Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease

Saborni Chakraborty; Bowie Yik-Ling Cheng; Desmond L Edwards; Joseph C Gonzalez; David Kung-Chun Chiu; Hong Zheng; Courtney Scallan; Xinrong Guo; Gene S Tan; Greg P Coffey; Pamela B Conley; Patrick S Hume; William J Janssen; Derek E Byers; Philip A Mudd; Jeffery Taubenberger; Matthew Memoli; Mark M Davis; Katrin F Chua; Michael S Diamond; Evangelos Andreakos; Purvesh Khatri; Taia T Wang

doi:10.1016/j.immuni.2024.10.002

Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease

Immunity. 2024 Nov 7:S1074-7613(24)00482-5. doi: 10.1016/j.immuni.2024.10.002. Online ahead of print.

Authors

Saborni Chakraborty¹, Bowie Yik-Ling Cheng¹, Desmond L Edwards², Joseph C Gonzalez³, David Kung-Chun Chiu⁴, Hong Zheng¹, Courtney Scallan¹, Xinrong Guo¹, Gene S Tan⁵, Greg P Coffey⁶, Pamela B Conley⁶, Patrick S Hume⁷, William J Janssen⁷, Derek E Byers⁸, Philip A Mudd⁹, Jeffery Taubenberger¹⁰, Matthew Memoli¹¹, Mark M Davis¹², Katrin F Chua¹³, Michael S Diamond¹⁴, Evangelos Andreakos¹⁵, Purvesh Khatri¹⁶, Taia T Wang¹⁷

Affiliations

¹ Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ J. Craig Venter Institute, La Jolla, San Diego, CA 92037, USA; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, San Diego, CA 92037, USA.
⁶ Nuvig Therapeutics Inc., Redwood City, CA 94061, USA.
⁷ Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO 80206, USA.
⁸ Department of Medicine, Division of Pulmonology and Critical Care Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
⁹ Department of Emergency Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
¹⁰ Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
¹¹ LID Clinical Studies Unit, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
¹² Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; HHMI, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA; Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
¹⁴ Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
¹⁵ Laboratory of Immunobiology, Center for Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
¹⁶ Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁷ Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].

PMID: 39541970
DOI: 10.1016/j.immuni.2024.10.002

Abstract

While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains.

Keywords: CD209; IgG glycosylation; IgG sialylation; RE1-silencing transcription factor; REST; airway inflammation; alveolar macrophage; antibody signaling; influenza immunity.