, and dissemination of such findings to inform future research design and implementation successes.