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.

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.