Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19
| Autor: | Jay Lalezari, Jonah B. Sacha, Matthew Ryou, Kush Dhody, Michael J. Corley, Monica Herrera, Eric W. Hall, Hallison Rodrigues, Enver Aklin, Byung Park, Alina Pang, Bruce Pattterson, Edgar B. Francisco, Kazem Kazempour, Gabriela M. Webb, Amruta Pise, Helen L. Wu, Nader Pourhassan, Harish Seetthamraju, Lama Kdouh, Alena Lelic, Christopher Sugai, Scott Kelly, Lishomwa C. Ndhlovu |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
ARDS business.industry T cell virus diseases Inflammation Viremia medicine.disease CCL5 Article 3. Good health 03 medical and health sciences Cytokine release syndrome 0302 clinical medicine Immune system medicine.anatomical_structure 030220 oncology & carcinogenesis Blocking antibody Immunology medicine medicine.symptom business 030304 developmental biology |
| Zdroj: | medRxiv |
| Popis: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date1. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation2. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-193,4. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19. |
| Databáze: | OpenAIRE |
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