Upregulation of CD47 is a host checkpoint response to pathogen recognition
| Autor: | Mark M. Davis, Lamin B. Cham, Thai Nguyen, Ronald J. Messer, Benjamin Fram, Kim J. Hasenkrug, Katrin D. Mayer-Barber, Cesar J. Lopez Angel, Karin E. Peterson, Denise M. Monack, Aijaz Ahmed, Maxim Markovic, Michal Caspi Tal, Lara Myers, Laughing Bear Torrez Dulgeroff, Debashis Sahoo, Irving L. Weissman, Jens Kortmann, Karl S. Lang, Tom Adomati, Jayakumar Rajadas, Jeffrey S. Glenn, Raja Kalluru, Clayton W. Winkler, Ed Pham, Ehydel Castro, Ying Ying Yiu, Eric Gars, Daniel M. Corey, Sarah Danielle Galloway, Niaz Banaei, Tyson A. Woods, Dhananjay Wagh, Paige Hansen, Michaela Hasenkrug, Aaron B. Carmody, Andrea C. Bohrer |
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| Přispěvatelé: | Vance, Russell |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
animal diseases medicine.medical_treatment Medizin Adaptive Immunity Inbred C57BL Mice 0302 clinical medicine Receptors Lymphocytic choriomeningitis virus Innate 2.1 Biological and endogenous factors host response Aetiology CD47 Lung innate immunity Mice Knockout 0303 health sciences Tumor Pattern recognition receptor Acquired immune system cd47 QR1-502 Up-Regulation Infectious Diseases Receptors Pattern Recognition 030220 oncology & carcinogenesis Cytokines Female medicine.symptom Infection Research Article Knockout CD47 Antigen Inflammation Pattern Recognition Biology pathogen recognition receptors Microbiology Host-Microbe Biology Cell Line Immunomodulation Vaccine Related Betacoronavirus 03 medical and health sciences Immune system Antigen Cell Line Tumor Biodefense Virology medicine Animals Humans immune checkpoint 030304 developmental biology Innate immune system SARS-CoV-2 Prevention Inflammatory and immune system Immunity Mycobacterium tuberculosis Immunotherapy Immunity Innate Immune checkpoint Mice Inbred C57BL Emerging Infectious Diseases Good Health and Well Being A549 Cells Immunology Immunization |
| Zdroj: | mBio mBio, Vol 11, Iss 3, p e01293-20 (2020) mBio, vol 11, iss 3 mBio, Vol 11, Iss 3 (2020) |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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