Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease
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.
Authors
- Evangelos Andreakos (ORCID: https://orcid.org/0000-0001-5536-1661)
- Courtney Scallan (ORCID: https://orcid.org/0000-0003-4371-8744)
- Mark M. Davis (ORCID: https://orcid.org/0000-0001-6868-657X)
- Xinrong Guo (ORCID: https://orcid.org/0000-0002-0079-2015)
- Hong Zheng (ORCID: https://orcid.org/0000-0002-8884-8211)
- Pamela B. Conley (ORCID: https://orcid.org/0000-0001-9400-6531)
- Philip A. Mudd (ORCID: https://orcid.org/0000-0002-3860-5473)
- Matthew J. Memoli (ORCID: https://orcid.org/0000-0001-6393-5178)
- Joseph C. González (ORCID: https://orcid.org/0000-0002-3282-0041)
- David Kung‐Chun Chiu (ORCID: https://orcid.org/0000-0002-9700-4707)
- Saborni Chakraborty (ORCID: https://orcid.org/0000-0003-0502-3757)
- Taia T. Wang (ORCID: https://orcid.org/0000-0002-3894-685X)
- Bowie Yik-Ling Cheng (ORCID: https://orcid.org/0000-0003-0794-6133)
- Jeffery K. Taubenberger (ORCID: https://orcid.org/0000-0002-9694-7228)
- Derek E. Byers (ORCID: https://orcid.org/0000-0001-7371-9153)
- Michael Diamond (ORCID: https://orcid.org/0000-0002-8791-3165)
- Patrick S. Hume (ORCID: https://orcid.org/0000-0002-5861-7375)
- William J. Janssen (ORCID: https://orcid.org/0000-0002-6397-3454)
- Katrin F. Chua (ORCID: https://orcid.org/0000-0003-3821-4226)
- Purvesh Khatri (ORCID: https://orcid.org/0000-0002-4143-4708)
- Gene S. Tan
- Desmond L. Edwards
- Greg Coffey
Institutions
- Academy of Athens (GR)
- Biomedical Research Foundation of the Academy of Athens (GR)
- Stanford University (US)
Publication Details
- Journal
- Immunity
- Published
- 2024-11-13
- DOI
- https://doi.org/10.1016/j.immuni.2024.10.002
- Citations
- 23
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 5.38
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Moderna
- National Institutes of Health