Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral th...Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.展开更多
The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has resulted in numerous confirmed cases and deaths worldwide.Recent studies have shown that people living with HIV(PLWH)are prone to develop se...The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has resulted in numerous confirmed cases and deaths worldwide.Recent studies have shown that people living with HIV(PLWH)are prone to develop severe illness and poor outcomes if they experience coronavirus disease 2019(COVID-19),especially those with uncontrolled viremia and low CD4 T-cell count.Therefore,many countries prioritized PLWH for COVID-19 vaccination.However,lower magnitude or faster waning humoral immune responses elicited by other vaccines have been documented in PLWH,raising concerns regarding the efficacy of the COVID-19 vaccine in these specific populations.Here,we summarize the current progress in the immunogenicity and efficacy of different types of SARS-CoV-2 vaccinations in PLWH and highlight several challenges faced by PLWH in the current COVID-19 pandemics.展开更多
The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a tremendous burden on public health and world economies.An efficient host immune response to acute SARS-CoV-2 infection requires ...The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a tremendous burden on public health and world economies.An efficient host immune response to acute SARS-CoV-2 infection requires rapid and early activation of the innate immune system.Natural killer(NK)cells represent a critical component of the innate immunity.Here,the appearance of CD56-CD16+NK cells and unconventional CD56^(dim) CD16^(neg) NK cells during the course of SARS-CoV-2 infection,and the phenotype and effector functions of NK cells during SARS-CoV-2 infection were summarized.The involvement of the dysregulated NK cells in the immunopathogenesis of the coronavirus disease 2019(COVID-19)and clinical trials of adoptive NK cell–based therapies against COVID-19 were also discussed.展开更多
The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications a...The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes.Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations;however,these clinical trials have excluded immunocompromised populations.Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines,raising concerns regarding the efficacy of COVID-19 vaccination in these populations.Thus,there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations.Here,we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations,including HIV-infected patients and those receiving immunosuppressive treatment,especially solid organ transplant recipients and those undergoing anti-CD20 treatment.We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.展开更多
Background:The ongoing global coronavirus disease 2019(COVID-19)pandemic is posing a serious public health threat to nations worldwide.Understanding the pathogenesis of the disease and host immune responses will facil...Background:The ongoing global coronavirus disease 2019(COVID-19)pandemic is posing a serious public health threat to nations worldwide.Understanding the pathogenesis of the disease and host immune responses will facilitate the discovery of therapeutic targets and better management of infected patients.Metabolomics technology can provide an unbiased tool to explore metabolic perturbation.Methods:Twenty-six healthy controls and 50 COVID-19 patients with mild,moderate,and severe symptoms in the Fifth Medical Center of PLA General Hospital from January 22 to February 16,2020 were recruited into the study.Fasting blood samples were collected and subject to metabolomics analysis by liquid chromatography–mass spectrometry.Metabolite abundance was measured by peak area and was log-transformed before statistical analysis.The principal component analysis,different expression analysis,and metabolic pathway analysis were performed using R package.Co-regulated metabolites and their associations with clinical indices were identified by the weighted correlation network analysis and Spearman correlation coefficients.The potential metabolite biomarkers were analyzed using a random forest model.Results:We uncovered over 100 metabolites that were associated with COVID-19 disease and many of them correlated with disease severity.Sets of highly correlated metabolites were identified and their correlations with clinical indices were presented.Further analyses linked the differential metabolites with biochemical reactions,metabolic pathways,and biomedical MeSH terms,offering contextual insights into disease pathogenesis and host responses.Finally,a panel of metabolites was discovered to be able to discriminate COVID-19 patients from healthy controls,and also another list for mild against more severe cases.Our findings showed that in COVID-19 patients,citrate cycle,sphingosine 1-phosphate in sphingolipid metabolism,and steroid hormone biosynthesis were downregulated,while purine metabolism and tryptophan metabolism were disturbed.Conclusion:This study discovered key metabolites as well as their related biological and medical concepts pertaining to COVID-19 pathogenesis and host immune response,which will facilitate the selection of potential biomarkers for prognosis and discovery of therapeutic targets.展开更多
Background:The development of severe coronavirus disease 2019(COVID-19)is associated with systemic hyperinflammation,which drives multi-organ failure and death.Disease deterioration tends to occur when the virus is re...Background:The development of severe coronavirus disease 2019(COVID-19)is associated with systemic hyperinflammation,which drives multi-organ failure and death.Disease deterioration tends to occur when the virus is receding;however,whether other factors besides viral products are involved in the inflammatory cascade remains unclear.Methods:Twenty-eight COVID-19 patients with laboratory-confirmed SARS-CoV-2 infection hospitalized at the Fifth Medical Center of Chinese PLA General Hospital from January 23 to February 20,2020 and nine healthy donors during the same period were recruited in the study.COVID-19 patients were grouped as mild,moderate,severe based on disease severity.Plasma damage-associated molecular patterns(DAMPs),including high mobility group box 1(HMGB1),calprotectin(S100A8/A9),surfactant protein A(SP-A),cold-inducible RNA-binding protein(CIRBP),and Histone H4 were detected by ELISA assay,and analyzed in combination with clinical data.Plasma cytokines,chemokines and lymphocytes were determined by flow cytometry.Results:Plasma levels of HMGB1(38292.3±4564.4 vs.32686.3±3678.1,P=0.002),S100A8/A9(1490.8±819.3 vs.742.2±300.8,P=0.015),and SP-A(6713.6±1708.7 vs.5296.3±1240.4,P=0.048)were increased in COVID-19 patients compared to healthy donors,while CIRBP(57.4±30.7 vs.111.9±55.2,P=0.004)levels decreased.Five DAMPs did not vary among mild,moderate,and severe patients.Moreover,SP-A levels correlated positively with inflammatory cytokines and negatively with time elapsed after symptom onset,whereas CIRBP showed an opposite pattern.Conclusions:These findings suggest SP-A may involve in the inflammation of COVID-19,while CIRBP likely plays a protective role.Therefore,DAMPs represent a potential target in the prevention or treatment of COVID-19.展开更多
基金supported by the Peking University Clinical Scientist Program Special(BMU2019LCKXJ013)the National Natural Science Foundation Innovation Research Group Project(81721002)+2 种基金the Sanming Project of Medicine Project in Shenzhen(SZSM201612014)the Yunnan Applied Basic Research Projects-Union Foundation by Yunnan Provincial Department of Science and Technology and Kunming Medical University(202001AY070001-154)the Scientific Research Fund of Education Department of Yunnan Province(2021J0297)。
文摘Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.
基金supported by the National Natural Science Foundation of China(No.82101837)the Beijing Natural Science Foundation(No.7222171)Emergency Key Program of Guangzhou Laboratory(EKPG21-30-4).
文摘The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has resulted in numerous confirmed cases and deaths worldwide.Recent studies have shown that people living with HIV(PLWH)are prone to develop severe illness and poor outcomes if they experience coronavirus disease 2019(COVID-19),especially those with uncontrolled viremia and low CD4 T-cell count.Therefore,many countries prioritized PLWH for COVID-19 vaccination.However,lower magnitude or faster waning humoral immune responses elicited by other vaccines have been documented in PLWH,raising concerns regarding the efficacy of the COVID-19 vaccine in these specific populations.Here,we summarize the current progress in the immunogenicity and efficacy of different types of SARS-CoV-2 vaccinations in PLWH and highlight several challenges faced by PLWH in the current COVID-19 pandemics.
基金National Natural Science Foundation of China(82101837)National Key R&D Program of China(2020YFC08860900)+1 种基金Youth Talent Lifting Project(2020-JCJQQT-034)Beijing Natural Science Foundation(7222171).
文摘The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a tremendous burden on public health and world economies.An efficient host immune response to acute SARS-CoV-2 infection requires rapid and early activation of the innate immune system.Natural killer(NK)cells represent a critical component of the innate immunity.Here,the appearance of CD56-CD16+NK cells and unconventional CD56^(dim) CD16^(neg) NK cells during the course of SARS-CoV-2 infection,and the phenotype and effector functions of NK cells during SARS-CoV-2 infection were summarized.The involvement of the dysregulated NK cells in the immunopathogenesis of the coronavirus disease 2019(COVID-19)and clinical trials of adoptive NK cell–based therapies against COVID-19 were also discussed.
基金National Natural Science Foundation of China (No.82101837)Beijing Natural Science Foundation(No.7222171)Emergency Key Program of Guangzhou Laboratory (No.EKPG21-30-4)。
文摘The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes.Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations;however,these clinical trials have excluded immunocompromised populations.Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines,raising concerns regarding the efficacy of COVID-19 vaccination in these populations.Thus,there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations.Here,we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations,including HIV-infected patients and those receiving immunosuppressive treatment,especially solid organ transplant recipients and those undergoing anti-CD20 treatment.We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.
基金supported by grants from the Innovative Research Team in the National Natural Science Foundation of China[81721002]the National Science and Technology Major Project[2018ZX10301202].
基金This work was supported by grants from the Youth Talent Lifting Project(2020-JCJQ-QT-034)the National Science and Technology Major Project of the Ministry of Science and Technology of China(2017ZX10202102-004-002).
文摘Background:The ongoing global coronavirus disease 2019(COVID-19)pandemic is posing a serious public health threat to nations worldwide.Understanding the pathogenesis of the disease and host immune responses will facilitate the discovery of therapeutic targets and better management of infected patients.Metabolomics technology can provide an unbiased tool to explore metabolic perturbation.Methods:Twenty-six healthy controls and 50 COVID-19 patients with mild,moderate,and severe symptoms in the Fifth Medical Center of PLA General Hospital from January 22 to February 16,2020 were recruited into the study.Fasting blood samples were collected and subject to metabolomics analysis by liquid chromatography–mass spectrometry.Metabolite abundance was measured by peak area and was log-transformed before statistical analysis.The principal component analysis,different expression analysis,and metabolic pathway analysis were performed using R package.Co-regulated metabolites and their associations with clinical indices were identified by the weighted correlation network analysis and Spearman correlation coefficients.The potential metabolite biomarkers were analyzed using a random forest model.Results:We uncovered over 100 metabolites that were associated with COVID-19 disease and many of them correlated with disease severity.Sets of highly correlated metabolites were identified and their correlations with clinical indices were presented.Further analyses linked the differential metabolites with biochemical reactions,metabolic pathways,and biomedical MeSH terms,offering contextual insights into disease pathogenesis and host responses.Finally,a panel of metabolites was discovered to be able to discriminate COVID-19 patients from healthy controls,and also another list for mild against more severe cases.Our findings showed that in COVID-19 patients,citrate cycle,sphingosine 1-phosphate in sphingolipid metabolism,and steroid hormone biosynthesis were downregulated,while purine metabolism and tryptophan metabolism were disturbed.Conclusion:This study discovered key metabolites as well as their related biological and medical concepts pertaining to COVID-19 pathogenesis and host immune response,which will facilitate the selection of potential biomarkers for prognosis and discovery of therapeutic targets.
基金This work was supported by the Innovation Groups of the National Natural Science Foundation of China(No.81721002)the National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2017ZX10202102-004-002)。
文摘Background:The development of severe coronavirus disease 2019(COVID-19)is associated with systemic hyperinflammation,which drives multi-organ failure and death.Disease deterioration tends to occur when the virus is receding;however,whether other factors besides viral products are involved in the inflammatory cascade remains unclear.Methods:Twenty-eight COVID-19 patients with laboratory-confirmed SARS-CoV-2 infection hospitalized at the Fifth Medical Center of Chinese PLA General Hospital from January 23 to February 20,2020 and nine healthy donors during the same period were recruited in the study.COVID-19 patients were grouped as mild,moderate,severe based on disease severity.Plasma damage-associated molecular patterns(DAMPs),including high mobility group box 1(HMGB1),calprotectin(S100A8/A9),surfactant protein A(SP-A),cold-inducible RNA-binding protein(CIRBP),and Histone H4 were detected by ELISA assay,and analyzed in combination with clinical data.Plasma cytokines,chemokines and lymphocytes were determined by flow cytometry.Results:Plasma levels of HMGB1(38292.3±4564.4 vs.32686.3±3678.1,P=0.002),S100A8/A9(1490.8±819.3 vs.742.2±300.8,P=0.015),and SP-A(6713.6±1708.7 vs.5296.3±1240.4,P=0.048)were increased in COVID-19 patients compared to healthy donors,while CIRBP(57.4±30.7 vs.111.9±55.2,P=0.004)levels decreased.Five DAMPs did not vary among mild,moderate,and severe patients.Moreover,SP-A levels correlated positively with inflammatory cytokines and negatively with time elapsed after symptom onset,whereas CIRBP showed an opposite pattern.Conclusions:These findings suggest SP-A may involve in the inflammation of COVID-19,while CIRBP likely plays a protective role.Therefore,DAMPs represent a potential target in the prevention or treatment of COVID-19.
