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Browsing by Author "Rogers, Lisa M."
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Item 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 MedicineGroup 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.Item Cytotrophoblasts suppress macrophage-mediated inflammation through a contact-dependent mechanism(Wiley, 2021) Eastman, Alison J.; Vrana, Erin N.; Grimaldo, Maria T.; Jones, Amanda D.; Rogers, Lisa M.; Alcendor, Donald J.; Aronoff, David M.; Medicine, School of MedicineProblem: Gestational membrane (GM) infection provokes inflammation and can result in preterm prelabor rupture of membranes (PPROM). The choriodecidual layer of the GM includes decidual stromal cells (DSC), cytotrophoblasts (CTB), and macrophages (Mφ). Our laboratory has previously shown that DSCs suppress Mφ TNF-α production through secreted prostaglandin E2 . We hypothesized that CTBs would also inhibit Mφ cytokine expression through secreted mediators. Method of study: THP.1 Mφ-like cells with an NF-κB reporter construct or human blood monocyte-derived Mφ were co-cultured with the Jeg3 CTB cell line or primary human CTBs and challenged with group B streptococcus (GBS) or Toll-like receptor (TLR) agonists. Conditioned medium generated from CTB cultures was applied to Mφ cultures before infection or treatment. Alternatively, CTBs were co-incubated with, but physically separated from, Mφ and GBS or TLR-stimulated. NF-κB was assessed via alkaline phosphatase assay, and proinflammatory mediators were assessed by qRT-PCR and ELISA. Results: CTBs suppressed GBS- or TLR-stimulated Mφ NF-κB activity, and TNF-α and MMP9 production. Direct physical contact between CTBs and Mφ was required for full immunosuppression. Immunosuppression could be overcome by increasing the ratio of Mφ to CTB. Conclusions: CTBs limit Mφ NF-κB activation and production of TNF-α and MMP9 through an as-yet unknown, cell-to-cell contact-mediated mechanism. This suppression is distinct from the PGE2 -mediated Mφ TNF-α suppression by DSC, suggesting that DSCs and CTBs regulate Mφ inflammation through distinct mechanisms. How Mφ integrates these signals in an intact GM will be paramount to determining causes and prevention of PPROM.Item Environmental Toxicant Exposure Paralyzes Human Placental Macrophage Responses to Microbial Threat(American Chemical Society, 2023) Stephens, Victoria R.; Moore, Rebecca E.; Spicer, Sabrina K.; Talbert, Julie A.; Lu, Jacky; Chinni, Riya; Chambers, Schuyler A.; Townsend, Steven D.; Manning, Shannon D.; Rogers, Lisa M.; Aronoff, David M.; Vue, Zer; Neikirk, Kit; Hinton, Antentor O., Jr.; Damo, Steven M.; Noble, Kristen N.; Eastman, Alison J.; McCallister, Monique M.; Osteen, Kevin G.; Gaddy, Jennifer A.; Medicine, School of MedicineExposure to environmental toxicants (such as dioxins) has been epidemiologically linked to adverse reproductive health outcomes, including placental inflammation and preterm birth. However, the molecular underpinnings that govern these outcomes in gravid reproductive tissues remain largely unclear. Placental macrophages (also known as Hofbauer cells) are crucial innate immune cells that defend the gravid reproductive tract and help promote maternal-fetal tolerance. We hypothesized that exposure to environmental toxicants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could alter placental macrophage responses to inflammatory insults such as infection. To test this, placental macrophages were cultured in the presence or absence of TCDD and then infected with the perinatal pathogen Group B Streptococcus (GBS). Our results indicate that TCDD is lethal to placental macrophages at and above a 5 nM concentration and that sublethal dioxin exposure inhibits phagocytosis and cytokine production. Taken together, these results indicate that TCDD paralyzes placental macrophage responses to bacterial infection.Item EP4 and EP2 receptor activation of protein kinase A by prostaglandin E2 impairs macrophage phagocytosis of Clostridium sordellii(Wiley Blackwell (Blackwell Publishing), 2014-01) Rogers, Lisa M.; Thelen, Tennille; Fordyce, Krystle; Bourdonnay, Emilie; Lewis, Casey; Yu, Han; Zhang, Junyong; Xie, Jingli; Serezani, Carlos H.; Peters-Golden, Marc; Aronoff, David M.; Department of Microbiology & Immunology, IU School of MedicinePROBLEM: Clostridium sordellii causes endometrial infections, but little is known regarding host defenses against this pathogen. METHOD OF STUDY: We tested the hypothesis that the immunoregulatory lipid prostaglandin (PG) E2 suppresses human macrophage clearance of C. sordellii through receptor-induced increases in intracellular cyclic adenosine monophosphate (cAMP). The THP-1 macrophage cell line was used to quantify C. sordellii phagocytosis. RESULTS: PGE2 increased cAMP levels, activated protein kinase A (PKA), and inhibited the class A scavenger receptor-dependent phagocytosis of C. sordellii. Activation of the EP2 and EP4 receptors increased intracellular cAMP and inhibited phagocytosis, with evidence favoring a more important role for EP4 over EP2. This was supported by EP receptor expression data and the use of pharmacological receptor antagonists. In addition, the PKA isoform RI appeared to be more important than RII in mediating the suppression of ingestion of C. sordellii. CONCLUSION: The endogenous lipid mediator PGE2 impairs human innate immune responses against C. sordellii.Item Folate Receptor Beta Signaling in the Regulation of Macrophage Antimicrobial Immune Response: A Scoping Review(Karger, 2024-02-23) Castelo Branco, Anna C. C.; Rogers, Lisa M.; Aronoff, David M.; Medicine, School of MedicineIntroduction: Folate, vitamin B9, is a water-soluble vitamin that is essential to cellular proliferation and division. In addition to the reduced folate carrier, eukaryotic cells take up folate through endocytosis mediated by one of two GPI-anchored folate receptors (FRs), FRα or FRβ. Two other isoforms of FR exist, FRγ and FRδ, neither of which support endocytic activities of FR signaling. FRβ is expressed primarily by monocytes and macrophages and highly expressed on activated macrophages. Macrophage expression of FRβ suggests a role for this receptor in modulating function of these immune sentinels, particularly as they engage in inflammatory processes. Despite several studies suggesting that folates can suppress inflammatory responses of macrophages to proinflammatory stimuli, there appears to be a lack of basic research examining the role of FRβ in modulating macrophage responses to microbial sensing. We therefore conducted a scoping review to assess evidence within the published literature addressing the question, "what is known about the extent to which FRβ regulates macrophage responses to sensing, and responding to, microorganisms?". Methods: As a strategy for the study selection, we queried articles indexed in the research database PubMed and the search engine Google Scholar (up until August 12, 2023), including combinations of the research words: macrophage, folate receptor beta, FOLR2. Results: We identified 2 relevant articles out of 153 that are worth discussing here, none of which directly addressed our research question. Conclusion: There is an unmet need to better define the contribution of FRβ to regulating the macrophage response to microbes.Item 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 MedicineGroup 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.Item Palmitate and group B Streptococcus synergistically and differentially induce IL-1β from human gestational membranes(Frontiers Media, 2024-05-23) Gaddy, Jennifer A.; Moore, Rebecca E.; Lochner, Jonathan S.; Rogers, Lisa M.; Noble, Kristen N.; Giri, Ayush; Aronoff, David M.; Cliffel, David; Eastman, Alison J.; Medicine, School of MedicineIntroduction: Rupture of the gestational membranes often precedes major pregnancy complications, including preterm labor and preterm birth. One major cause of inflammation in the gestational membranes, chorioamnionitis (CAM) is often a result of bacterial infection. The commensal bacterium Streptococcus agalactiae, or Group B Streptococcus (GBS) is a leading infectious cause of CAM. Obesity is on the rise worldwide and roughly 1 in 4 pregnancy complications is related to obesity, and individuals with obesity are also more likely to be colonized by GBS. The gestational membranes are comprised of several distinct cell layers which are, from outermost to innermost: maternally-derived decidual stromal cells (DSCs), fetal cytotrophoblasts (CTBs), fetal mesenchymal cells, and fetal amnion epithelial cells (AECs). In addition, the gestational membranes have several immune cell populations; macrophages are the most common phagocyte. Here we characterize the effects of palmitate, the most common long-chain saturated fatty acid, on the inflammatory response of each layer of the gestational membranes when infected with GBS, using human cell lines and primary human tissue. Results: Palmitate itself slightly but significantly augments GBS proliferation. Palmitate and GBS co-stimulation synergized to induce many inflammatory proteins and cytokines, particularly IL-1β and matrix metalloproteinase 9 from DSCs, CTBs, and macrophages, but not from AECs. Many of these findings are recapitulated when treating cells with palmitate and a TLR2 or TLR4 agonist, suggesting broad applicability of palmitate-pathogen synergy. Co-culture of macrophages with DSCs or CTBs, upon co-stimulation with GBS and palmitate, resulted in increased inflammatory responses, contrary to previous work in the absence of palmitate. In whole gestational membrane biopsies, the amnion layer appeared to dampen immune responses from the DSC and CTB layers (the choriodecidua) to GBS and palmitate co-stimulation. Addition of the monounsaturated fatty acid oleate, the most abundant monounsaturated fatty acid in circulation, dampened the proinflammatory effect of palmitate. Discussion: These studies reveal a complex interplay between the immunological response of the distinct layers of the gestational membrane to GBS infection and that such responses can be altered by exposure to long-chain saturated fatty acids. These data provide insight into how metabolic syndromes such as obesity might contribute to an increased risk for GBS disease during pregnancy.Item Persistent bacteremia and psoas abscess caused by a lethal toxin-deficient Paeniclostridiumsordellii(Elsevier, 2022) Varley, Cara D.; Rogers, Lisa M.; Dixon, Beverly Rea; Bernard, Sarah C.; Lacy, D. Borden; Sulpizio, Emilio; Aronoff, David M.; Townes, John M.; Medicine, School of MedicineWe present a case of persistent bacteremia and psoas abscess from Paeniclostridium sordellii without severe symptoms or the classically associated toxic shock syndrome. Further laboratory evaluation demonstrated that the Paeniclostridium sordellii isolate lacked the lethal toxin gene and there was no cytotoxicity to exposed Vero cells.Item 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 MedicinePerinatal 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.Item 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 MedicineStreptococcus 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.