Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19
Bruce K Patterson, Harish Seethamraju, Kush Dhody, Michael J Corley, Kazemm Kazempour, Jay P Lalezari, Alina PS Pang, Christopher Sugai, Edgar B Francisco, Amruta Pise, Hallison Rodrigues, Matthew Ryou, Helen L Wu, Gabriela M Webb, Byung S Park, Scott Kelly, Nadar Pourhassan, Alena Lelic, Lama Kdouh, Monica Herrera, Eric Hall, Enver Aklin, View ORCID ProfileLishomwa Ndhlovu, Jonah B Sacha
doi: https://doi.org/10.1101/2020.05.02.20084673
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
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Abstract
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 date. 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 ventilation. 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-19. 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 .
When you have a hypothesis backed by strong anecdotal evidence, the challenging part of a scientific publication is providing a plausible mechanism to support your hypothesis.
HIGHLY impressive!
Bruce K Patterson, Harish Seethamraju, Kush Dhody, Michael J Corley, Kazemm Kazempour, Jay P Lalezari, Alina PS Pang, Christopher Sugai, Edgar B Francisco, Amruta Pise, Hallison Rodrigues, Matthew Ryou, Helen L Wu, Gabriela M Webb, Byung S Park, Scott Kelly, Nadar Pourhassan, Alena Lelic, Lama Kdouh, Monica Herrera, Eric Hall, Enver Aklin, View ORCID ProfileLishomwa Ndhlovu, Jonah B Sacha
doi: https://doi.org/10.1101/2020.05.02.20084673
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
AbstractInfo/HistoryMetrics Preview PDF
Abstract
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 date. 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 ventilation. 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-19. 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 .
When you have a hypothesis backed by strong anecdotal evidence, the challenging part of a scientific publication is providing a plausible mechanism to support your hypothesis.
HIGHLY impressive!
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