Untimely TGFβ responses in COVID-19 limit antiviral functions of NK cells

Abstract

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Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

“…First, TxA2 / TPr activation stimulates activation of the TGFβ pathway, 8 and early, untimely TGFβ responses in SARS-CoV-2 infection limit antiviral function of natural killer (NK) cells. 9 Second, PGD2/DPr2 signaling suppresses innate mucosal antiviral responses by inhibiting expression of IFN-λ, the first line of defense against viruses at mucosal surfaces. Notably IFN-λ is markedly suppressed in the upper respiratory tract in COVID-19.…”

“…7 Thromboxane A2 and isoprostanes stimulate TPr-mediated activation of the TGFβ pathway, 8 and early, untimely TGFβ responses in SARS-CoV-2 infection limit antiviral function of natural killer (NK) cells and promote progression to severe COVID-19 disease. 9 Theken and FitzGerald have proposed early administration of a TxA2 antagonist as an antithrombotic agent to limit progression of disease in SARS-CoV-2 infection, and administration of an antagonist to block PGD2 / D-prostanoid receptor 2 (DPr2, formerly referred to as CRTH2) in order to boost interferon lambda (IFN-λ) response in the upper respiratory tract, thereby limiting SARS-CoV-2 replication and transmission. 10 11 Ramatroban is the only dual TxA2/TPr and PGD2/DPr2 receptor antagonist available for clinical study and has been proposed as an antithrombotic and immunomodulator agent in COVID-19.…”

Treatment of COVID-19 pneumonia and acute respiratory distress with ramatroban, a thromboxane A2 and prostaglandin D2 receptor antagonist: A 4-Patient Case Series Report

“…First, TxA 2 / TPr activation stimulates activation of the TGFβ pathway, 8 and early, untimely TGFβ responses in SARS-CoV-2 infection limit antiviral function of natural killer (NK) cells. 9 Second, PGD 2 /DPr2 signaling suppresses innate mucosal antiviral responses by inhibiting expression of IFN-λ, the rst line of defense against viruses at mucosal surfaces. Notably IFN-λ is markedly suppressed in the upper respiratory tract in COVID-19.…”

“…7 Thromboxane A 2 and isoprostanes stimulate TPr-mediated activation of the TGFβ pathway, 8 and early, untimely TGFβ responses in SARS-CoV-2 infection limit antiviral function of natural killer (NK) cells and promote progression to severe COVID-19 disease. 9 Theken and FitzGerald have proposed early administration of a TxA 2 antagonist as an antithrombotic agent to limit progression of disease in SARS-CoV-2 infection, and administration of an antagonist to block PGD 2 / D-prostanoid receptor 2 (DPr2, formerly referred to as CRTH2) in order to boost interferon lambda (IFN-λ) response in the upper respiratory tract, thereby limiting SARS-CoV-2 replication and transmission. 10 11 Ramatroban is the only dual TxA 2 /TPr and PGD 2 /DPr2 receptor antagonist available for clinical study and has been proposed as an antithrombotic and immunomodulator agent in COVID-19.…”

Strategies for fighting pandemic virus infections: Integration of virology and drug delivery

“…In patients with severe COVID-19 infections, a decrease of blood NK cells was observed [ 238 , 239 ]. Furthermore, at an early phase of SARS-CoV-2 infections, high levels of blood NK cells are correlated with a rapid decrease in viral load [ 240 ]. However, the functions of NK cells in patients with severe infections were largely suppressed by transforming growth factor-β (TGF-β) [ 240 ].…”