Treatment with soluble CD24 attenuates COVID-19-associated systemic immunopathology
No-Joon Song, Carter Allen, Anna E Vilgelm, Brian P Riesenberg, Kevin P Weller, Kelsi Reynolds, Karthik B Chakravarthy, Amrendra Kumar, Aastha Khatiwada, Zequn Sun, Anjun Ma, Yuzhou Chang, Mohamed Yusuf, Anqi Li, Cong Zeng, John P Evans, Donna Bucci, Manuja Gunasena, Menglin Xu, Namal P M Liyanage, Chelsea Bolyard, Maria Velegraki, Shan-Lu Liu, Qin Ma, Martin Devenport, Yang Liu, Pan Zheng, Carlos D Malvestutto, Dongjun Chung, Zihai Li, No-Joon Song, Carter Allen, Anna E Vilgelm, Brian P Riesenberg, Kevin P Weller, Kelsi Reynolds, Karthik B Chakravarthy, Amrendra Kumar, Aastha Khatiwada, Zequn Sun, Anjun Ma, Yuzhou Chang, Mohamed Yusuf, Anqi Li, Cong Zeng, John P Evans, Donna Bucci, Manuja Gunasena, Menglin Xu, Namal P M Liyanage, Chelsea Bolyard, Maria Velegraki, Shan-Lu Liu, Qin Ma, Martin Devenport, Yang Liu, Pan Zheng, Carlos D Malvestutto, Dongjun Chung, Zihai Li
Abstract
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.
Keywords: CD24Fc; COVID-19; Cytokine score; Immunophenotyping; Soluble CD24.
Conflict of interest statement
The authors declare that they have no competing interests.
© 2022. The Author(s).
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Source: PubMed