ABSTRACT
Altered myeloid inflammation and lymphopenia are hallmarks of severe infections, including with SARS-CoV-2. Here, we identified a gene program, defined by correlation with EN-RAGE (S100A12) gene expression, which was up-regulated in airway and blood myeloid cells from COVID-19 patients. The EN-RAGE program was expressed in 7 cohorts and observed in patients with both COVID-19 and acute respiratory distress syndrome (ARDS) from other causes. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGE+ myeloid cells express features consistent with suppressor cell functionality, with low HLA-DR and high PD-L1 surface expression and higher expression of T cell-suppressive genes. Sustained EN-RAGE signature expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell exhaustion markers, such as PD-1. IL-6 treatment of monocytes in vitro upregulated many of the severity-associated genes in the EN-RAGE gene program, along with potential mediators of T cell suppression, such as IL-10. Blockade of IL-6 signaling by tocilizumab in a placebo-controlled clinical trial led to a rapid normalization of ENRAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.
Subject(s)
Respiratory Distress Syndrome , Parkinson Disease , Chronobiology Disorders , Death , COVID-19 , Inflammation , LymphopeniaABSTRACT
Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19, thus defining an anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.
Subject(s)
Sarcoma, Myeloid , Pneumonia , Neurocognitive Disorders , COVID-19 , Inflammation , LymphopeniaABSTRACT
We identified a novel SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 remnant nasal/nasopharyngeal swab samples from 44 counties in California. Named B.1.427/B.1.429 or 20C/L452R, the variant emerged around May 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020 to January 29, 2021, exhibiting an estimated 18.6-24% increase in transmissibility relative to wild-type circulating strains. This variant is characterized by three mutations in the spike protein, including a L452R substitution in the receptor-binding domain. Our analyses revealed 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation found in SARS-CoV-2 variants of concern (B.1.1.7, B.1.351, and P.1 lineages). Antibody neutralization assays showed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California associated with decreased antibody neutralization warrants further investigation.