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Beta-glucan Trained Immunity in Macrophages as Immunotherapy Against Infection

dc.contributor.advisorSherwood, Edward
dc.creatorStothers, Cody Lee Austin
dc.date.accessioned2021-06-22T16:59:45Z
dc.date.created2021-05
dc.date.issued2021-05-17
dc.date.submittedMay 2021
dc.identifier.urihttp://hdl.handle.net/1803/16668
dc.description.abstractInfection remains a common and deadly risk for vulnerable patients due to rising antibiotic resistance, aging populations, and increasingly complex medical care. Prophylactic immunomodulation that bolsters host immunity is a novel strategy to combat infection. Treatment with beta-glucan, the most abundant component of the fungal cell wall, has been shown to provoke resistance to infection. More recently, beta-glucan has been found to induce innate immune memory, also termed trained immunity, in monocytes. However, given that beta-glucan provides prolonged protection against infection, we sought to define the contribution of long-lived macrophages to beta-glucan-induced protection. We show that beta-glucan protected mice from Pseudomonas aeruginosa infection by augmenting recruitment of innate leukocytes to the site of infection and facilitating local clearance of bacteria. Adoptive transfer of beta-glucan-trained macrophages into mice prior to infection also conferred protection. Beta-glucan-trained macrophages adopted an antimicrobial phenotype characterized by enhanced phagocytosis and reactive oxygen species production. Beta-glucan training induced sustained enhancements in glycolytic and oxidative metabolism, along with increased mitochondrial mass and membrane potential. Investigation of the response of macrophages to beta-glucan showed broad transcriptomic changes consistent with early activation of the inflammatory response followed by sustained alterations in transcripts associated with augmented metabolism, cellular differentiation, and antimicrobial function. Trained macrophages constitutively secreted CCL chemokines. Interestingly, induction of the trained phenotype was independent of Dectin-1 or Toll-like receptor-2 receptors commonly associated with beta-glucan recognition. Together, these findings provide evidence that beta-glucan induces a unique trained phenotype in macrophages that drives enhanced antimicrobial function and, ultimately, protection from infection.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.subjectMacrophage
dc.subjectimmunometabolism
dc.subjecttrained immunity
dc.subjectinnate immune memory
dc.titleBeta-glucan Trained Immunity in Macrophages as Immunotherapy Against Infection
dc.typeThesis
dc.date.updated2021-06-22T16:59:45Z
dc.type.materialtext
thesis.degree.namePhD
thesis.degree.levelDoctoral
thesis.degree.disciplineMicrobe-Host Interactions
thesis.degree.grantorVanderbilt University Graduate School
local.embargo.terms2022-05-01
local.embargo.lift2022-05-01
dc.creator.orcid0000-0003-1919-9032
dc.contributor.committeeChairSerezani, Henrique


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