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Posted On: 03/01/2022 11:48:38 PM
Post# of 148902
I saw this report referenced on another board. Over my head, but I thought one of our high-tech posters might let us know if this work presents any new hypotheses relevant to Leronlimab. There is a mention of LL (they called it Leronlima). Several of the authors are from Brazil. Excerpts and link below.
Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States
Abstract
Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.
Discussion
Nonetheless, our manuscript has some limitations that need to be considered. The datasets included in our study did not investigate the impact of different SARS-CoV-2 variants on the transcriptome of COVID-19 patients. Hence, further studies are needed to investigate how the different SARS-CoV-2 variants intersect with the other hyperinflammatory conditions that we investigated. We also did not consider the influence of age, sex, and comorbidities on the common transcriptome signatures of COVID-19 and the other hyperinflammatory conditions. In addition, our work requires future mechanistic investigation to further explore and validate the role of molecules studied here as predictors of COVID-19 severity. However, in support of our findings, several of the dysregulated molecules shared by COVID-19 and other acute inflammatory states have been successfully investigated for the treatment of SARS-CoV-2 infection. For instance, inhibition of the CCR5-CCL4 axis by Leronlima (anti-CCR5 monoclonal antibody) [116], or the blockade of cytokine signaling by Tocilizumab (anti-IL-6R) [117], Adalimumab (anti-TNF-α) [118], or Anakinra (anti-IL1R) [119] have been shown to ameliorate, in some cases, severe COVID-19 manifestations. Furthermore, Ruxolitinib, a JAK1/JAK2 inhibitor acting downstream of JAK-dependent chemokines/cytokines such as IFN-γ, IL-1β, IL-6, TNF, G-CSF, CXCL9, and CXCL10 [101,120], has shown promising results in treating COVID-19
https://www.mdpi.com/2073-4409/11/5/847/htm?f...dsBzKrhTLo
Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States
Abstract
Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.
Discussion
Nonetheless, our manuscript has some limitations that need to be considered. The datasets included in our study did not investigate the impact of different SARS-CoV-2 variants on the transcriptome of COVID-19 patients. Hence, further studies are needed to investigate how the different SARS-CoV-2 variants intersect with the other hyperinflammatory conditions that we investigated. We also did not consider the influence of age, sex, and comorbidities on the common transcriptome signatures of COVID-19 and the other hyperinflammatory conditions. In addition, our work requires future mechanistic investigation to further explore and validate the role of molecules studied here as predictors of COVID-19 severity. However, in support of our findings, several of the dysregulated molecules shared by COVID-19 and other acute inflammatory states have been successfully investigated for the treatment of SARS-CoV-2 infection. For instance, inhibition of the CCR5-CCL4 axis by Leronlima (anti-CCR5 monoclonal antibody) [116], or the blockade of cytokine signaling by Tocilizumab (anti-IL-6R) [117], Adalimumab (anti-TNF-α) [118], or Anakinra (anti-IL1R) [119] have been shown to ameliorate, in some cases, severe COVID-19 manifestations. Furthermore, Ruxolitinib, a JAK1/JAK2 inhibitor acting downstream of JAK-dependent chemokines/cytokines such as IFN-γ, IL-1β, IL-6, TNF, G-CSF, CXCL9, and CXCL10 [101,120], has shown promising results in treating COVID-19
https://www.mdpi.com/2073-4409/11/5/847/htm?f...dsBzKrhTLo
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