COVID-19 cytokine storm: the interplay between inflammation and coagulation

José, Ricardo J.; Manuel, Ari

doi:10.1016/s2213-2600(20)30216-2

Cited by 1,154 publications

(1,203 citation statements)

References 11 publications

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“…In addition to neutralizing and eliminating the virus, the immune response may cause harmful tissue damage at both the local and systemic levels, when the regulatory mechanisms are dysfunctional. In a subset of individuals infected with SARS-CoV-2 dysregulated immune responses are observed, manifesting as a cytokine storm (3)(4)(5), which is reminiscent of immunopathology seen in other corona-viruses SARS-CoV and MERS-CoV (6). These observations suggest that the degree of dysregulation of immune response is likely to be an important factor, in addition to viral load, in determining the severity of COVID-19 (7,8).…”

Section: Introductionmentioning

confidence: 98%

Mechanistic modeling of the SARS-CoV-2 and immune system interplay unravels design principles for diverse clinicopathological outcomes

Sahoo

Hari

Jhunjhunwala

et al. 2020

Preprint

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The disease caused by SARS-CoV-2 is a global pandemic that threatens to bring long-term changes worldwide. Approximately 80% of infected patients are asymptomatic or have mild symptoms such as fever or cough, while rest of the patients have varying degrees of severity of symptoms, with 3-4% mortality rate. Severe symptoms such as pneumonia and Acute Respiratory Distress Syndrome can be caused by tissue damage mostly due to aggravated and unresolved innate and adaptive immune response, often resulting from a cytokine storm. However, the mechanistic underpinnings of such responses remain elusive, with an incomplete understanding of how an intricate interplay among infected cells and cells of innate and adaptive immune system can lead to such diverse clinicopathological outcomes. Here, we use a dynamical systems approach to dissect the emergent nonlinear intra-host dynamics among virally infected cells, the immune response to it and the consequent immunopathology. By mechanistic analysis of cell-cell interactions, we have identified key parameters affecting the diverse clinical phenotypes associated with COVID-19. This minimalistic yet rigorous model can explain the various phenotypes observed across the clinical spectrum of COVID-19, various co-morbidity risk factors such as age and obesity, and the effect of antiviral drugs on different phenotypes. It also reveals how a fine-tuned balance of infected cell killing and resolution of inflammation can lead to infection clearance, while disruptions can drive different severe phenotypes. These results will help further the case of rational selection of drug combinations that can effectively balance viral clearance and minimize tissue damage simultaneously. Significance StatementThe SARS-CoV-2 pandemic has already infected millions of people, and thousands of lives have been lost to it. The pandemic has already tested the limits of our public healthcare systems with a wide spectrum of clinicopathological symptoms and outcomes. The mechanistic underpinnings of the resultant immunopathology caused by the viral infection still remains to be elucidated. Here we propose a minimalistic but rigorous description of the interactions of the virus infected cells and the core components of the immune system that can potentially explain such diversity in the observed clinical outcomes. Our proposed framework could enable a platform to determine the efficacy of various treatment combinations and can contributes a conceptual understanding of dynamics of disease pathogenesis in SARS-CoV-2 infections.

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Section: Introductionmentioning

confidence: 98%

Mechanistic modeling of the SARS-CoV-2 and immune system interplay unravels design principles for diverse clinicopathological outcomes

Sahoo

Hari

Jhunjhunwala

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…It is associated with signi cant mortality in high risk patients, with poor prognostic features upon admission. The spectrum of the disease is broad, including pneumonia, sepsis, and acute respiratory distress syndrome (ARDS) 3 . Hypoxemia, de ned as a decrease in the partial pressure of oxygen is an ominous sign of COVID-19, and it is usually an indicator of disease severity 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

Taniguchi‐Ponciano

Vadillo

Mayani

et al. 2020

Preprint

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Since its emergence, in December 2019, COVID-19 has resulted in more than 12 million people infected and has killed more than 570000. Hypoxemia has been identified as one of the main clinical manifestations of this disease, especially in severe cases. We have previously reported that in critically ill COVID-19 patients there is a shift towards an immature myeloid profile in peripheral blood cells, including band neutrophils, immature monocytes, metamyelocytes, monocyte-macrophages, monocytoid precursors, and promyelocytes-myelocytes, which, together with mature monocytes and segmented neutrophils, comprise the vast majority of blood cells in these patients. Such an immature myeloid profile may be the result of a physiological response known as emergency myelopoiesis. In the present study, we performed scRNAseq from leukocytes from five critically ill COVID-19 patients and characterized the expression of hypoxia-inducible factor1α (HIF1α) mRNA and its transcriptionally regulated genes. HIF1α is a master transcription factor involved in the cellular response to hypoxia. We herein report that these cellular subsets express high levels of HIF1α mRNA and several of their transcriptional targets, including those related to inflammation, such as CXCL8, CXCR1, CXCR2, and CXCR4; those potentially involved in virus sensing, such as TLR2 and TLR4; and those related to metabolism, such as SLC2A3, PFKFB3, PGK1, GAPDH and SOD2. The up-regulation and participation of HIF1α in relevant events such as inflammation, immunometabolism, and TLR make it a potential molecular marker for COVID-19 severity and, interestingly, could represent a potential target for molecular therapy.

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“…These changes in immune cells may also be connected to increased neutrophil counts in these patients (42). The cytokine storm-related to innate immune changes may be linked to changes in angiogenesis and coagulation, suggesting a potential relationship between inflammation, thromboembolism (43), and coagulation (44).…”

Section: Discussionmentioning

confidence: 98%

A blood-based comprehensive and systems-level analysis of disease stages, immune regulation and symptoms in COVID-19 patients

Sadanandam

Bopp

Dixit

et al. 2020

Preprint

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COVID-19 patients show significant clinical heterogeneity in presentation and outcomes that makes pandemic control and strategy difficult; optimising management requires a systems biology approach of understanding the disease. Here we sought to understand and infer complex system-wide changes in patients infected with coronaviruses (SARS-CoV and SARS-CoV-2; n=38 and 57 samples) at two different disease stages compared with healthy individuals (n=16) and patients with other infections (n=144). We applied inferential statistics/machine-learning approaches (the COVID-engine platform) to RNA profiles derived from peripheral blood mononuclear cells (PBMCs). Compared to healthy individuals, an integrated blood-based gene signatures distinguished acute-like (mimicking coronavirus-infected patients with prolonged hospitalisation) from recovering-like patients. These signatures also hierarchically represented systems-level parameters associated with PBMC including dysregulated cytokines, genes, pathways, networks of pathways/concepts, immune status, and cell types. Proof-of-principle confirmatory observations included PBMC-associated increases in ACE2, cytokine storm-associated IL6, enhanced innate immunity (macrophages and neutrophils), and lower adaptive T and B cell immunity in patients with acute-like disease compared to those with recovery-like disease. Patients in the recovery-like stage had significantly enhanced TNF, IFN-g, anti-viral, HLA-DQA1, and HLA-F gene expression and cytolytic activity, and reduced pro-viral gene expression compared to those in the acute-like stage in PBMC. Besides, PBMC-derived surrogate-based approach revealed overlapping genes associated with comorbidities (associated diabetes), and disease-like symptoms (associated with thromboembolism, pneumonia, lung disease and septicaemia). Overall, our study involving PBMC-based RNA profiling may further help understand complex and variable systems-wide responses displayed by coronavirus-infected patients.

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COVID-19 cytokine storm: the interplay between inflammation and coagulation

Cited by 1,154 publications

References 11 publications

Mechanistic modeling of the SARS-CoV-2 and immune system interplay unravels design principles for diverse clinicopathological outcomes

Mechanistic modeling of the SARS-CoV-2 and immune system interplay unravels design principles for diverse clinicopathological outcomes

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

A blood-based comprehensive and systems-level analysis of disease stages, immune regulation and symptoms in COVID-19 patients

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