Browsing by Author "Aronoff, David M."

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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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    Association of genetically-predicted placental gene expression with adult blood pressure traits
    (Wolters Kluwer, 2023) Hellwege, Jacklyn N.; Stallings, Sarah C.; Piekos, Jacqueline A.; Jasper, Elizabeth A.; Aronoff, David M.; Edwards, Todd L.; Velez Edwards, Digna R.; Medicine, School of Medicine
    Objective: Blood pressure is a complex, polygenic trait, and the need to identify prehypertensive risks and new gene targets for blood pressure control therapies or prevention continues. We hypothesize a developmental origins model of blood pressure traits through the life course where the placenta is a conduit mediating genomic and nongenomic transmission of disease risk. Genetic control of placental gene expression has recently been described through expression quantitative trait loci (eQTL) studies which have identified associations with childhood phenotypes. Methods: We conducted a transcriptome-wide gene expression analysis estimating the predicted gene expression of placental tissue in adult individuals with genome-wide association study (GWAS) blood pressure summary statistics. We constructed predicted expression models of 15 154 genes from reference placenta eQTL data and investigated whether genetically-predicted gene expression in placental tissue is associated with blood pressure traits using published GWAS summary statistics. Functional annotation of significant genes was generated using FUMA. Results: We identified 18, 9, and 21 genes where predicted expression in placenta was significantly associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), respectively. There were 14 gene-tissue associations (13 unique genes) significant only in placenta. Conclusions: In this meta-analysis using S-PrediXcan and GWAS summary statistics, the predicted expression in placenta of 48 genes was statistically significantly associated with blood pressure traits. Notable findings included the association of FGFR1 expression with increased SBP and PP. This evidence of gene expression variation in placenta preceding the onset of adult blood pressure phenotypes is an example of extreme preclinical biological changes which may benefit from intervention.
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    Avoidance of Emergency Care in the Southeastern United States During the COVID-19 Pandemic
    (Oxford University Press, 2022-04-08) Gettler, Erin; Stern, Rebecca; Ni, Bin; Munro, Heather M.; Steinwandel, Mark; Aronoff, David M.; Gupta, Deepak K.; Sanderson, Maureen; Shrubsole, Martha J.; Lipworth, Loren; Medicine, School of Medicine
    In a low-income cohort in the Southeastern United States, 5% of participants avoided emergency medical care during the coronavirus disease 2019 pandemic, primarily due to fear and visitor restrictions. Younger age, self-perceived lower health status, lack of a personal doctor, and decreased income were associated with greater likelihood of deferring emergency care.
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    Business of Medicine: Developing Leaders in Academic Medicine and Learning Health Systems
    (Dove Press, 2024-06-24) Sotto-Santiago, Sylk; Neal, Chemen; Caudill, Darren; Gist, Amanda; Eastwick, Susannah; Palmer, Megan M.; Geraci, Mark W.; Aronoff, David M.; Medicine, School of Medicine
    Purpose: To develop healthcare professionals as clinical leaders in academic medicine and learning health system; and uncover organizational barriers, as well as pathways and practices to facilitate career growth and professional fulfillment. Methods: The Department of Medicine strategic plan efforts prompted the development of a business of medicine program informed by a needs assessment and realignment between academic departments and the healthcare system. The business of medicine leadership program launched in 2017. This descriptive case study presents its 5th year evaluation. Competencies were included from the Physician MBA program and from specific departmental needs and goals. Results: The program hosted a total of 102 clinical faculty. We had a 37% response rate of those retained at Indiana University School of Medicine. Overall, responses conveyed a positive experience in the course. Over 80% of participants felt that they gained skills in professional reflection, professional socialization, goal orientation, critical thinking, and commitment to profession. Financial literacy was overwhelmingly the skill that was reported to be the most valuable. Finance and accounting were mentioned as the most difficult concepts to understand. Familiar concepts included communication, LEAN, and wellness related topics. One hundred percent of participants said they are utilizing the skills gained in this program in their current role and that they would recommend the course to others. Conclusion: Business of medicine courses are more common now with programs describing elements informed by health system operations. However, few programs incorporate aspects of wellness, equity, diversity, inclusion, and health equity. Our program makes the case for multiple ways to develop inclusive leaders through a focused five-month program. It also recognizes that to really impact the learning health system, health professionals need leadership development and leaders suited to work alongside career administrators, all aiming towards a common goal of equitable patient-centered care.
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    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 Medicine
    Problem: 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.
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    Distinct Group B Streptococcus Sequence and Capsule Types Differentially Impact Macrophage Stress and Inflammatory Signaling Responses
    (American Society for Microbiology, 2021-04-16) Flaherty, Rebecca A.; Aronoff, David M.; Gaddy, Jennifer A.; Petroff, Margaret G.; Manning, Shannon D.; Medicine, School of Medicine
    Group B Streptococcus (GBS) is an opportunistic bacterial pathogen that can contribute to the induction of preterm birth in colonized pregnant women and to severe neonatal disease. Many questions regarding the mechanisms that drive GBS-associated pathogenesis remain unanswered, and it is not yet clear why virulence has been observed to vary so extensively across GBS strains. Previously, we demonstrated that GBS strains of different sequence types (STs) and capsule (CPS) types induce different cytokine profiles in infected THP-1 macrophage-like cells. Here, we expanded on these studies by utilizing the same set of genetically diverse GBS isolates to assess ST and CPS-specific differences in upstream cell death and inflammatory signaling pathways. Our results demonstrate that particularly virulent STs and CPS types, such as the ST-17 and CPS III groups, induce enhanced Jun-N-terminal protein kinase (JNK) and NF-κB pathway activation following GBS infection of macrophages compared with other ST or CPS groups. Additionally, we found that ST-17, CPS III, and CPS V GBS strains induce the greatest levels of macrophage cell death during infection and exhibit a more pronounced ability to be internalized and to survive in macrophages following phagocytosis. These data provide further support for the hypothesis that variable host innate immune responses to GBS, which significantly impact pathogenesis, stem in part from genotypic and phenotypic differences among GBS isolates. These and similar studies may inform the development of improved diagnostic, preventive, or therapeutic strategies targeting invasive GBS infections.
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    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 Medicine
    Exposure 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.
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    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 Medicine
    PROBLEM: 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.
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    Epidemiological Trends of Racial Differences in Early- and Late-onset Group B Streptococcus Disease in Tennessee
    (Oxford University Press, 2021) Hamdan, Lubna; Vandekar, Simon; Spieker, Andrew J.; Rahman, Herdi; Ndi, Danielle; Shekarabi, Emily S.; Thota, Jyotsna; Rankin, Danielle A.; Haddadin, Zaid; Markus, Tiffanie; Aronoff, David M.; Schaffner, William; Gaddy, Jennifer A.; Halasa, Natasha B.; Medicine, School of Medicine
    Background: The rates of early-onset group B Streptococcus (GBS) disease (EOGBS) have declined since the implementation of universal screening and intrapartum antibiotic prophylaxis guidelines but late-onset (LOGBS) rates remain unchanged. Racial differences in GBS disease rates have been previously documented, with Black infants having higher rates of EOGBS and LOGBS, but it is not known if these have persisted. Therefore, we sought to determine the differences in EOGBS and LOGBS disease by race over the past decade in Tennessee. Methods: This study used active population-based and laboratory-based surveillance data for invasive GBS disease conducted through Active Bacterial Core surveillance in selected counties across Tennessee. We included infants younger than 90 days and who had invasive GBS disease between 2009 and 2018. Results: A total of 356 GBS cases were included, with 60% having LOGBS. EOGBS and LOGBS had decreasing temporal trends over the study period. Overall, there were no changes in temporal trend noted in the rates of EOGBS and LOGBS among White infants. However, Black infants had significantly decreasing EOGBS and LOGBS temporal trends (relative risk [95% confidence interval], .87 [.79, .96] [P = .007] and .90 [.84-.97] [P = .003], respectively). Conclusions: Years after the successful implementation of the universal screening guidelines, our data revealed an overall decrease in LOGBS rates, primarily driven by changes among Black infants. More studies are needed to characterize the racial disparities in GBS rates, and factors driving them. Prevention measures such as vaccination are needed to have a further impact on disease rates.
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    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 Medicine
    Introduction: 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.