Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2–induced lung exudative vasculitis and predicts COVID-19 severity

Iwamura, Chiaki; Hirahara, Kiyoshi; Kiuchi, Masahiro; Ikehara, Sanae; Azuma, Kazuhiko; Shimada, Tadanaga; Kuriyama, Sachiko; Ohki, Syota; Yamamoto, Emiri; Inaba, Yosuke; Shiko, Yuki; Aoki, Ami; Kokubo, Kota; Hirasawa, Rui; Hishiya, Takahisa; Tsuji, Kaori; Nagaoka, Tetsutaro; Ishikawa, Satoshi; Kojima, Akira; Mito, Haruki; Hase, Ryota; Kasahara, Yasunori; Kuriyama, Naohide; Tsukamoto, Tetsuya; Nakamura, Sukeyuki; Urushibara, Takashi; Kaneda, Satoru; Sakao, Seiichiro; Tobiume, Minoru; Suzuki, Yoshio; Tsujiwaki, Mitsuhiro; Kubo, Terufumi; Hasegawa, Tadashi; Nakase, Hiroshi; Nishida, Osamu; Takahashi, Kazuhisa; Baba, Komei; Iizumi, Yoko; Okazaki, Toshiya; Kimura, Motoko; Yoshino, Ichiro; Igari, Hidetoshi; Nakajima, Hiroshi; Suzuki, Takuji; Hanaoka, Hideki; Nakada, Taka‐aki; Ikehara, Yuzuru; Yokote, Koutaro; Nakayama, Toshinori

doi:10.1073/pnas.2203437119

Cited by 18 publications

(17 citation statements)

References 54 publications

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“…There was a significant increase in S100A9 in bronchiolar ROIs of Delta‐ and Omicron‐infected lungs, without differential expression between lungs infected with both variants. THBS1, which is involved in the platelet activation‐related pathway, was upregulated in fatal COVID‐19 cases compared to moderate cases 32 . Delta‐ and Omicron‐infected lungs had significant gene enrichment in alveolar ROIs.…”

Section: Discussionmentioning

confidence: 96%

“…THBS1, which is involved in the platelet activation-related pathway, was upregulated in fatal COVID-19 cases compared to moderate cases. 32 Deltaand Omicron-infected lungs had significant gene enrichment in alveolar ROIs. These results suggested that both SARS-CoV-2 variants represent severe disease progression in macaques at an early infection stage.…”

Section: Spatial Transcriptomic Profile Of Host Response To Delta And...mentioning

confidence: 94%

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Comparative spatial transcriptomic profiling of severe acute respiratory syndrome coronavirus 2 Delta and Omicron variants infections in the lungs of cynomolgus macaques

Kim

Baek

et al. 2023

Journal of Medical Virology

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Recently emerging severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron variants are generally less pathogenic than previous strains. However, elucidating the molecular basis for pulmonary immune response alterations is challenging owing to the virus's heterogeneous distribution within complex tissue structure. Here, we revealed the spatial transcriptomic profiles of pulmonary microstructures at the SARS‐CoV‐2 infection site in the nine cynomolgus macaques upon inoculation with the Delta and Omicron variants. Delta‐ and Omicron‐infected lungs had upregulation of genes involved in inflammation, cytokine response, complement, cell damage, proliferation, and differentiation pathways. Depending on the tissue microstructures (alveoli, bronchioles, and blood vessels), there were differences in the types of significantly upregulated genes in each pathway. Notably, a limited number of genes involved in cytokine and cell damage response were differentially expressed between bronchioles of the Delta‐ and Omicron‐infection groups. These results indicated that despite a significant antigenic shift in SARS‐CoV‐2, the host immune response mechanisms induced by the variants were relatively consistent, with limited transcriptional alterations observed only in large airways. This study may aid in understanding the pathogenesis of SARS‐CoV‐2 and developing a clinical strategy for addressing immune dysregulation by identifying potential transcriptional biomarkers within pulmonary microstructures during infection with emerging variants.

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Section: Discussionmentioning

confidence: 96%

Section: Spatial Transcriptomic Profile Of Host Response To Delta And...mentioning

confidence: 94%

Comparative spatial transcriptomic profiling of severe acute respiratory syndrome coronavirus 2 Delta and Omicron variants infections in the lungs of cynomolgus macaques

Kim

Baek

et al. 2023

Journal of Medical Virology

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“…Although there are some cases of the model for the mortality by COVID-19 using methods of machine learning [ [39] , [40] , [41] ], few studies have developed that of the aggravation. In fact, one study recently explored a possibility of a biomarker of the aggravation as a candidate for an explorative variable in the model [ 42 ]. However, we demonstrated that certain risk factors could be available to predict the aggravation as same as the mortality such as the four groups in SUD and ADL.…”

Section: Discussionmentioning

confidence: 99%

Validation of a specialized evaluation system for COVID-19 in Japan: A retrospective, multicenter cohort study

Furuhata

Araki

2023

Journal of Infection and Chemotherapy

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“…The samples were aliquoted and then stored at -80 °C. The details of the enrolled patients are described in our previous study [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

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

Aoki,

Iwamura,

Kiuchi

et al. 2024

J Clin Immunol

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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.

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Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2–induced lung exudative vasculitis and predicts COVID-19 severity

Cited by 18 publications

References 54 publications

Comparative spatial transcriptomic profiling of severe acute respiratory syndrome coronavirus 2 Delta and Omicron variants infections in the lungs of cynomolgus macaques

Comparative spatial transcriptomic profiling of severe acute respiratory syndrome coronavirus 2 Delta and Omicron variants infections in the lungs of cynomolgus macaques

Validation of a specialized evaluation system for COVID-19 in Japan: A retrospective, multicenter cohort study

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

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