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dc.rights.licenseRestricted to current Rensselaer faculty, staff and students. Access inquiries may be directed to the Rensselaer Libraries.
dc.contributorLinhardt, Robert J.
dc.contributorBarquera, Blanca L.
dc.contributorKoffas, Mattheos A. G.
dc.contributorWang, Chunyu
dc.contributor.authorKim, So Young
dc.date.accessioned2021-11-03T09:08:03Z
dc.date.available2021-11-03T09:08:03Z
dc.date.created2019-02-20T13:25:51Z
dc.date.issued2018-12
dc.identifier.urihttps://hdl.handle.net/20.500.13015/2356
dc.descriptionDecember 2018
dc.descriptionSchool of Science
dc.description.abstractAdditionally, we evaluated heparin of varying structure for their in vitro potential as antivirals against ZIKV and DENV infection and discovered that heparin surprisingly promotes ZIKV replication in a structure specific manner rather than inhibiting as it does against DENV infection, implying alternative mechanism of involvement of GAGs in ZIKV pathogenesis perhaps through signaling transduction. In the second part of my dissertation work, I investigated the role of GAGs in innate immunity of marine animals against bacterial infection based on their known role in human innate immunity. Interaction of heparin and human antimicrobial peptide (AMP), LL-37, results in activation of immune-cell chemotaxis through formyl peptide receptors (Fprs) during innate immunity. Piscidins 1 and 3, AMPs from Osteichthyes (bony fish) are major component of fish mast cells along with heparin and copper ions as first line of defense. Based on their physicochemical similarities between LL-37 and piscidins 1 and 3, we performed interactome study of piscidins, heparin, and copper ions for their involvement in fish innate immunity against bacterial infection. Using surface plasmon resonance, we learned that micromolar binding interactions between piscidin and heparin are copper-dependent, however this interaction is reduced at acidic pH resembling the environment of phagosomes. We also discovered that heparin weakens antimicrobial activity of piscidin 3 in the presence of Cu2+, however antimicrobial activity of piscidin 1 in the presence of Cu2+ and piscidin-mediated Fpr1 aggregation are not affected by heparin. These findings in my dissertation work furthers our understanding of role of GAGs in microbial pathogenesis in human and marine animal hosts and facilitate rational design of carbohydrate-based antimicrobial therapeutics against these infectious diseases.
dc.description.abstractGlycosaminoglycans (GAGs) are anionic linear polysaccharides with a repeating disaccharide unit. Located on cell surface and extracellular matrix, GAGs are involved in key biological processes including cellular signaling, immunity, and pathogenesis. Various bacterial, viral, and parasitic pathogens successfully invade host cells through interacting with host cell surface GAGs, which result in many pathological processes, such as adhesion, cell-to-cell communication, biochemical cascades, and the immune response. For example, pathogenic flaviviruses like dengue and West Nile virus (DENV & WNV) bind host cell surface GAGs through their surface envelope proteins as a first step in the host cell invasion. In the past few years, another flavivirus Zika virus (ZIKV) has become a global human health threat due to its unique ability to cross placental barrier and cause fetal anomalies in pregnant women, however the role of GAGs had not been investigated prior to my dissertation work. Based on great structural similarities between ZIKV and DENV envelope proteins, we hypothesized that ZIKV envelope protein may also bind GAGs during host cell invasion of placenta. The GAG composition analysis based on liquid chromatography mass spectrometry method revealed that chondroitin sulfate (CS) is the major GAG in human placenta and we discovered subnanomolar binding interactions between human placental CS and ZIKV envelope protein suggesting that ZIKV may utilize host cell surface GAGs during vertical transmission of human placenta. Building on these findings, we further characterized GAG disaccharide composition of additional relevant tissues (Aedes mosquitoes, human fetal neural progenitor cells, and eye tissues) and discussed their potential involvement in ZIKV pathogenesis.
dc.language.isoENG
dc.publisherRensselaer Polytechnic Institute, Troy, NY
dc.relation.ispartofRensselaer Theses and Dissertations Online Collection
dc.subjectBiochemistry and biophysics
dc.titleGlycosaminoglycans in infectious diseases
dc.typeElectronic thesis
dc.typeThesis
dc.digitool.pid179524
dc.digitool.pid179525
dc.digitool.pid179527
dc.digitool.pid179526
dc.rights.holderThis electronic version is a licensed copy owned by Rensselaer Polytechnic Institute, Troy, NY. Copyright of original work retained by author.
dc.description.degreePhD
dc.relation.departmentBiochemistry and Biophysics Program


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