Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients

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2024年4月22日

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Ami Aoki,
Chiaki Iwamura,
Masahiro Kiuchi,
Kaori Tsuji,
Atsushi Sasaki,
Takahisa Hishiya,
Rui Hirasawa,
Kota Kokubo,
Sachiko Kuriyama,
Atsushi Onodera,
Tadanaga Shimada,
Tetsutaro Nagaoka,
Satoru Ishikawa,
Akira Kojima,
Haruki Mito,
Ryota Hase,
Yasunori Kasahara,
Naohide Kuriyama,
Sukeyuki Nakamura,
Takashi Urushibara,
Satoru Kaneda,
Seiichiro Sakao,
Osamu Nishida,
Kazuhisa Takahashi,
Motoko Y. Kimura,
Shinichiro Motohashi,
Hidetoshi Igari,
Yuzuru Ikehara,
Hiroshi Nakajima,
Takuji Suzuki,
Hideki Hanaoka,
Taka-aki Nakada,
Toshiaki Kikuchi,
Toshinori Nakayama,
Koutaro Yokote,
Kiyoshi Hirahara

摘要

Purpose

Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs.

Methods

We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs.

Results

Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor.

Conclusion

Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.