Upregulation of CD47 Is a Host Checkpoint Response to Pathogen Recognition
Michal Caspi Tal,
Laughing Bear Torrez Dulgeroff,
Lara Myers,
Lamin B. Cham,
Katrin D. Mayer-Barber,
Andrea C. Bohrer,
Ehydel Castro,
Ying Ying Yiu,
Cesar Lopez Angel,
Ed Pham,
Aaron B. Carmody,
Ronald J. Messer,
Eric Gars,
Jens Kortmann,
Maxim Markovic,
Michaela Hasenkrug,
Karin E. Peterson,
Clayton W. Winkler,
Tyson A. Woods,
Paige Hansen,
Sarah Galloway,
Dhananjay Wagh,
Benjamin J. Fram,
Thai Nguyen,
Daniel Corey,
Raja Sab Kalluru,
Niaz Banaei,
Jayakumar Rajadas,
Denise M. Monack,
Aijaz Ahmed,
Debashis Sahoo,
Mark M. Davis,
Jeffrey S. Glenn,
Tom Adomati,
Karl S. Lang,
Irving L. Weissman,
Kim J. Hasenkrug
Affiliations
Michal Caspi Tal
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Laughing Bear Torrez Dulgeroff
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Lara Myers
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Lamin B. Cham
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
Katrin D. Mayer-Barber
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Andrea C. Bohrer
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Ehydel Castro
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
Ying Ying Yiu
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Cesar Lopez Angel
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
Ed Pham
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
Aaron B. Carmody
Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Ronald J. Messer
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Eric Gars
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
Jens Kortmann
Genentech Inc., South San Francisco, California, USA
Maxim Markovic
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Michaela Hasenkrug
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Karin E. Peterson
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Clayton W. Winkler
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Tyson A. Woods
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Paige Hansen
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Sarah Galloway
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Dhananjay Wagh
Stanford Functional Genomics Facility, Stanford University School of Medicine, Stanford, California, USA
Benjamin J. Fram
Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
Thai Nguyen
Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
Daniel Corey
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Raja Sab Kalluru
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
Niaz Banaei
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
Jayakumar Rajadas
Biomaterials and Advanced Drug Delivery Laboratory, Cardio Vascular Institute, Stanford University School of Medicine, Stanford, California, USA
Denise M. Monack
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
Aijaz Ahmed
Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
Debashis Sahoo
Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
Mark M. Davis
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
Jeffrey S. Glenn
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
Tom Adomati
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
Karl S. Lang
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
Irving L. Weissman
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
Kim J. Hasenkrug
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
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.
