Author: Sen Chaudhuri, Arka
Title: The damage-associated molecular pattern molecule S100A4 exerts robust mucosal adjuvant activity
Advisors: Zou, Xiang (HTI)
To, Tony (HTI)
Degree: Ph.D.
Year: 2020
Subject: Adjuvants, Immunologic
Vaccines
Hong Kong Polytechnic University -- Dissertations
Department: Department of Health Technology and Informatics
Pages: xvii, 125 pages : color illustrations
Language: English
Abstract: Lack of a potent and safe mucosal adjuvant has hampered the development of mucosal vaccination largely because of immune tolerance at mucosal sites. Efforts have focused on the exploitation of pathogen-associated molecular pattern (PAMP) molecules (e.g., bacterial toxins). However, a similarly potent class of immune stimulators, the damage-associated molecular pattern (DAMP) molecules, has been largely overlooked. DAMPs are a group of endogenous substances that are released from mammalian cells upon tissue injury. A major advantage of using DAMP molecules as clinically applicable adjuvants lies in its more reliable safety profile because of their human origin. The objective of this study was to identify a potent DAMP molecule that could be exploited for mucosal adjuvanticity using a mouse intranasal immunization model. A panel of DAMP molecules, including S100A4, cyclophilin A, HMGB1, and uric acid, was initially screened for their mucosal adjuvant activity based on capability to augment antigen specific antibody production after immunization and in vitro dendritic cell activation. Uric acid, HMGB1 were unable to deliver any effect, cyclophilin A where promising but S100A4 demonstrated overall superiority, and was chosen for further exploration of its mucosal adjuvant activity. Following intranasal immunization of C57BL/6 mice with OVA, an experimental vaccine antigen, in the presence of S100A4 as an adjuvant, OVA-specific IgG antibody levels in the circulation as well as IgA levels at various mucosal sites were augmented as analysed by ELISA, which was consistent with the enumeration of the number of antibody-forming cells in the bone marrow by ELISPOT. S100A4 dramatically promoted the formation of the germinal centre as evidenced by the expression of GL-7, a recognized marker for the germinal centre, on spleen B cells using confocal microscopy. Interestingly, increased lipid accumulation in the spleens from mice that received S100A4 was detected using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), which also supported S100A4-induced enhancement in germinal centre activity as vigorously proliferating germinal centre B cells require lipid-derived fatty acids for the metabolic energy supply. To my knowledge, this is the first study using this label-free technology to reveal germinal centre responses, which has a broad implication to the study of non-rodent animal models which usually lack commercially available antibodies that recognize germinal centre markers (e.g., GL-7). In addition, S100A4 also facilitated T cell memory responses. Furthermore, my data demonstrated that S100A4 promoted the activation of dendritic cells and mast cells in vitro, two cell types critically important for bridging the innate and adaptive immune responses at the mucosal sites. Of note, the potency of S100A4 as a mucosal adjuvant reached impressive levels comparable to cholera toxin which is described as the gold standard mucosal adjuvant. Last but not least, I demonstrated that S100A4 was able to potently promote humoral immune responses against the spike protein of SARS-CoV-2, the virus causing COVID-19, after intranasal immunization using the spike protein as the vaccine antigen. This study presented compelling data supporting that S100A4 may be exploited as a promising, novel mucosal adjuvant, which has a timely impact on our designing of vaccination strategies especially in the global context of the COVID-19 pandemic. My study has set a solid foundation for further evaluation of the translational significance of S100A4 in boosting mucosal vaccination.
Rights: All rights reserved
Access: open access

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