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Upregulation of CD47 Is a Host Checkpoint Response to Pathogen Recognition.
Tal, Michal Caspi; Torrez Dulgeroff, Laughing Bear; Myers, Lara; Cham, Lamin B; Mayer-Barber, Katrin D; Bohrer, Andrea C; Castro, Ehydel; Yiu, Ying Ying; Lopez Angel, Cesar; Pham, Ed; Carmody, Aaron B; Messer, Ronald J; Gars, Eric; Kortmann, Jens; Markovic, Maxim; Hasenkrug, Michaela; Peterson, Karin E; Winkler, Clayton W; Woods, Tyson A; Hansen, Paige; Galloway, Sarah; Wagh, Dhananjay; Fram, Benjamin J; Nguyen, Thai; Corey, Daniel; Kalluru, Raja Sab; Banaei, Niaz; Rajadas, Jayakumar; Monack, Denise M; Ahmed, Aijaz; Sahoo, Debashis; Davis, Mark M; Glenn, Jeffrey S; Adomati, Tom; Lang, Karl S; Weissman, Irving L; Hasenkrug, Kim J.
  • Tal MC; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Torrez Dulgeroff LB; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Myers L; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Cham LB; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Mayer-Barber KD; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Bohrer AC; Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • Castro E; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Yiu YY; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Lopez Angel C; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Pham E; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Carmody AB; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Messer RJ; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
  • Gars E; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
  • Kortmann J; Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.
  • Markovic M; Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Hasenkrug M; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Peterson KE; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
  • Winkler CW; Genentech Inc., South San Francisco, California, USA.
  • Woods TA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Hansen P; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Galloway S; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Wagh D; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Fram BJ; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Nguyen T; Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
  • Corey D; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Kalluru RS; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Banaei N; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Rajadas J; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Monack DM; Stanford Functional Genomics Facility, Stanford University School of Medicine, Stanford, California, USA.
  • Ahmed A; Biomaterials and Advanced Drug Delivery Laboratory, Cardio Vascular Institute, Stanford University School of Medicine, Stanford, California, USA.
  • Sahoo D; Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.
  • Davis MM; Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.
  • Glenn JS; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Adomati T; Ludwig Cancer Center, Stanford University School of Medicine, Stanford, California, USA.
  • Lang KS; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
  • Weissman IL; Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
  • Hasenkrug KJ; Biomaterials and Advanced Drug Delivery Laboratory, Cardio Vascular Institute, Stanford University School of Medicine, Stanford, California, USA.
mBio ; 11(3)2020 06 23.
Article in English | MEDLINE | ID: covidwho-612678
Semantic information from SemMedBD (by NLM)
1. Downstream LOCATION_OF Antigen-Presenting Cells
Subject
Downstream
Predicate
LOCATION_OF
Object
Antigen-Presenting Cells
2. cytosolic receptor STIMULATES CD47
Subject
cytosolic receptor
Predicate
STIMULATES
Object
CD47
3. Hepatitis C PROCESS_OF Patients
Subject
Hepatitis C
Predicate
PROCESS_OF
Object
Patients
4. Plasma PART_OF Patients
Subject
Plasma
Predicate
PART_OF
Object
Patients
5. Dendritic Cells LOCATION_OF CD47
Subject
Dendritic Cells
Predicate
LOCATION_OF
Object
CD47
6. Plasma LOCATION_OF cytokine
Subject
Plasma
Predicate
LOCATION_OF
Object
cytokine
7. Pathogenic organism LOCATION_OF Receptor
Subject
Pathogenic organism
Predicate
LOCATION_OF
Object
Receptor
8. CD47 AUGMENTS Immune response
Subject
CD47
Predicate
AUGMENTS
Object
Immune response
9. Receptor INHIBITS 961
Subject
Receptor
Predicate
INHIBITS
Object
961
10. Up-Regulation (Physiology) AFFECTS Immunoregulation
Subject
Up-Regulation (Physiology)
Predicate
AFFECTS
Object
Immunoregulation
11. CD47 Antigen|CD47 AFFECTS Immune response
Subject
CD47 Antigen|CD47
Predicate
AFFECTS
Object
Immune response
12. Up-Regulation (Physiology) CAUSES pattern recognition receptor signaling pathway
Subject
Up-Regulation (Physiology)
Predicate
CAUSES
Object
pattern recognition receptor signaling pathway
13. receptor INHIBITS CD47
Subject
receptor
Predicate
INHIBITS
Object
CD47
14. Specific antigen PART_OF Pathogenic organism
Subject
Specific antigen
Predicate
PART_OF
Object
Pathogenic organism
15. Downstream LOCATION_OF Antigen-Presenting Cells
Subject
Downstream
Predicate
LOCATION_OF
Object
Antigen-Presenting Cells
16. cytosolic receptor STIMULATES CD47
Subject
cytosolic receptor
Predicate
STIMULATES
Object
CD47
17. Hepatitis C PROCESS_OF Patients
Subject
Hepatitis C
Predicate
PROCESS_OF
Object
Patients
18. Plasma PART_OF Patients
Subject
Plasma
Predicate
PART_OF
Object
Patients
19. Dendritic Cells LOCATION_OF CD47
Subject
Dendritic Cells
Predicate
LOCATION_OF
Object
CD47
20. Plasma LOCATION_OF cytokine
Subject
Plasma
Predicate
LOCATION_OF
Object
cytokine
21. Pathogenic organism LOCATION_OF Receptors, Pattern Recognition
Subject
Pathogenic organism
Predicate
LOCATION_OF
Object
Receptors, Pattern Recognition
22. CD47 AUGMENTS Immune response
Subject
CD47
Predicate
AUGMENTS
Object
Immune response
23. Receptors, Pattern Recognition INHIBITS CD47
Subject
Receptors, Pattern Recognition
Predicate
INHIBITS
Object
CD47
24. Up-Regulation (Physiology) AFFECTS Immunoregulation
Subject
Up-Regulation (Physiology)
Predicate
AFFECTS
Object
Immunoregulation
25. CD47 Antigen|CD47 AFFECTS Immune response
Subject
CD47 Antigen|CD47
Predicate
AFFECTS
Object
Immune response
26. Up-Regulation (Physiology) CAUSES pattern recognition receptor signaling pathway
Subject
Up-Regulation (Physiology)
Predicate
CAUSES
Object
pattern recognition receptor signaling pathway
27. receptor INHIBITS CD47
Subject
receptor
Predicate
INHIBITS
Object
CD47
28. Specific antigen PART_OF Pathogenic organism
Subject
Specific antigen
Predicate
PART_OF
Object
Pathogenic organism
ABSTRACT
It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions. A CD47 mimic that acts as an essential virulence factor is encoded by all poxviruses, but CD47 expression on infected cells was found to be upregulated even by pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that encode no mimic. CD47 upregulation was revealed to be a host response induced by the stimulation of both endosomal and cytosolic pathogen recognition receptors (PRRs). Furthermore, proinflammatory cytokines, including those found in the plasma of hepatitis C patients, upregulated CD47 on uninfected dendritic cells, thereby linking innate modulation with downstream adaptive immune responses. Indeed, results from antibody-mediated CD47 blockade experiments as well as CD47 knockout mice revealed an immunosuppressive role for CD47 during infections with lymphocytic choriomeningitis virus and Mycobacterium tuberculosis Since CD47 blockade operates at the level of pattern recognition receptors rather than at a pathogen or antigen-specific level, these findings identify CD47 as a novel potential immunotherapeutic target for the enhancement of immune responses to a broad range of infectious agents.IMPORTANCE Immune responses to infectious agents are initiated when a pathogen or its components bind to pattern recognition receptors (PRRs). PRR binding sets off a cascade of events that activates immune responses. We now show that, in addition to activating immune responses, PRR signaling also initiates an immunosuppressive response, probably to limit inflammation. The importance of the current findings is that blockade of immunomodulatory signaling, which is mediated by the upregulation of the CD47 molecule, can lead to enhanced immune responses to any pathogen that triggers PRR signaling. Since most or all pathogens trigger PRRs, CD47 blockade could be used to speed up and strengthen both innate and adaptive immune responses when medically indicated. Such immunotherapy could be done without a requirement for knowing the HLA type of the individual, the specific antigens of the pathogen, or, in the case of bacterial infections, the antimicrobial resistance profile.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: CD47 Antigen / Receptors, Pattern Recognition / Immunomodulation / Betacoronavirus Limits: Animals / Female / Humans / Male Language: English Year: 2020 Document Type: Article Affiliation country: MBio.01293-20

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Full text: Available Collection: International databases Database: MEDLINE Main subject: CD47 Antigen / Receptors, Pattern Recognition / Immunomodulation / Betacoronavirus Limits: Animals / Female / Humans / Male Language: English Year: 2020 Document Type: Article Affiliation country: MBio.01293-20