骨髄細胞の観点におけるインターフェロン反応遅延と重症化

新型コロナウィルスのワクチンの接種率が半分以上の
イスラエル、アメリカ、イギリスでは
新型コロナウィルスの感染者数が減っています。
特にイスラエルは顕著です。
しかし、ブレークスルー感染
つまりワクチンを接種しても一定割合は感染しますし、
接種から時間が経てば、抗体量も下がってくるので
それによって新型コロナウィルスに感染しやすくなります。
しかし、もう一つの軸として
感染した時の症状の程度というのがあります。
ワクチンを接種すれば、感染したとしても
重症化を防ぐことができるというのは
インフルエンザなどと共通することです。
重症化すると医療リソースを多く投資する必要がありますから
ワクチン以外でも重症化因子、機序を把握する事が重要です。
ー
以前から指摘されている(2-4)28-30のに加えて
Melissa Saichi, Maha Zohra Ladjemi, Sarantis Korniotis(敬称略)ら
フランスの医療研究グループは
細胞単位の解析で重症の患者では
インターフェロンの反応性が落ちていることが示されています(1)。
(Fig.2Dより)
ただし、インターフェロンで逆効果も指摘されています(5)。
おそらくこれは、Ref.(6)Fig.2bで示されるように
インターフェロンが遅れた後、長い期間過剰に放出されることで
逆に組織を損傷している可能性が考えられます。
ー
ここで考えないといけないのは
少なくともインターフェロンの初期の反応性がなぜ落ちているのか？
という点です。
それについていくつか示唆します。
ー
一つは、骨髄性免疫細胞の状況(Landscape:表現型、数、種類)が
リスクが高い人で感染前から異なる可能性です。
例えば、肥満の人は肺の好中球の数が増えると言われています(7,8)。
肥満は重症化のリスク因子で
かつ肺での好中球増加が示されていますから
肥満によって肥満細胞や血液の状態が変わることで
肺胞の組織の状態、周辺の免疫細胞の特性が変わることが考えられます。
Ref.(9)で示されるように
インターフェロンは骨髄系免疫細胞である
樹状細胞、単球からも放出されます。
従って、好中球も含めて肺の骨髄系免疫細胞の状態が
すでに感染前から重症化する人が特異的な状態にある可能性があります。
それによってインターフェロンの新型コロナウィルスに対する
感受性が低下している可能性が考えられます。
ー
一方、マウスでの肺の細胞レベルの加齢の影響について
調べられています(10)。
その中で加齢のマウスにおいて
全体的に転写因子のばらつき(Transcriptional noise)が
加齢マウスで大きいことが示されていますが、
特に好中球が大きくなっていることがわかります(Fig.2より)。
この好中球は細胞外にDNAを放出するNETsがあります。
これが肺の上皮組織のダメージに関係している可能性があります(11)。
ー
上述したインターフェロンの反応性に関わる生理は
cGAS-STING経路です。
この経路によって細胞核の遺伝子に働きかけ
インターフェロンが細胞内から放出されます。
このcGAS-STNIG経路においては
それを誘発させる金属としてマンガン(Mn)が重要であることが
示唆されています(12)。
ただし、普段食生活する中で
マンガンが不足することはほとんどないとされています。
不足すると骨に異常が出るとされています(13)。
しかし、一つ注目すべき微量金属です。
ー
このような遅れは、
B細胞による抗体放出でも指摘されています(14)。
これもおそらくcGAS-STNIG経路の感受性のような
ウィルスに対する抗体産生経路の中の感受性が関係している
と推測しています。

(Reference)
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Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity
Nature Cell Biology (2021)
ー
Author information
Author notes
These authors contributed equally: Melissa Saichi, Maha Zohra Ladjemi, Sarantis Korniotis.
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Affiliations
Université de Paris, INSERM U976, Paris, France
Melissa Saichi, Sarantis Korniotis, Lucile Massenet-Regad, Elise Amblard, Floriane Noel, Jasna Medvedovic & Vassili Soumelis
Institut Cochin, INSERM U1016, CNRS UMR8104, Université de Paris, Paris, France
Maha Zohra Ladjemi, Christophe Rousseau, Zakaria Ait Hamou & Frédéric Pène
Service de Médecine Intensive & Réanimation, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris. Centre & Université de Paris, Paris, France
Maha Zohra Ladjemi, Zakaria Ait Hamou & Frédéric Pène
Université Paris-Saclay, Saint-Aubin, France
Lucile Massenet-Regad
Université de Paris, Centre de Recherches Interdisciplinaires, Paris, France
Elise Amblard
Institut du Cerveau (ICM), Plateforme de Génotypage Séquençage, Paris, France
Yannick Marie & Delphine Bouteiller
Sorbonne Universités, Université Pierre et Marie Curie, Paris, France
Yannick Marie
AP-HP, Hôpital Saint-Louis, Laboratoire d’Immunologie-Histocompatibilité, Paris, France
Vassili Soumelis
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Author information
Affiliations
Champalimaud Center for the Unknown, Lisbon, Portugal
Thiago Carvalho
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Florian Krammer
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
Akiko Iwasaki
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA
Akiko Iwasaki
Howard Hughes Medical Institute, Chevy Chase, MD, USA
Akiko Iwasaki
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Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF
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Author information
Author notes
Daniela F. Quail and Oakley C. Olson: These authors contributed equally to this work.
Affiliations
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA
Daniela F. Quail, Oakley C. Olson, Leila Akkari, Marsha L. Quick, Nir Ben-Chetrit & Johanna A. Joyce
Department of Medicine, Weill Cornell Medical College, New York, New York, 10065, USA
Priya Bhardwaj, I-Chun Chen, Nils Wendel, Nir Ben-Chetrit & Andrew J. Dannenberg
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA
Logan A. Walsh
Ludwig Institute for Cancer Research, Lausanne, 1066, Switzerland
Leila Akkari & Johanna A. Joyce
Department of Oncology, University of Lausanne, Lausanne, 1066, Switzerland
Leila Akkari & Johanna A. Joyce
Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, New York, 10065, USA
Jeanne Walker & Peter R. Holt
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Sheri A. C. McDowell, Robin B. E. Luo, Azadeh Arabzadeh, Samuel Doré, Nicolas C. Bennett, Valérie Breton, Elham Karimi, Morteza Rezanejad, Ryan R. Yang, Katherine D. Lach, Marianne S. M. Issac, Bozena Samborska, Lucas J. M. Perus, Dan Moldoveanu, Yuhong Wei, Benoit Fiset, Roni F. Rayes, Ian R. Watson, Lawrence Kazak, Marie-Christine Guiot, Pierre O. Fiset, Jonathan D. Spicer, Andrew J. Dannenberg, Logan A. Walsh & Daniela F. Quail 
Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration
Nature Cancer (2021)
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Author information
Affiliations
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
Sheri A. C. McDowell, Robin B. E. Luo, Azadeh Arabzadeh, Samuel Doré, Nicolas C. Bennett, Valérie Breton, Elham Karimi, Ryan R. Yang, Bozena Samborska, Lucas J. M. Perus, Dan Moldoveanu, Yuhong Wei, Benoit Fiset, Roni F. Rayes, Ian R. Watson, Lawrence Kazak, Jonathan D. Spicer, Logan A. Walsh & Daniela F. Quail
Department of Physiology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Sheri A. C. McDowell, Nicolas C. Bennett, Lucas J. M. Perus & Daniela F. Quail
Department of Human Genetics, McGill University, Montreal, Quebec, Canada
Robin B. E. Luo, Samuel Doré & Logan A. Walsh
Departments of Psychology and Computer Science, University of Toronto, Toronto, Ontario, Canada
Morteza Rezanejad
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
Ryan R. Yang
Department of Pathology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Katherine D. Lach, Marianne S. M. Issac, Marie-Christine Guiot & Pierre O. Fiset
Department of Biochemistry, McGill University, Montreal, Quebec, Canada
Dan Moldoveanu, Ian R. Watson & Lawrence Kazak
Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
Roni F. Rayes, Jonathan D. Spicer & Daniela F. Quail
Montreal Neurological Institute, McGill University Health Centre, Montreal, Quebec, Canada
Marie-Christine Guiot
Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada
Jonathan D. Spicer
Department of Medicine, Weill Cornell Medical College, New York, New York, USA
Andrew J. Dannenberg
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Author information
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Immunoregulation Laboratory, Francis Crick Institute, London, UK
Andreas Wack
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An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics
Nature Communications volume 10, Article number: 963 (2019) 
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Author information
Author notes
These authors contributed equally: Ilias Angelidis, Lukas M. Simon.
Affiliations
Helmholtz Zentrum München, Institute of Lung Biology and Disease, Member of the German Center for Lung Research (DZL), Munich, 85764, Germany
Ilias Angelidis, Isis E. Fernandez, Maximilian Strunz, Christoph H. Mayr, Flavia R. Greiffo, Meshal Ansari & Herbert B. Schiller
Helmholtz Zentrum München, Institute of Computational Biology, Munich, 85764, Germany
Lukas M. Simon, George Tsitsiridis, Meshal Ansari & Fabian J. Theis
Helmholtz Zentrum München, Institute of Human Genetics, Munich, 85764, Germany
Elisabeth Graf & Tim-Matthias Strom
Department of Internal Medicine, Division of Pulmonary and Critical Care, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, 94305, CA, USA
Monica Nagendran & Tushar Desai
Department of Medicine, Division of Respiratory Sciences and Critical Care Medicine, University of Colorado, Aurora, 80045, CO, USA
Oliver Eickelberg
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Munich, 82152, Germany
Matthias Mann
Department of Mathematics, Technische Universität München, Munich, 85748, Germany
Fabian J. Theis
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Manganese Deficiency
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Carolina Lucas, Jon Klein, Maria E. Sundaram, Feimei Liu, Patrick Wong, Julio Silva, Tianyang Mao, Ji Eun Oh, Subhasis Mohanty, Jiefang Huang, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Benjamin Israelow, Chantal B. F. Vogels, M. Catherine Muenker, C-Hong Chang, Arnau Casanovas-Massana, Adam J. Moore, Joseph Zell, John B. Fournier, Yale IMPACT Research Team, Anne L. Wyllie, Melissa Campbell, Alfred Lee, Hyung J. Chun, Nathan D. Grubaugh, Wade L. Schulz, Shelli Farhadian, Charles Dela Cruz, Aaron M. Ring, Albert C. Shaw, Adam V. Wisnewski, Inci Yildirim, Albert I. Ko, Saad Omer & Akiko Iwasaki 
Delayed production of neutralizing antibodies correlates with fatal COVID-19
Nature Medicine (2021)
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Author information
Author notes
These authors contributed equally: Carolina Lucas, Jon Klein.
Affiliations
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
Carolina Lucas, Jon Klein, Feimei Liu, Patrick Wong, Julio Silva, Tianyang Mao, Ji Eun Oh, Subhasis Mohanty, Jiefang Huang, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Benjamin Israelow, Alice Lu-Culligan, Anjelica Martin, Daniel Kim, Eric Song, Eriko Kudo, Melissa Linehan, Nicole Sonnert, Tyler Rice, William Khoury-Hanold, Yexin Yang, Yiyun Cao, Aaron M. Ring, Albert C. Shaw & Akiko Iwasaki
ICES, Toronto, ON, Canada
Maria E. Sundaram
Centre for Vaccine Preventable Diseases, University of Toronto Dalla Lana School of Public Health, Toronto, ON, Canada
Maria E. Sundaram & Rick Martinello
Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA
Subhasis Mohanty, Jiefang Huang, Benjamin Israelow, John B. Fournier, Rupak Datta, Melissa Campbell, Shelli Farhadian, Albert C. Shaw, Albert I. Ko & Saad Omer
Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
Chantal B. F. Vogels, M. Catherine Muenker, Arnau Casanovas-Massana, Adam J. Moore, Alexander James Robertson, Alice Zhao, Anderson Brito, Anne E. Watkins, Caitlin J. Chun, Chaney C. Kalinich, Christina A. Harden, Cole Jensen, Coriann E. Dorgay, Elizabeth B. White, Isabel Ott, Joseph Fauver, Kristina Brower, Mary Petrone, Maxine Kuang, Natasha C. Balkcom, Zitong Lin, Anne L. Wyllie, Nathan D. Grubaugh, Albert I. Ko & Saad Omer
Department of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA
C-Hong Chang & Hyung J. Chun
Department of Internal Medicine/Section General Medicine, Yale University School of Medicine, New Haven, CT, USA
Joseph Zell & Adam V. Wisnewski
Department of Hematology, Yale University School of Medicine, New Haven, CT, USA
Alfred Lee
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
Wade L. Schulz
Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA
Denise Shepard & Wade L. Schulz
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, USA
Charles Dela Cruz
Department of Pediatric, Section of Infectious Diseases and Global Health, Yale University School of Medicine, New Haven, CT, USA
Inci Yildirim
Yale Institute for Global Health, Yale University, New Haven, CT, USA
Inci Yildirim & Saad Omer
Howard Hughes Medical Institute, Chevy Chase, MD, USA
Akiko Iwasaki
Yale School of Medicine, New Haven, CT, USA
Abeer Obaid, Allison Nelson, Angela Nunez, Bertie Geng, Codruta Todeasa, David McDonald, Erin Silva, Giuseppe DeIuliis, Harold Rahming, Hong-Jai Park, Irene Matos, Jessica Nouws, Jordan Valdez, Kadi-Ann Rose, Laura Glick, Lokesh Sharma, Lorenzo Sewanan, Lynda Knaggs, Maksym Minasyan, Maria Batsu, Maura Nakahata, Michael Simonov, Mikhail Smolgovsky, Nida Naushad, Pavithra Vijayakumar, Ryan Handoko, Santos Bermejo, Xiaohua Peng & Yvette Strong
Department of Biochemistry and of Molecular Biology, Yale University School of Medicine, New Haven, CT, USA
Edward Courchaine & Sean Bickerton
Yale Viral Hepatitis Program, Yale University School of Medicine, New Haven, CT, USA
Joseph Lim
Yale Center for Clinical Investigation, Yale University School of Medicine, New Haven, CT, USA
Kelly Anastasio & Tara Alpert
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
Michael H. Askenase & Sofia Velazquez
Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, New Haven, CT, USA
Sarah Prophet
Consortia
Yale IMPACT Research Team
Abeer Obaid, Alexander James Robertson, Alice Lu-Culligan, Alice Zhao, Allison Nelson, Anderson Brito, Angela Nunez, Anjelica Martin, Anne E. Watkins, Bertie Geng, Caitlin J. Chun, Chaney C. Kalinich, Christina A. Harden, Codruta Todeasa, Cole Jensen, Coriann E. Dorgay, Daniel Kim, David McDonald, Denise Shepard, Edward Courchaine, Elizabeth B. White, Eric Song, Erin Silva, Eriko Kudo, Giuseppe DeIuliis, Harold Rahming, Hong-Jai Park, Irene Matos, Isabel Ott, Jessica Nouws, Jordan Valdez, Joseph Fauver, Joseph Lim, Kadi-Ann Rose, Kelly Anastasio, Kristina Brower, Laura Glick, Lokesh Sharma, Lorenzo Sewanan, Lynda Knaggs, Maksym Minasyan, Maria Batsu, Mary Petrone, Maxine Kuang, Maura Nakahata, Melissa Linehan, Michael H. Askenase, Michael Simonov, Mikhail Smolgovsky, Natasha C. Balkcom, Nicole Sonnert, Nida Naushad, Pavithra Vijayakumar, Rick Martinello, Rupak Datta, Ryan Handoko, Santos Bermejo, Sarah Prophet, Sean Bickerton, Sofia Velazquez, Tara Alpert, Tyler Rice, William Khoury-Hanold, Xiaohua Peng, Yexin Yang, Yiyun Cao, Yvette Strong & Zitong Lin
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(15)
Oliver Soehnlein & Peter Libby 
Targeting inflammation in atherosclerosis — from experimental insights to the clinic
Nature Reviews Drug Discovery (2021)
ー
Author information
Affiliations
Institute for Experimental Pathology, Center for Molecular Biology of Inflammation, Westfälische Wilhelms-Universität, Münster, Germany
Oliver Soehnlein
Institute for Cardiovascular Prevention, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany
Oliver Soehnlein
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
Oliver Soehnlein
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Peter Libby
ー