The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome

Косырева, А. М.; Джалилова, Д. Ш.; Lokhonina, Anastasia; Vishnyakova, Polina; Fatkhudinov, Timur

doi:10.3389/fimmu.2021.682871

Cited by 89 publications

(85 citation statements)

References 209 publications

(289 reference statements)

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“…Both Siglec‐1 and STAT1 were lower among severely affected COVID‐19 patients compared to mildly affected COVID‐19 patients, especially in plasmablasts and monocytes. This is of particular interest since, these cells are considered the main players of pathogenesis in severe COVID‐19 [ 20 , 21 ]. The data suggest that certain viral factors may limit proper STAT1 and IRF9 function in severe COVID‐19 patients in these cells and that the inhibition of translocation of STATs is more pronounced than the inhibition of phosphorylation [ 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

Altered increase in STAT1 expression and phosphorylation in severe COVID‐19

et al. 2021

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The interferon pathway, a key antiviral defense mechanism, is being considered as a therapeutic target in COVID‐19. Both, substitution of interferon and JAK/STAT inhibition to limit cytokine storms have been proposed. However, little is known about possible abnormalities in STAT signaling in immune cells during SARS‐CoV‐2 infection. We investigated downstream targets of interferon signaling, including STAT1, STAT2, pSTAT1 and 2, and IRF1, 7 and 9 by flow cytometry in 30 patients with COVID‐19, 17 with mild, and 13 with severe infection. We report upregulation of STAT1 and IRF9 in mild and severe COVID‐19 cases, which correlated with the IFN‐signature assessed by Siglec‐1 (CD169) expression on peripheral monocytes. Interestingly, Siglec‐1 and STAT1 in CD14+ monocytes and plasmablasts showed lower expression among severe cases compared to mild cases. Contrary to the baseline STAT1 expression, the phosphorylation of STAT1 was enhanced in severe COVID‐19 cases, indicating a dysbalanced JAK/STAT signaling that fails to induce transcription of interferon stimulated response elements (ISRE). This abnormality persisted after IFN‐α and IFN‐γ stimulation of PBMCs from patients with severe COVID‐19. Data suggest impaired STAT1 transcriptional upregulation among severely infected patients may represent a potential predictive biomarker and would allow stratification of patients for certain interferon‐pathway targeted treatments.

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Section: Discussionmentioning

confidence: 99%

Altered increase in STAT1 expression and phosphorylation in severe COVID‐19

et al. 2021

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“…Acute lung injury (ALI) that progresses rapidly to ARDS is the leading cause of high mortality in pneumonia, including SARS-CoV-2-associated pneumonia. The transition of ALI to ARDS happens due to diffuse alveolar damage, usually as a consequence of an exaggerated and uncontrolled systemic inflammatory reaction [19].…”

Section: Ards In Covid-19mentioning

confidence: 99%

“…In the early stages of ALI, activation of antigen presenting cells (APCs) like macrophages and dendritic cells triggers immune response and facilitates the production of pro-inflammatory cytokines (mainly TNF , IL-1, and IL-6), as well as prostaglandins and histamine. These substances increase permeability of endothelium and facilitate migration of neutrophils, macrophages, and lymphocytes to location of inflammation, which exacerbates injury and triggers ARDS [19].…”

Section: Ards In Covid-19mentioning

confidence: 99%

Serum Surfactant Protein-D (SP-D) Level: Does it Correlates with Pulmonary Compliance and ARDS in Severe Cases of COVID-19?

Jayadi¹,

Airlangga²,

Kusuma³

et al. 2022

IJRP

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Acute Respiratory Distress Syndrome (ARDS) happens to 67% of all severe COVID-19 cases with mortality rate of 50-94%. Main characteristics of ARDS are poor oxygenation and non-compliant lungs. The lungs are like inflatable balloons that are actively inflated by the positive pressure within and/or the negative pressure created in the pleural cavity. Compliance is the ability of the lungs to distend at a certain level of transpulmonary pressure.Surfactant lowers the surface tension of the alveoli so that end-expiratory pulmonary collapse could be prevented and pulmonary compliance could be maintained. Surfactants also play an important role in the host's defense against infection.Surfactants comprise of phospholipids, cholesterol and surfactant proteins (SP) SP-A, -B, -C and -D. Previous study showed that concentration of SP-D was significantly higher in ARDS patients. Higher serum SP-D concentrations were associated with a greater risk of death, fewer ventilator-free days, and fewer organ failure-free days. This review highlights the role of surfactant especially SP-D in pulmonary compliance and ARDS in COVID-19.

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“…Activation of M1 macrophages in large amount causes 'macrophage activation syndrome' (MAS), which is involved in SARS-CoV-2 induced ARDS. Therefore, switching macrophage polarization from M1 to M2 phenotype in the early phase of the disease can resolve inflammation and reduce excessive pro-inflammatory cytokines production within cytokine storm (Gracia-Hernandez et al, 2020;Kosyreva et al, 2021).…”

Section: Immune System Response and Cytokine Storm In Covid-19mentioning

confidence: 99%

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Nazerian

Vakili

Ebrahimi

et al. 2021

Front. Cell Dev. Biol.

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Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.

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The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome

Cited by 89 publications

References 209 publications

Altered increase in STAT1 expression and phosphorylation in severe COVID‐19

Altered increase in STAT1 expression and phosphorylation in severe COVID‐19

Serum Surfactant Protein-D (SP-D) Level: Does it Correlates with Pulmonary Compliance and ARDS in Severe Cases of COVID-19?

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

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