ABSTRACT
Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.
Subject(s)
Betacoronavirus/pathogenicity , Cholesterol/biosynthesis , Coronavirus Infections/genetics , Cytokine Release Syndrome/genetics , Host-Pathogen Interactions/genetics , Leukocytes, Mononuclear/immunology , Pneumonia, Viral/genetics , Sterol Regulatory Element Binding Protein 2/genetics , Betacoronavirus/immunology , COVID-19 , Case-Control Studies , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Gene Expression Regulation , Heat-Shock Proteins/genetics , Heat-Shock Proteins/immunology , Host-Pathogen Interactions/immunology , Humans , Intensive Care Units , Interleukin-1beta/genetics , Interleukin-1beta/immunology , L-Lactate Dehydrogenase/genetics , L-Lactate Dehydrogenase/immunology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Lung/immunology , Lung/metabolism , Lung/virology , NF-kappa B/genetics , NF-kappa B/immunology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Primary Cell Culture , Proprotein Convertase 9/genetics , Proprotein Convertase 9/immunology , SARS-CoV-2 , Signal Transduction , Sterol Regulatory Element Binding Protein 2/immunology , Survival Analysis , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.