Objective:To compare the efficacy of pulsed-dose corticosteroids(≥250 mg methylprednisolone,3 days)and tocilizumab in treating COVID-19-related hyperinflammation.Methods:This prospective observational study included ...Objective:To compare the efficacy of pulsed-dose corticosteroids(≥250 mg methylprednisolone,3 days)and tocilizumab in treating COVID-19-related hyperinflammation.Methods:This prospective observational study included RT-PCR positive COVID-19 patients with acute respiratory distress syndrome,who were admitted to the COVID-19 Adult Intensive Care Unit of Prof Dr.Murat Dilmener Emergency Hospital(Istanbul,Turkey)between December 1,2020 and February 28,2021.Clinical,laboratory and radiological examinations were used to diagnose COVID-19 associated hyperinflammation.Three cohort groups were formed:the pulsed-dose corticosteroids group(250 mg methylprednisolone for 3 days),the tocilizumab group(8 mg/day single dose or 400 mg/day for 2 days),and the combined group(pulsed-dose corticosteroid+tocilizumab).The difference in mortality rates among the groups was compared primarily.The most common cause(s)of death was determined.Furthermore,adverse events(secondary infection,acute kidney injury,arrhythmia,gastrointestinal system bleeding)for 28 days were recorded.Results:A total of 60 patients were included in this study,with 20 patients in each group.There was no statistically significant difference between the 3 groups in mortality rates(55%in the pulsed corticosteroid group,60%in the tocilizumab group,50%in the combined group,χ2=0.404,P=0.817).Infectious causes were found to be the most common cause of mortality in all the three groups,and no difference was found between them(χ2=0.404,P=0.817).There was also no difference in the development of adverse events such as secondary infection,acute kidney injury,arrhythmia,and gastrointestinal bleeding among the groups(P>0.05).Conclusions:Corticosteroids can be used instead of tocilizumab to treat hyperinflammation in COVID-19 patients with acute respiratory distress syndrome.展开更多
Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release, underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis (FHL), a typically ...Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release, underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis (FHL), a typically pediatric onset autosomal recessive disorder with five known genetic subtypes (FHL1 - 5). FHL1 mutations have been mapped to chromosome 9, while the respective genes mutated in FHL2 (PRF1), FHL3 (UNC13D/Munc13-4), FHL4 (STX11) and FHL5 (STXBP2/ Munc18b/Munc18-2) have been identified. Perforin gene mutation directly affected the cytolytic activity of the cytotoxic granules. All the other FHL mutations appear to affect some aspect of cytotoxic granule exocytosis, resulting in impaired target cell killing by cytolytic T lymphocytes (CTLs) and/or natural killer (NK) cells. Recent findings suggest that failure to kill and detach from target cells, and prolonged synapse connection time, promote cytokine hypersecretion by the defective CTLs and NKs, which in turn result in systemic inflammation. Deciphering the genetics of FHL has contributed towards our understanding of the cell biology of hyperinflammatory responses and hemophagocytic lymphohistiocytosis accompanying pathological conditions such as cancer and viral infections.展开更多
Influenza A virus(IAV)poses a significant threat to human health.The outcome of IAV results from the viral-host interaction,with the underlying molecular mechanisms largely unknown.By integrating the plasma proteomics...Influenza A virus(IAV)poses a significant threat to human health.The outcome of IAV results from the viral-host interaction,with the underlying molecular mechanisms largely unknown.By integrating the plasma proteomics data of the IAV-infected patients into the viral-inflammation protein-protein interaction(VI-PPI)network created in this study,purine nucleoside phosphorylase(PNP),the critical enzyme in purine salvage,was identified as a potential hub gene that connected the different stages of IAV infection.Extended survival rates and reduced pulmonary inflammatory lesions were observed in alveolar epithelial cell(AEC)-specific PNP conditional knockout mice upon H1N1 infection.Mechanistically,PB1-F2 of IAV was revealed as a novel viral transcriptional factor to bind to the TATA box of PNP promoter,leading to enhanced purine salvage in H1N1-challenged AECs.The activation of PNP-mediated purine salvage was verified in IAV-infected patients and A549 cells.PNP knockdown elicited a purine metabolic shift from augmented salvage pathway to de novo synthesis,constraining both viral infection and pro-inflammatory signaling through APRT-AICAR-AMPK activation.Moreover,durdihydroartemisinin(DHA),predicted by VI-PPI as a novel PNP inhibitor,exerted beneficial effects on the survival and weight gain of H1N1-challenged mice via its direct binding to PNP.To reveal for the first time,we found that PNP,activated by IAV,plays a hub role within H1N1-host interaction,simultaneously modulating viral replication and hyperinflammation through purine salvage.Our study sheds new light on a“two-for-one”strategy by targeting purine salvage in combating IAV-related pathology,suggesting PNP as a potential novel anti-influenza host target.展开更多
The coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Hepatic involvement is common in SARS-CoV-2-infected individuals.It is currently accepted that th...The coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Hepatic involvement is common in SARS-CoV-2-infected individuals.It is currently accepted that the direct and indirect hepatic effects of SARS-CoV-2 infection play a significant role in COVID-19.In individuals with pre-existing infectious and non-infectious liver disease,who are at a remarkably higher risk of developing severe COVID-19 and death,this pathology is most medically relevant.This review emphasizes the current pathways regarded as contributing to the gastrointestinal and hepatic ailments linked to COVID-19-infected patients due to an imbalanced interaction among the liver,systemic inflammation,disrupted coagulation,and the lung.展开更多
Hemophagocytic lymphohistiocytosis(HLH)is a rare but devastating disease characterized by dysregulated immune response and hyp er inflammation.To our knowledge,pregnancy-induced HLH has been rarely reported in the lit...Hemophagocytic lymphohistiocytosis(HLH)is a rare but devastating disease characterized by dysregulated immune response and hyp er inflammation.To our knowledge,pregnancy-induced HLH has been rarely reported in the literature.A 30-year・old pregnant woman presented persistent fever for 21 days since 17 weeks of pregnancy.The possible etiologies such as infection,autoimmune disorder,and malignancy had been ruled out based on a series of exhaustive examinations.The disease progressed despite the use of broadspectrum antibiotics and dexamethasone.The patient was diagnosed as pregnancy-induced HLH,and finally recovered completely after termination of pregnancy by caesarean and the continuous use of glucocorticoid which played a crucial part in controlling hyp er inflammation.Pregnancy-induced HLH could be fatal if effective treatment was not initiated timely.Further studies are needed to improve early diagnosis and etiology identification of HLH.展开更多
Accumulating evidence indicates a potential role for bacterial lipopolysaccharide(LPs)in the overactivation of the immune response during SARS-CoV-2 infection.LPS is recognized by Toll-like receptor 4,mediating proinf...Accumulating evidence indicates a potential role for bacterial lipopolysaccharide(LPs)in the overactivation of the immune response during SARS-CoV-2 infection.LPS is recognized by Toll-like receptor 4,mediating proinflammatory effects.We previously reported that LPS directly interacts with SARS-CoV-2 spike(S)protein and enhances proinflammatory activities.Using native gel electrophoresis and hydrogen-deuterium exchange mass spectrometry,we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the S protein.Molecular simulations validated by a microscale thermophoresis binding assay revealed that LPS binds to the S2 pocket with a lower affinity compared to S1,suggesting a role as an intermediate in LPS transfer.Congruently,nuclear factor-kappa B(NF-kB)activation in monocytic THP-1 cells is strongly boosted by S2.Using NF-kB reporter mice followed by bioimaging,a boosting effect was observed for both S1 and S2,with the former potentially facilitated by proteolysis.The Omicron S variant binds to LPS,but with reduced affinity and LPS boosting in vitro and in vivo.Taken together,the data provide a molecular mechanism by which S protein augments LPS-mediated hyperinflammation.展开更多
The ongoing spread of coronavirus disease 2019(COVID-19)constitutes an international concern on an unprecedented scale.To date,over 23 million people have been diagnosed with COVID-19 worldwide,and this disease has ca...The ongoing spread of coronavirus disease 2019(COVID-19)constitutes an international concern on an unprecedented scale.To date,over 23 million people have been diagnosed with COVID-19 worldwide,and this disease has caused more than 800,000 deaths.Hyperinflammation elicited by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has been reported to contribute to illness severity and death.1,2 Humoral immune responses play important roles in therapy and prophylaxis for SARS-CoV-2 infection.Since the receptor-binding domain(RBD)of the SARS-CoV-2 spike(S)glycoprotein binds to angiotensinconverting enzyme 2 to trigger virion endocytosis,antibodies against this domain may be able to neutralize SARS-CoV-2 and possibly provide protective immunity in COVID-19 patients.3 Clinical trials investigating the administration of convalescent plasma and the interleukin(IL)-6 antagonist tocilizumab to treat COVID-19 patients are currently underway,4 but the overly robust expansion of antibody-secreting cells(ASCs)could play a major role in the pathogenicity of SARS-CoV-2 in COVID-19 patients.5 Thus,a detailed characterization of the associations between humoral immune responses and inflammatory factors could result in a better understanding of SARS-CoV-2-host interactions in COVID-19 patients.展开更多
文摘Objective:To compare the efficacy of pulsed-dose corticosteroids(≥250 mg methylprednisolone,3 days)and tocilizumab in treating COVID-19-related hyperinflammation.Methods:This prospective observational study included RT-PCR positive COVID-19 patients with acute respiratory distress syndrome,who were admitted to the COVID-19 Adult Intensive Care Unit of Prof Dr.Murat Dilmener Emergency Hospital(Istanbul,Turkey)between December 1,2020 and February 28,2021.Clinical,laboratory and radiological examinations were used to diagnose COVID-19 associated hyperinflammation.Three cohort groups were formed:the pulsed-dose corticosteroids group(250 mg methylprednisolone for 3 days),the tocilizumab group(8 mg/day single dose or 400 mg/day for 2 days),and the combined group(pulsed-dose corticosteroid+tocilizumab).The difference in mortality rates among the groups was compared primarily.The most common cause(s)of death was determined.Furthermore,adverse events(secondary infection,acute kidney injury,arrhythmia,gastrointestinal system bleeding)for 28 days were recorded.Results:A total of 60 patients were included in this study,with 20 patients in each group.There was no statistically significant difference between the 3 groups in mortality rates(55%in the pulsed corticosteroid group,60%in the tocilizumab group,50%in the combined group,χ2=0.404,P=0.817).Infectious causes were found to be the most common cause of mortality in all the three groups,and no difference was found between them(χ2=0.404,P=0.817).There was also no difference in the development of adverse events such as secondary infection,acute kidney injury,arrhythmia,and gastrointestinal bleeding among the groups(P>0.05).Conclusions:Corticosteroids can be used instead of tocilizumab to treat hyperinflammation in COVID-19 patients with acute respiratory distress syndrome.
文摘Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release, underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis (FHL), a typically pediatric onset autosomal recessive disorder with five known genetic subtypes (FHL1 - 5). FHL1 mutations have been mapped to chromosome 9, while the respective genes mutated in FHL2 (PRF1), FHL3 (UNC13D/Munc13-4), FHL4 (STX11) and FHL5 (STXBP2/ Munc18b/Munc18-2) have been identified. Perforin gene mutation directly affected the cytolytic activity of the cytotoxic granules. All the other FHL mutations appear to affect some aspect of cytotoxic granule exocytosis, resulting in impaired target cell killing by cytolytic T lymphocytes (CTLs) and/or natural killer (NK) cells. Recent findings suggest that failure to kill and detach from target cells, and prolonged synapse connection time, promote cytokine hypersecretion by the defective CTLs and NKs, which in turn result in systemic inflammation. Deciphering the genetics of FHL has contributed towards our understanding of the cell biology of hyperinflammatory responses and hemophagocytic lymphohistiocytosis accompanying pathological conditions such as cancer and viral infections.
基金supported by the National Natural Science Foundation of China(81830101 and 82301991)。
文摘Influenza A virus(IAV)poses a significant threat to human health.The outcome of IAV results from the viral-host interaction,with the underlying molecular mechanisms largely unknown.By integrating the plasma proteomics data of the IAV-infected patients into the viral-inflammation protein-protein interaction(VI-PPI)network created in this study,purine nucleoside phosphorylase(PNP),the critical enzyme in purine salvage,was identified as a potential hub gene that connected the different stages of IAV infection.Extended survival rates and reduced pulmonary inflammatory lesions were observed in alveolar epithelial cell(AEC)-specific PNP conditional knockout mice upon H1N1 infection.Mechanistically,PB1-F2 of IAV was revealed as a novel viral transcriptional factor to bind to the TATA box of PNP promoter,leading to enhanced purine salvage in H1N1-challenged AECs.The activation of PNP-mediated purine salvage was verified in IAV-infected patients and A549 cells.PNP knockdown elicited a purine metabolic shift from augmented salvage pathway to de novo synthesis,constraining both viral infection and pro-inflammatory signaling through APRT-AICAR-AMPK activation.Moreover,durdihydroartemisinin(DHA),predicted by VI-PPI as a novel PNP inhibitor,exerted beneficial effects on the survival and weight gain of H1N1-challenged mice via its direct binding to PNP.To reveal for the first time,we found that PNP,activated by IAV,plays a hub role within H1N1-host interaction,simultaneously modulating viral replication and hyperinflammation through purine salvage.Our study sheds new light on a“two-for-one”strategy by targeting purine salvage in combating IAV-related pathology,suggesting PNP as a potential novel anti-influenza host target.
文摘The coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Hepatic involvement is common in SARS-CoV-2-infected individuals.It is currently accepted that the direct and indirect hepatic effects of SARS-CoV-2 infection play a significant role in COVID-19.In individuals with pre-existing infectious and non-infectious liver disease,who are at a remarkably higher risk of developing severe COVID-19 and death,this pathology is most medically relevant.This review emphasizes the current pathways regarded as contributing to the gastrointestinal and hepatic ailments linked to COVID-19-infected patients due to an imbalanced interaction among the liver,systemic inflammation,disrupted coagulation,and the lung.
文摘Hemophagocytic lymphohistiocytosis(HLH)is a rare but devastating disease characterized by dysregulated immune response and hyp er inflammation.To our knowledge,pregnancy-induced HLH has been rarely reported in the literature.A 30-year・old pregnant woman presented persistent fever for 21 days since 17 weeks of pregnancy.The possible etiologies such as infection,autoimmune disorder,and malignancy had been ruled out based on a series of exhaustive examinations.The disease progressed despite the use of broadspectrum antibiotics and dexamethasone.The patient was diagnosed as pregnancy-induced HLH,and finally recovered completely after termination of pregnancy by caesarean and the continuous use of glucocorticoid which played a crucial part in controlling hyp er inflammation.Pregnancy-induced HLH could be fatal if effective treatment was not initiated timely.Further studies are needed to improve early diagnosis and etiology identification of HLH.
基金This work was supported by BIl(A*STAR)core fundsgrants FY21_CF_HTPO SEED_ID_BIl_C211418001 funded by A*STAR+3 种基金the Swedish Research Council(projects 2017-02341 and 2020-02016)Edvard Welanders Stiftelse and Finsenstiftelsen(Hudfonden)the Torsten Soderberg,Crafoord,and Osterlund Foundations,Stiftelsen Lars Hiertas Minnethe Royal Physiographic Society of Lund,and the Swedish Government Funds for Clinical Research(ALF).
文摘Accumulating evidence indicates a potential role for bacterial lipopolysaccharide(LPs)in the overactivation of the immune response during SARS-CoV-2 infection.LPS is recognized by Toll-like receptor 4,mediating proinflammatory effects.We previously reported that LPS directly interacts with SARS-CoV-2 spike(S)protein and enhances proinflammatory activities.Using native gel electrophoresis and hydrogen-deuterium exchange mass spectrometry,we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the S protein.Molecular simulations validated by a microscale thermophoresis binding assay revealed that LPS binds to the S2 pocket with a lower affinity compared to S1,suggesting a role as an intermediate in LPS transfer.Congruently,nuclear factor-kappa B(NF-kB)activation in monocytic THP-1 cells is strongly boosted by S2.Using NF-kB reporter mice followed by bioimaging,a boosting effect was observed for both S1 and S2,with the former potentially facilitated by proteolysis.The Omicron S variant binds to LPS,but with reduced affinity and LPS boosting in vitro and in vivo.Taken together,the data provide a molecular mechanism by which S protein augments LPS-mediated hyperinflammation.
基金supported by the National Key R&D Program of China(2018YFA0507403 and 2019YFA0508502)the National Natural Science Foundation of China(81788101,81771685,and 81972679)the Emergency Project of Anhui Medical University of Science and Technology(YJGG202002).
文摘The ongoing spread of coronavirus disease 2019(COVID-19)constitutes an international concern on an unprecedented scale.To date,over 23 million people have been diagnosed with COVID-19 worldwide,and this disease has caused more than 800,000 deaths.Hyperinflammation elicited by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has been reported to contribute to illness severity and death.1,2 Humoral immune responses play important roles in therapy and prophylaxis for SARS-CoV-2 infection.Since the receptor-binding domain(RBD)of the SARS-CoV-2 spike(S)glycoprotein binds to angiotensinconverting enzyme 2 to trigger virion endocytosis,antibodies against this domain may be able to neutralize SARS-CoV-2 and possibly provide protective immunity in COVID-19 patients.3 Clinical trials investigating the administration of convalescent plasma and the interleukin(IL)-6 antagonist tocilizumab to treat COVID-19 patients are currently underway,4 but the overly robust expansion of antibody-secreting cells(ASCs)could play a major role in the pathogenicity of SARS-CoV-2 in COVID-19 patients.5 Thus,a detailed characterization of the associations between humoral immune responses and inflammatory factors could result in a better understanding of SARS-CoV-2-host interactions in COVID-19 patients.
