Publications by authors named "Ying Ying Yiu"

3 Publications

  • Page 1 of 1

CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with infection.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;

CD47 is an antiphagocytic "don't eat me" signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47 mice infected with , which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the ANKA () murine model. In vitro we tested the effect of anti-CD47 mAb on infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of -infected RBCs. Infection of C57BL/6 mice with is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of infection. Anti-CD47-treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47-treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47-treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood-brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8 T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.
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http://dx.doi.org/10.1073/pnas.1907653118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980459PMC
March 2021

Upregulation of CD47 Is a Host Checkpoint Response to Pathogen Recognition.

mBio 2020 06 23;11(3). Epub 2020 Jun 23.

Department of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.

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 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. 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.
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http://dx.doi.org/10.1128/mBio.01293-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315125PMC
June 2020

A functional subset of CD8 T cells during chronic exhaustion is defined by SIRPα expression.

Nat Commun 2019 02 15;10(1):794. Epub 2019 Feb 15.

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, MT, 59840, USA.

Prolonged exposure of CD8 T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8 T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα CD8 T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8 T cell-killing in vivo. SIRPα CD8 T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8 T cells during chronic infection expands the cytotoxic subset of SIRPα CD8 T cells.
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http://dx.doi.org/10.1038/s41467-019-08637-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377614PMC
February 2019