An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity

Francesco Borriello; Valentina Poli; Ellen Shrock; Roberto Spreafico; Xin Liu; Novalia Pishesha; Claire Carpenet; Janet Chou; Marco Di Gioia; Marisa E McGrath; Carly A Dillen; Nora A Barrett; Lucrezia Lacanfora; Marcella E Franco; Laura Marongiu; Yoichiro Iwakura; Ferdinando Pucci; Michael D Kruppa; Zuchao Ma; Douglas W Lowman; Harry E Ensley; Etsuro Nanishi; Yoshine Saito; Timothy R O'Meara; Hyuk-Soo Seo; Sirano Dhe-Paganon; David J Dowling; Matthew Frieman; Stephen J Elledge; Ofer Levy; Darrell J Irvine; Hidde L Ploegh; David L Williams; Ivan Zanoni

doi:10.1016/j.cell.2022.01.009

An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity

Cell. 2022 Feb 17;185(4):614-629.e21. doi: 10.1016/j.cell.2022.01.009. Epub 2022 Feb 10.

Authors

Francesco Borriello¹, Valentina Poli², Ellen Shrock³, Roberto Spreafico⁴, Xin Liu⁵, Novalia Pishesha⁵, Claire Carpenet⁵, Janet Chou², Marco Di Gioia², Marisa E McGrath⁶, Carly A Dillen⁶, Nora A Barrett⁷, Lucrezia Lacanfora⁸, Marcella E Franco⁸, Laura Marongiu⁹, Yoichiro Iwakura¹⁰, Ferdinando Pucci¹¹, Michael D Kruppa¹², Zuchao Ma¹³, Douglas W Lowman¹³, Harry E Ensley¹³, Etsuro Nanishi¹⁴, Yoshine Saito¹⁵, Timothy R O'Meara¹⁵, Hyuk-Soo Seo¹⁶, Sirano Dhe-Paganon¹⁶, David J Dowling¹⁴, Matthew Frieman⁶, Stephen J Elledge³, Ofer Levy¹⁷, Darrell J Irvine¹⁸, Hidde L Ploegh⁵, David L Williams¹², Ivan Zanoni¹⁹

Affiliations

¹ Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Division of Immunology, Boston, MA, USA; Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.
² Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Division of Immunology, Boston, MA, USA.
³ Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Program in Virology, Boston, MA, USA.
⁴ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Harvard Medical School, Boston, MA, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
⁶ University of Maryland School of Medicine, Department of Microbiology and Immunology, Baltimore, MD, USA.
⁷ Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Allergy and Clinical Immunology, Boston, MA, USA.
⁸ Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Division of Immunology, Boston, MA, USA; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
⁹ Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
¹⁰ Center for Animal Disease Models, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
¹¹ Department of Otolaryngology-Head and Neck Surgery, Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
¹² Department of Biomedical Sciences, Quillen College of Medicine, Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
¹³ Department of Surgery, Quillen College of Medicine, Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
¹⁴ Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Precision Vaccines Program, Boston, MA, USA.
¹⁵ Boston Children's Hospital, Precision Vaccines Program, Boston, MA, USA.
¹⁶ Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Biology, Boston, MA, USA.
¹⁷ Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Precision Vaccines Program, Boston, MA, USA; Broad Institute of MIT & Harvard, Cambridge, MA, USA.
¹⁸ Massachusetts Institute of Technology, Department of Biological Engineering and Department of Materials Science and Engineering, Koch Institute for Integrative Cancer Research, Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹⁹ Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Division of Immunology, Boston, MA, USA; Boston Children's Hospital, Division of Gastroenterology, Boston, MA, USA. Electronic address: ivan.zanoni@childrens.harvard.edu.

Abstract

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.

Keywords: Dectin; PAMP; PRR; SARS-CoV-2; coronavirus; inflammation; influenza A virus; innate immunity; interferon; pathogen-associated molecular pattern; pattern recognition receptor; viral glycoprotein.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adjuvants, Immunologic / pharmacology*
Aluminum Hydroxide / chemistry
Animals
Antibodies, Neutralizing / immunology
Antibody Specificity / immunology
Antigens, Viral / immunology*
B-Lymphocytes / immunology
COVID-19 / immunology
COVID-19 / prevention & control
COVID-19 / virology
Candida albicans / chemistry*
Chlorocebus aethiops
Epitopes / immunology
Immunity, Innate
Immunization
Inflammation / pathology
Interferons / metabolism
Lectins, C-Type / metabolism
Ligands
Lung / immunology
Lung / pathology
Lung / virology
Lymph Nodes / immunology
Lymph Nodes / metabolism
Macrophages / metabolism
Mannans / immunology*
Mice
Mice, Inbred C57BL
Paranasal Sinuses / metabolism
Protein Subunits / metabolism
Sialic Acid Binding Ig-like Lectin 1 / metabolism
Solubility
Spike Glycoprotein, Coronavirus / metabolism
T-Lymphocytes / immunology
Transcription Factor RelB / metabolism
Vero Cells
beta-Glucans / metabolism

Substances

Adjuvants, Immunologic
Antibodies, Neutralizing
Antigens, Viral
Epitopes
Lectins, C-Type
Ligands
Mannans
Protein Subunits
Relb protein, mouse
Sialic Acid Binding Ig-like Lectin 1
Spike Glycoprotein, Coronavirus
beta-Glucans
dectin-2, mouse
spike protein, SARS-CoV-2
Transcription Factor RelB
Aluminum Hydroxide
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding