Neutrophil extracellular traps in COVID-19

Zuo, Yu; Yalavarthi, Srilakshmi; Shi, Hui; Gockman, Kelsey; Zuo, Melanie; Madison, Jacqueline A; Blair, Christopher; Weber, Andrew G.; Barnes, Betsy J.; Egeblad, Mikala; Woods, Robert J.; Kanthi, Yogendra; Knight, Jason S.

doi:10.1172/jci.insight.138999

Cited by 1,153 publications

(1,459 citation statements)

References 69 publications

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“…We recently characterized the blood of 50 patients hospitalized with COVID-19 and found significantly elevated levels of NETs as compared with healthy controls [18]. Here, we extend that analysis by demonstrating particularly high levels of NETs in a subgroup of COVID-19 patients diagnosed with a thrombotic event.…”

Section: Discussionsupporting

confidence: 73%

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Neutrophil extracellular traps and thrombosis in COVID-19

Zuo

Yalavarthi

et al. 2020

Preprint

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126

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Background: Early studies of patients with COVID-19 have demonstrated markedly dysregulated coagulation and a high risk of morbid arterial and venous thrombotic events. While elevated levels of blood neutrophils and neutrophil extracellular traps (NETs) have been described in patients with COVID-19, their potential role in COVID-19-associated thrombosis remains unknown. Objectives: To elucidate the potential role of hyperactive neutrophils and NET release in COVID-19-associated thrombosis. Patients/Methods: This is a retrospective, case-control study of patients hospitalized with COVID-19 who developed thrombosis (n=11), as compared with gender- and age-matched COVID-19 patients without clinical thrombosis (n=33). In addition to capturing clinical data, we measured remnants of NETs (cell-free DNA, myeloperoxidase-DNA complexes, and citrullinated histone H3) and neutrophil-derived S100A8/A9 (calprotectin) in patient sera. Results: The majority of patients (9/11) were receiving at least prophylactic doses of heparinoids at the time thrombosis was diagnosed. As compared with controls, patients with COVID-19-associated thrombosis had significantly higher blood levels of markers of NETs (cell-free DNA, myeloperoxidase-DNA complexes, citrullinated histone H3) and neutrophil activation (calprotectin). The thrombosis group also had higher levels of D-dimer, CRP, ferritin, and platelets, but not troponin or neutrophils. Finally, there were strong associations between markers of hyperactive neutrophils (calprotectin and cell-free DNA) and D-dimer. Conclusion: Elevated levels of neutrophil activation and NET formation in patients hospitalized with COVID-19 are associated with higher risk of morbid thrombotic complications. These observations underscore the need for urgent investigation into the potential relationship between NETs and unrelenting thrombosis in COVID-19.

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Section: Discussionsupporting

confidence: 73%

“…Our group recently reported high levels of NETs in 50 patients hospitalized with COVID-19 as compared with healthy controls [18]. Here, we describe 11 cases of thrombosis in patients hospitalized with COVID-19 and demonstrate an association with neutrophil hyperactivity and NET release.…”

Section: Introductionmentioning

confidence: 54%

Neutrophil extracellular traps and thrombosis in COVID-19

Zuo

Yalavarthi

et al. 2020

Preprint

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126

115

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“…The simultaneous processing of S protein by elastase and TMPRSS2 proteases help the A2a subtype coronaviruses to more easily infect the large majority of Europeans and North Americans who possess the delC allele [ Figure 5]. Elevated levels of neutrophils are reported in SARS-CoV-2 infected patients with increased disease severity (48)(49)(50)(51). Our findings are indicative of the possibility of using elastase inhibitors as therapy to prevent infection by the A2a subtype of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 71%

“…The introduction of the new cleavage site for the elastase protease in A2a possibly provides this subtype an advantage over the other subtypes for entry into the host cell. Elastase is mainly expressed by host neutrophils that is elevated in COVID-19 patients (48)(49)(50)(51). Host TMPRSS2 is a key protein that enables cleavage of was not certified by peer review) is the author/funder.…”

Section: The Clade Specific D614g Mutation Provides Advantage To A2amentioning

confidence: 99%

Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression of TMPRSS2 and MX1 Genes

Bhattacharyya

Das

Ghosh

et al. 2020

Preprint

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COVID-19 pandemic is a major human tragedy. Worldwide, SARS-CoV-2 has already infected over 3 million and has killed about 230,000 people. SARS-CoV-2 originated in China and, within three months, has evolved to an additional 10 subtypes. One particular subtype with a non-silent (Aspartate to Glycine) mutation at 614 th position of the Spike protein (D614G) rapidly outcompeted other preexisting subtypes, including the ancestral. We assessed that D614G mutation generates an additional serine protease (Elastase) cleavage site near the S1-S2 junction of the Spike protein. We also identified that a single nucleotide deletion (delC) at a known variant site (rs35074065) in a cis-eQTL of TMPRSS2, is extremely rare in East Asians but is common in Europeans and North Americans. The delC allele facilitates entry of the 614G subtype into host cells, thus accelerating the spread of 614G subtype in Europe and North America where the delC allele is common. The delC allele at the cis-eQTL locus rs35074065 of TMPRSS2 leads to overexpression of both TMPRSS2 and a nearby gene MX1. The cis-eQTL site, rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.

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“…Not considered in this study is the specific form of neutrophil activation and cell death that floods COVID-19 patients with excess calprotectin. One consideration is NET release (39,40). NETs are extracellular webs of DNA, histones, and microbicidal proteins that appear to perpetuate many types of lung disease including smoking-related disease (41), cystic fibrosis (42), and ARDS (14,43,44).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

Shi

Zuo

Yalavarthi

et al. 2020

Preprint

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Severe cases of coronavirus disease 2019 (COVID-19) are regularly complicated by respiratory failure. While it has been suggested that elevated levels of blood neutrophils associate with worsening oxygenation in COVID-19, it is unknown whether neutrophils are drivers of the thrombo-inflammatory storm or simple bystanders. To better understand the potential role of neutrophils in COVID-19, we measured levels of the neutrophil activation marker S100A8/A9 (calprotectin) in hospitalized patients and determined its relationship to severity of illness and respiratory status. Patients with COVID-19 (n=172) had markedly elevated levels of calprotectin in their blood. Calprotectin tracked with other acute phase reactants including C-reactive protein, ferritin, lactate dehydrogenase, and absolute neutrophil count, but was superior in identifying patients requiring mechanical ventilation. In longitudinal samples, calprotectin rose as oxygenation worsened. When tested on day 1 or 2 of hospitalization (n=94 patients), calprotectin levels were significantly higher in patients who progressed to severe COVID-19 requiring mechanical ventilation (8039 +/- 7031 ng/ml, n=32) as compared to those who remained free of intubation (3365 +/- 3146, p<0.0001). In summary, serum calprotectin levels track closely with current and future COVID-19 severity, implicating neutrophils as potential perpetuators of inflammation and respiratory compromise in COVID-19.

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Neutrophil extracellular traps in COVID-19

Cited by 1,153 publications

References 69 publications

Neutrophil extracellular traps and thrombosis in COVID-19

Neutrophil extracellular traps and thrombosis in COVID-19

Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression of TMPRSS2 and MX1 Genes

Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

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