Journal Article

Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology

Chang, Yuzhou, Chung, Dongjun, Bucci, Donna, Li, Anqi, Song, No-Joon, Bolyard, Chelsea, Ma, Qin, Devenport, Martin, Li, Zihai, Reynolds, Kelsi, Zeng, Cong, Liyanage, Namal P. M., Sun, Zequn, Zheng, Pan, Evans, John P., Xu, Menglin, Chakravarthy, Karthik B., Liu, Shan-Lu, Malvestutto, Carlos D., Allen, Carter, Liu, Yang, Riesenberg, Brian P., Kumar, Amrendra, Vilgelm, Anna E., Gunasena, Manuja, Velegraki, Maria, Ma, Anjun, Weller, Kevin P., Yusuf, Mohamed, Khatiwada, Aastha

2022

Overview

Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through direct lysis of infected lung epithelial cells, which releases damage-associated molecular patterns and induces a pro-inflammatory cytokine milieu causing systemic inflammation. Anti-viral and anti-inflammatory agents have shown limited therapeutic efficacy. Soluble CD24 (CD24Fc) blunts the broad inflammatory response induced by damage-associated molecular patterns via binding to extracellular high mobility group box 1 and heat shock proteins, as well as regulating the downstream Siglec10-Src homology 2 domain–containing phosphatase 1 pathway. A recent randomized phase III trial evaluating CD24Fc for patients with severe COVID-19 (SAC-COVID; NCT04317040) demonstrated encouraging clinical efficacy. Methods Using a systems analytical approach, we studied peripheral blood samples obtained from patients enrolled at a single institution in the SAC-COVID trial to discern the impact of CD24Fc treatment on immune homeostasis. We performed high dimensional spectral flow cytometry and measured the levels of a broad array of cytokines and chemokines to discern the impact of CD24Fc treatment on immune homeostasis in patients with COVID-19. Results Twenty-two patients were enrolled, and the clinical characteristics from the CD24Fc vs. placebo groups were matched. Using high-content spectral flow cytometry and network-level analysis, we found that patients with severe COVID-19 had systemic hyper-activation of multiple cellular compartments, including CD8 + T cells, CD4 + T cells, and CD56 + natural killer cells. Treatment with CD24Fc blunted this systemic inflammation, inducing a return to homeostasis in NK and T cells without compromising the anti-Spike protein antibody response. CD24Fc significantly attenuated the systemic cytokine response and diminished the cytokine coexpression and network connectivity linked with COVID-19 severity and pathogenesis. Conclusions Our data demonstrate that CD24Fc rapidly down-modulates systemic inflammation and restores immune homeostasis in SARS-CoV-2-infected individuals, supporting further development of CD24Fc as a novel therapeutic against severe COVID-19.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Alarmins - immunology / Alarmins - metabolism / Analysis / Anti-inflammatory agents / Antibodies / Antibody response / Antiviral agents / Antiviral drugs / Cancer Research / CD24 Antigen - chemistry / CD24 Antigen - therapeutic use / CD24Fc / CD4 antigen / CD56 antigen / CD8 antigen / Chemokines / Chromosomal proteins / Clinical trials / Coronaviruses / COVID-19 / COVID-19 - immunology / COVID-19 - prevention & control / COVID-19 - virology / COVID-19 vaccines / Cytokine Release Syndrome - immunology / Cytokine Release Syndrome - metabolism / Cytokine Release Syndrome - prevention & control / Cytokine score / Cytokine storm / Cytokines / Double-Blind Method / Enrollments / Epithelial cells / Female / Flow cytometry / Health aspects / Heat shock proteins / Heat-Shock Proteins - immunology / Heat-Shock Proteins - metabolism / Hematology / High mobility group proteins / HMGB1 Protein - immunology / HMGB1 Protein - metabolism / Homeostasis / Homeostasis - drug effects / Homeostasis - immunology / Homology / Hospitalization / Hospitals / Humans / Immunophenotyping / Infections / Inflammation / Inflammation - immunology / Inflammation - metabolism / Inflammation - prevention & control / Killer cells / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Killer Cells, Natural - virology / Lymphocytes T / Lysis / Male / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Middle Aged / Mortality / Natural killer cells / Oncology / Patients / Peripheral blood / Phosphatases / SARS-CoV-2 - drug effects / SARS-CoV-2 - immunology / SARS-CoV-2 - physiology / Severe acute respiratory syndrome coronavirus 2 / Solubility / Soluble CD24 / Spike protein / T cells / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / T-Lymphocytes - virology / Treatment Outcome / Viral antibodies / Viral infections