COVID-19: a case for inhibiting IL-17?

Pacha, Omar; Sallman, Mary Alice; Evans, Scott E.

doi:10.1038/s41577-020-0328-z

Cited by 278 publications

(298 citation statements)

References 9 publications

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“…Thus, our results could reflect the re-circulation of these cells from the lung or secondary lymphoid organs after infection and support the possibility of IL-17 in mediating neutrophil damage to the lungs. Together, this would support proposed anti-IL-17 or JAK2 inhibitor therapies for severe COVID-19 disease 39-41 .…”

Section: Discussionmentioning

confidence: 60%

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Carissimo

Kwok

et al. 2020

Preprint

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39SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 40 pandemic. Severe complications are observed only in a small proportion of infected 41 patients but the cellular mechanisms underlying this progression are still unknown. 42Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients 43 revealed a dramatic increase in the number of immature neutrophils. This increase 44 strongly correlated with disease severity and was associated with elevated IL-6 and 45 IP-10 levels, two key players in the cytokine storm. The most pronounced decrease 46 in cell counts was observed for CD8 T-cells and VD2 γδ T-cells, which both exhibited 47 increased differentiation and activation. ROC analysis revealed that the count ratio of 48 immature neutrophils to CD8 or VD2 T-cells predicts pneumonia onset (0.9071) as 49 well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a 50 useful prognostic marker for preventive patient management and improved 51 healthcare resource management. 52

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Section: Discussionmentioning

confidence: 60%

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Carissimo

Kwok

et al. 2020

Preprint

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“…In comparison, the lack of any detectable SARS-CoV-2-specific CD4+ T cells producing IL4 or IL17 suggests that antigen-specific Th2 or Th17 responses are not key for recovery from COVID-19. In fact, Th2 and Th17 responses have been suggested to be detrimental for recovery from highly pathogenic coronavirus infections -Th2 responses due to their association with lung immunopathology in the context of SARS-CoV (Deming et al, 2006;Yasui et al, 2008), and Th17 responses due to the close associations of ARDS (exacerbated by Th17 responses) and IL6 (a Th17-associated cytokine) with severe COVID-19 (Hotez et al, 2020;Pacha et al, 2020). Interestingly, while we did not detect any IL6 production by SARS-CoV-2-specific CD4+ T cells (whereas IL6 induction was readily detectable upon LPS stimulation of monocytes, data not shown), IL6+ CD4+ T cells were reported to be elevated during severe COVID-19 (Zhou et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential

Neidleman

Luo

Frouard

et al. 2020

Preprint

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Convalescing COVID-19 patients mount robust T cell responses against SARS-CoV-2, suggesting an important role for T cells in viral clearance. To date, the phenotypes of SARS-CoV-2-specific T cells remain poorly defined. Using 38-parameter CyTOF, we phenotyped longitudinal specimens of SARS-CoV-2-specific CD4+ and CD8+ T cells from four individuals who recovered from mild COVID-19. SARS-CoV-2-specific CD4+ T cells were exclusively Th1 cells, and predominantly Tcm with phenotypic features of robust helper function. SARS-CoV-2specific CD8+ T cells were predominantly atypical Temra cells in a state of less terminal differentiation and therefore capable of expansion. Subsets of SARS-CoV-2-specific T cells exhibit features of being long-lived and capable of homeostatic proliferation consistent with their persistence for over two months. Our results suggest that long-lived and robust T cell immunity is generated following natural SARS-CoV-2 infection, and support an important role for SARS-CoV-2-specific T cells in host control of COVID-19.

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“…Preliminary results from two small studies suggest inhibition of the IL-6 pathways by tocilizumab and siltuximab resulted in treatment benefit for COVID-19 patients (Gritti et al, 2020;Xu et al, 2020). Comparable to what was found for MERS-CoV and SAR-CoV infections, IL-17A has also been associated with disease severity and lung injury in COVID-19 (Pacha et al, 2020). Similarly, increased VEGF levels promote vascular permeability and leakage, helping in the pathophysiology of hypotension and pulmonary dysfunction (Teuwen et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Abbreviations: BCR, B-cell receptor; BioMAP, Biologically Multiplexed Activity Profiling; BT System, co-culture of CD19+ B cells and PBMC that utilizes BCR stimulation and sub-mitogenic TCR stimulation; HDFSAg system, co-culture of human primary dermal fibroblasts and PBMC that is stimulated with sub-mitogenic TCR levels; Ig, immunoglobulin; IgG Immunoglobulin G; IL, interleukin; PBMC, Peripheral Blood Mononuclear Cell; SAg system, co-culture of endothelial cells and PBMC stimulated with mitogenic levels of TCR ligands; TCR, T-cell receptor; /TH2 system, co-culture of endothelial cells and Th2 blasts stimulated with TCR ligands and cytokines; Th2, T helper type 2; VEGF, vascular endothelial growth factor . (Megna et al, 2020;Pacha et al, 2020). Results from the BioSeek analysis described above using the BT and HDFSAg co-cell culture systems demonstrated that PTC299 significantly inhibits the production of IL-17A and IL-17F.…”

Section: Figure 4 Ptc299 Inhibits Production Of Inflammatory Cytokinmentioning

confidence: 97%

The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines

Luban

Sattler

Mühlberger

et al. 2020

Preprint

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SUMMARYThe coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.

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COVID-19: a case for inhibiting IL-17?

Cited by 278 publications

References 9 publications

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early prognostic marker for severe COVID-19

SARS-CoV-2-specific T cells exhibit phenotypic features reflecting robust helper function, lack of terminal differentiation, and high proliferative potential

The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines

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