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Chen Q, Xu R, Gu Y, Peng J, Ma C, Su D, Liu S, Ge D, Yang Y, Ning W. Respiratory pathogen analysis in pediatric inpatients unraveled the infection pattern of Mycoplasma pneumoniae post the COVID-19 pandemic. Front Public Health 2024; 12:1437508. [PMID: 39444963 PMCID: PMC11496064 DOI: 10.3389/fpubh.2024.1437508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024] Open
Abstract
Background To counteract the COVID-19 pandemic, nonpharmaceutical interventions (NPIs) were implemented globally, exerting a profound influence on a wide spectrum of infectious diseases, encompassing respiratory tract infections (RTIs). Subsequent to the easing of NPIs, China experienced a significant outbreak of Mycoplasma pneumoniae (MP). Methods Over a decade from 2015 to 2024, our study scrutinized 12 common infectious diseases among pediatric children. Etiologically diagnostic data and clinical outcome metrics of children with RTIs, tested for 13 pathogens, were analyzed to evaluate changes during and after the pandemic compared to pre-pandemic periods, with a notable emphasis on age profile and coinfection patterns of MP. Results Among 57,471 hospitalized children, 23,178 were diagnosed with infectious diseases. Under NPIs, most respiratory infections declined compared to pre-pandemic levels, rebounding by 69.64% in 2023. While the infection rate of common respiratory pathogens decreased, cases of respiratory syncytial virus increased during the period of extensive NPI implementation. In 2023, pediatric intensive care unit durations for these pathogens increased, suggesting greater severity of illness compared to 2019. MP exhibited the highest infection rate (31.38% average), with a notable outbreak post-pandemic due to severity increase in <3 year olds and rise among older children. NPIs reduced MP coinfections and mitigated their severity, while exerting a significant influence on bacterial coinfections with MP over the span of 5 years, in contrast to their impact on viral pathogens. Conclusion NPIs effectively curb transmission of respiratory infections by most pathogens, resulting in increased average age of MP infections and altered patterns of coinfection post-pandemic.
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Affiliation(s)
- Qihong Chen
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Ruizhi Xu
- Institute for Clinical Medical Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Gu
- Institute for Clinical Medical Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Jie Peng
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Chiyuan Ma
- Institute for Clinical Medical Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Dubin Su
- Institute for Clinical Medical Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Shuai Liu
- Institute for Clinical Medical Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Dandan Ge
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Yungang Yang
- Department of Pediatrics, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Department of Pediatrics, Pediatric Key Laboratory of Xiamen, the First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Wanshan Ning
- Institute for Clinical Medical Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Bie Y, Zhang J, Chen J, Zhang Y, Huang M, Zhang L, Zhou X, Qiu Y. Design of antiviral AGO2-dependent short hairpin RNAs. Virol Sin 2024; 39:645-654. [PMID: 38734183 PMCID: PMC11401469 DOI: 10.1016/j.virs.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
The increasing emergence and re-emergence of RNA virus outbreaks underlines the urgent need to develop effective antivirals. RNA interference (RNAi) is a sequence-specific gene silencing mechanism that is triggered by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs), which exhibits significant promise for antiviral therapy. AGO2-dependent shRNA (agshRNA) generates a single-stranded guide RNA and presents significant advantages over traditional siRNA and shRNA. In this study, we applied a logistic regression algorithm to a previously published chemically siRNA efficacy dataset and built a machine learning-based model with high predictive power. Using this model, we designed siRNA sequences targeting diverse RNA viruses, including human enterovirus A71 (EV71), Zika virus (ZIKV), dengue virus 2 (DENV2), mouse hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and transformed them into agshRNAs. We validated the performance of our agshRNA design by evaluating antiviral efficacies of agshRNAs in cells infected with different viruses. Using the agshRNA targeting EV71 as an example, we showed that the anti-EV71 effect of agshRNA was more potent compared with the corresponding siRNA and shRNA. Moreover, the antiviral effect of agshRNA is dependent on AGO2-processed guide RNA, which can load into the RNA-induced silencing complex (RISC). We also confirmed the antiviral effect of agshRNA in vivo. Together, this work develops a novel antiviral strategy that combines machine learning-based algorithm with agshRNA design to custom design antiviral agshRNAs with high efficiency.
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Affiliation(s)
- Yuanyuan Bie
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jieling Zhang
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Jiyao Chen
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
| | - Yumin Zhang
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
| | - Muhan Huang
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
| | - Leike Zhang
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xi Zhou
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
| | - Yang Qiu
- Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
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Wang T, Chen H, Li N, Zhang B, Min H. Aqueous humor proteomics analyzed by bioinformatics and machine learning in PDR cases versus controls. Clin Proteomics 2024; 21:36. [PMID: 38764026 PMCID: PMC11103871 DOI: 10.1186/s12014-024-09481-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 04/07/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND To comprehend the complexities of pathophysiological mechanisms and molecular events that contribute to proliferative diabetic retinopathy (PDR) and evaluate the diagnostic value of aqueous humor (AH) in monitoring the onset of PDR. METHODS A cohort containing 16 PDR and 10 cataract patients and another validation cohort containing 8 PDR and 4 cataract patients were studied. AH was collected and subjected to proteomics analyses. Bioinformatics analysis and a machine learning-based pipeline called inference of biomolecular combinations with minimal bias were used to explore the functional relevance, hub proteins, and biomarkers. RESULTS Deep profiling of AH proteomes revealed several insights. First, the combination of SIAE, SEMA7A, GNS, and IGKV3D-15 and the combination of ATP6AP1, SPARCL1, and SERPINA7 could serve as surrogate protein biomarkers for monitoring PDR progression. Second, ALB, FN1, ACTB, SERPINA1, C3, and VTN acted as hub proteins in the profiling of AH proteomes. SERPINA1 was the protein with the highest correlation coefficient not only for BCVA but also for the duration of diabetes. Third, "Complement and coagulation cascades" was an important pathway for PDR development. CONCLUSIONS AH proteomics provides stable and accurate biomarkers for early warning and diagnosis of PDR. This study provides a deep understanding of the molecular mechanisms of PDR and a rich resource for optimizing PDR management.
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Affiliation(s)
- Tan Wang
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuai Fu Yuan, Dongcheng District, Beijing, 100730, China
- Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Huan Chen
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuai Fu Yuan, Dongcheng District, Beijing, 100730, China
- Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Ningning Li
- Operating Room, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Bao Zhang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, 611130, China
| | - Hanyi Min
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuai Fu Yuan, Dongcheng District, Beijing, 100730, China.
- Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
- Department of Ophthalmology, Aier Eye Hospital, Tianjin University, Nankai District, Fukang Road No.102, Tianjin, China.
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Mahin A, Soman SP, Modi PK, Raju R, Keshava Prasad TS, Abhinand CS. Meta-analysis of the serum/plasma proteome identifies significant associations between COVID-19 with Alzheimer's/Parkinson's diseases. J Neurovirol 2024; 30:57-70. [PMID: 38167982 DOI: 10.1007/s13365-023-01191-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/22/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2024]
Abstract
In recent years, we have seen the widespread devastations and serious health complications manifested by COVID-19 globally. Although we have effectively controlled the pandemic, uncertainties persist regarding its potential long-term effects, including prolonged neurological issues. To gain comprehensive insights, we conducted a meta-analysis of mass spectrometry-based proteomics data retrieved from different studies with a total of 538 COVID-19 patients and 523 healthy controls. The meta-analysis revealed that top-enriched pathways were associated with neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD). Further analysis confirmed a direct correlation in the expression patterns of 24 proteins involved in Alzheimer's and 23 proteins in Parkinson's disease with COVID-19. Protein-protein interaction network and cluster analysis identified SNCA as a hub protein, a known biomarker for Parkinson's disease, in both AD and PD. To the best of our knowledge, this is the first meta-analysis study providing proteomic profiling evidence linking COVID-19 to neurological complications.
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Affiliation(s)
- Althaf Mahin
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Sreelakshmi Pathappillil Soman
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Prashant Kumar Modi
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, Karnataka, 575018, India.
| | | | - Chandran S Abhinand
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to Be University), Mangalore, 575018, India.
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Mizuno H, Murakami N. Multi-omics Approach in Kidney Transplant: Lessons Learned from COVID-19 Pandemic. CURRENT TRANSPLANTATION REPORTS 2023; 10:173-187. [PMID: 38152593 PMCID: PMC10751044 DOI: 10.1007/s40472-023-00410-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2023] [Indexed: 12/29/2023]
Abstract
Purpose of Review Multi-omics approach has advanced our knowledge on transplantation-associated clinical outcomes, such as acute rejection and infection, and emerging omics data are becoming available in kidney transplant and COVID-19. Herein, we discuss updated findings of multi-omics data on kidney transplant outcomes, as well as COVID-19 and kidney transplant. Recent Findings Transcriptomics, proteomics, and metabolomics revealed various inflammation pathways associated with kidney transplantation-related outcomes and COVID-19. Although multi-omics data on kidney transplant and COVID-19 is limited, activation of innate immune pathways and suppression of adaptive immune pathways were observed in the active phase of COVID-19 in kidney transplant recipients. Summary Multi-omics analysis has led us to a deeper exploration and a more comprehensive understanding of key biological pathways in complex clinical settings, such as kidney transplantation and COVID-19. Future multi-omics analysis leveraging multi-center biobank collaborative will further advance our knowledge on the precise immunological responses to allograft and emerging pathogens.
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Affiliation(s)
- Hiroki Mizuno
- Transplant Research Center, Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave. EBRC 305, Boston, MA 02115, USA
- Dvision of Nephrology and Rheumatology, Toranomon Hospital, Tokyo, Japan
| | - Naoka Murakami
- Transplant Research Center, Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave. EBRC 305, Boston, MA 02115, USA
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Zhang Z, Cao C, Zhou CL, Li X, Miao C, Shen L, Singla RK, Lu X. Identification of a novel 5-methylcytosine-related signature for prognostic prediction of kidney renal papillary cell carcinoma and a Putative target for drug repurposing. Transl Oncol 2023; 36:101741. [PMID: 37523897 PMCID: PMC10400932 DOI: 10.1016/j.tranon.2023.101741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 03/14/2023] [Accepted: 07/17/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Many studies have demonstrated the crucial roles of 5-methylcytosine (m5C) RNA methylation in cancer pathogenesis. METHODS Two datasets, including TCGA-KIRP and ICGC, and related clinical information were downloaded, where the expression of 13 m5C regulators was examined. We applied LASSO regression to construct a multi-m5C-regulator-based signature in the TCGA cohort, which was further validated using the ICGC cohort. Univariate and multivariate Cox regressions were applied to evaluate the independent prognostic value of our model. The differences in biological functions and immune characterizations between high and low-risk groups divided based on the risk scores were also investigated via multiple approaches, such as enrichment analyses, mutation mining, and immune scoring. Finally, the sensitivities of commonly used targeted drugs were tested, and the connectivity MAP (cMAP) was utilized to screen potentially effective molecules for patients in the high-risk group. Experimental validation was done following qPCR tests in Caki-2 and HK-2 cell lines. RESULTS 3 m5C regulators, including ALYREF, DNMT3B and YBX1, were involved in our model. Survival analysis revealed a worse prognosis for patients in the high-risk group. Cox regression results indicated our model's superior predictive performance compared to single-factor prognostic evaluation. Functional enrichment analyses indicated a higher mutation frequency and poorer tumor microenvironment of patients in the high-risk group. qPCR-based results revealed that ALYREF, DNMT3B, and YBX1 were significantly up-regulated in Caki-2 cell lines compared with HK-2 cell lines. Molecules like BRD-K72451865, Levosimendan, and BRD-K03515135 were advised by cMAP for patients in the high-risk group. CONCLUSION Our study presented a novel predictive model for KIRP prognosis. Furthermore, the results of our analysis provide new insights for investigating m5C events in KIRP pathogenesis.
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Affiliation(s)
- Zhen Zhang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
| | - Chunhua Cao
- Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China; Institute of Oncology, Hubei University of Arts and Science, Xiangyang 441021, China
| | - Chun-Li Zhou
- Department of Anesthesiology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China
| | - Xilong Li
- Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Changhong Miao
- Department of Anesthesiology, Cancer Hospital of Fudan University, Shanghai 200032, China
| | - Li Shen
- Department of Biomedical Engineering, Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Rajeev K Singla
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab-144411, India.
| | - Xihua Lu
- Department of Anesthesiology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
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Zhang F, Luna A, Tan T, Chen Y, Sander C, Guo T. COVIDpro: Database for Mining Protein Dysregulation in Patients with COVID-19. J Proteome Res 2023; 22:2847-2859. [PMID: 37555633 DOI: 10.1021/acs.jproteome.3c00092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
The ongoing pandemic of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 still has limited treatment options. Our understanding of the molecular dysregulations that occur in response to infection remains incomplete. We developed a web application COVIDpro (https://www.guomics.com/covidPro/) that includes proteomics data obtained from 41 original studies conducted in 32 hospitals worldwide, involving 3077 patients and covering 19 types of clinical specimens, predominantly plasma and serum. The data set encompasses 53 protein expression matrices, comprising a total of 5434 samples and 14,403 unique proteins. We identified a panel of proteins that exhibit significant dysregulation, enabling the classification of COVID-19 patients into severe and non-severe disease categories. The proteomic signatures achieved promising results in distinguishing severe cases, with a mean area under the curve of 0.87 and accuracy of 0.80 across five independent test sets. COVIDpro serves as a valuable resource for testing hypotheses and exploring potential targets for novel treatments in COVID-19 patients.
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Affiliation(s)
- Fangfei Zhang
- Fudan University, 220 Handan Road, Shanghai 200433, China
- Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province 310024, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province 310024, China
- Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou, Zhejiang 310030, China
| | - Augustin Luna
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
- Broad Institute of MIT and Harvard, Cambridge, Cambridge, Massachusetts 02142, United States
| | - Tingting Tan
- Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province 310024, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province 310024, China
- Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou, Zhejiang 310030, China
| | - Yingdan Chen
- Westlake Omics (Hangzhou) Biotechnology Company Limited, Hangzhou, Zhejiang Province 310024, China
| | - Chris Sander
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
- Broad Institute of MIT and Harvard, Cambridge, Cambridge, Massachusetts 02142, United States
| | - Tiannan Guo
- Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province 310024, China
- Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province 310024, China
- Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Hangzhou, Zhejiang 310030, China
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Kong J, Bie Y, Ji W, Xu J, Lyu B, Xiong X, Qiu Y, Zhou X. Alphavirus infection triggers antiviral RNAi immunity in mammals. Cell Rep 2023; 42:112441. [PMID: 37104090 DOI: 10.1016/j.celrep.2023.112441] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/29/2023] [Accepted: 04/11/2023] [Indexed: 04/28/2023] Open
Abstract
RNA interference (RNAi) is a well-established antiviral immunity. However, for mammalian somatic cells, antiviral RNAi becomes evident only when viral suppressors of RNAi (VSRs) are disabled by mutations or VSR-targeting drugs, thereby limiting its scope as a mammalian immunity. We find that a wild-type alphavirus, Semliki Forest virus (SFV), triggers the Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs) in both mammalian somatic cells and adult mice. These SFV-vsiRNAs are located at a particular region within the 5' terminus of the SFV genome, Argonaute loaded, and active in conferring effective anti-SFV activity. Sindbis virus, another alphavirus, also induces vsiRNA production in mammalian somatic cells. Moreover, treatment with enoxacin, an RNAi enhancer, inhibits SFV replication dependent on RNAi response in vitro and in vivo and protects mice from SFV-induced neuropathogenesis and lethality. These findings show that alphaviruses trigger the production of active vsiRNA in mammalian somatic cells, highlighting the functional importance and therapeutic potential of antiviral RNAi in mammals.
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Affiliation(s)
- Jing Kong
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuanyuan Bie
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenting Ji
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Jiuyue Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bao Lyu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaobei Xiong
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
| | - Yang Qiu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Xi Zhou
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
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Berezhnoy G, Bissinger R, Liu A, Cannet C, Schäfer H, Kienzle K, Bitzer M, Häberle H, Göpel S, Trautwein C, Singh Y. Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome patients. Front Immunol 2023; 14:1144224. [PMID: 37228606 PMCID: PMC10203989 DOI: 10.3389/fimmu.2023.1144224] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 04/17/2023] [Indexed: 05/27/2023] Open
Abstract
Background Deep metabolomic, proteomic and immunologic phenotyping of patients suffering from an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Several studies have described the role of small as well as complex molecules such as metabolites, cytokines, chemokines and lipoproteins during infection and in recovered patients. In fact, after an acute SARS-CoV-2 viral infection almost 10-20% of patients experience persistent symptoms post 12 weeks of recovery defined as long-term COVID-19 syndrome (LTCS) or long post-acute COVID-19 syndrome (PACS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these biomolecules altogether govern pathophysiology is largely underexplored. Thus, a clear understanding of how these parameters within an integrated fashion could predict the disease course would help to stratify LTCS patients from acute COVID-19 or recovered patients. This could even allow to elucidation of a potential mechanistic role of these biomolecules during the disease course. Methods This study comprised subjects with acute COVID-19 (n=7; longitudinal), LTCS (n=33), Recov (n=12), and no history of positive testing (n=73). 1H-NMR-based metabolomics with IVDr standard operating procedures verified and phenotyped all blood samples by quantifying 38 metabolites and 112 lipoprotein properties. Univariate and multivariate statistics identified NMR-based and cytokine changes. Results Here, we report on an integrated analysis of serum/plasma by NMR spectroscopy and flow cytometry-based cytokines/chemokines quantification in LTCS patients. We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls (HC) or acute COVID-19 patients. Subsequently, correlation analysis in LTCS group only among cytokines and amino acids revealed that histidine and glutamine were uniquely attributed mainly with pro-inflammatory cytokines. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared with HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their phenylalanine, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except for IL-18 chemokine, which tended to be higher in LTCS patients. Conclusion The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict ongoing severity of LTCS patients.
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Affiliation(s)
- Georgy Berezhnoy
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
| | - Rosi Bissinger
- Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany
| | - Anna Liu
- Research Institute of Women’s Health, University of Tübingen, Tübingen, Germany
| | - Claire Cannet
- Bruker BioSpin, Applied Industrial and Clinical Division, Ettlingen, Germany
| | - Hartmut Schäfer
- Bruker BioSpin, Applied Industrial and Clinical Division, Ettlingen, Germany
| | - Katharina Kienzle
- Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany
| | - Michael Bitzer
- Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany
- Center for Personalized Medicine, University Hospital Tübingen, Tubingen, Germany
| | - Helene Häberle
- Department of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Siri Göpel
- Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany
| | - Christoph Trautwein
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
| | - Yogesh Singh
- Research Institute of Women’s Health, University of Tübingen, Tübingen, Germany
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- Next Generation Sequencing (NGS) Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany
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10
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Stricker S, Ziegahn N, Karsten M, Boeckel T, Stich-Boeckel H, Maske J, Rugo E, Balazs A, Millar Büchner P, Dang-Heine C, Schriever V, Eils R, Lehmann I, Sander LE, Ralser M, Corman VM, Mall MA, Sawitzki B, Roehmel J. RECAST: Study protocol for an observational study for the understanding of the increased REsilience of Children compared to Adults in SARS-CoV-2 infecTion. BMJ Open 2023; 13:e065221. [PMID: 37068896 PMCID: PMC10111194 DOI: 10.1136/bmjopen-2022-065221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2023] Open
Abstract
INTRODUCTION The SARS-CoV-2 pandemic remains a threat to public health. Soon after its outbreak, it became apparent that children are less severely affected. Indeed, opposing clinical manifestations between children and adults are observed for other infections. The SARS-CoV-2 outbreak provides the unique opportunity to study the underlying mechanisms. This protocol describes the methods of an observational study that aims to characterise age dependent differences in immune responses to primary respiratory infections using SARS-CoV-2 as a model virus and to assess age differences in clinical outcomes including lung function. METHODS AND ANALYSIS The study aims to recruit at least 120 children and 60 adults that are infected with SARS-CoV-2 and collect specimen for a multiomics analysis, including single cell RNA sequencing of nasal epithelial cells and peripheral blood mononuclear cells, mass cytometry of whole blood samples and nasal cells, mass spectrometry-based serum and plasma proteomics, nasal epithelial cultures with functional in vitro analyses, SARS-CoV-2 antibody testing, sequencing of the viral genome and lung function testing. Data obtained from this multiomics approach are correlated with medical history and clinical data. Recruitment started in October 2020 and is ongoing. ETHICS AND DISSEMINATION The study was reviewed and approved by the Ethics Committee of Charité - Universitätsmedizin Berlin (EA2/066/20). All collected specimens are stored in the central biobank of Charité - Universitätsmedizin Berlin and are made available to all participating researchers and on request. TRIAL REGISTRATION NUMBER DRKS00025715, pre-results publication.
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Affiliation(s)
- Sebastian Stricker
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Niklas Ziegahn
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Martin Karsten
- Karsten, Rugo, Wagner, Paediatric Practice, Berlin, Germany
| | - Thomas Boeckel
- Boeckel, Haverkaemper, Paediatric Practice and Practice for Paediatric Cardiology, Berlin, Germany
| | | | - Jakob Maske
- Maske, Pankok, Paediatric Practice, Berlin, Germany
| | - Evelyn Rugo
- Karsten, Rugo, Wagner, Paediatric Practice, Berlin, Germany
| | - Anita Balazs
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Pamela Millar Büchner
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Chantip Dang-Heine
- Clinical Study Center (CSC), Berlin Institute of Health at Charité, Berlin, Germany
| | - Valentin Schriever
- Department of Paediatric Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Roland Eils
- Center for Digital Health, Berlin Institute of Health at Charité, Berlin, Germany
- Molecular Epidemiology Unit, Berlin Institute of Health at Charité, Berlin, Germany
| | - Irina Lehmann
- Center for Digital Health, Berlin Institute of Health at Charité, Berlin, Germany
- German Center for Lung Research, Giessen, Germany
| | - Leif E Sander
- Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Markus Ralser
- Department of Biochemistry, Charité Universitätsmedizin Berlin, Berlin, Germany
- Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK
| | - Victor M Corman
- Institute of Virology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Marcus A Mall
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Giessen, Germany
| | - Birgit Sawitzki
- Berlin Institute of Health, Berlin, Germany
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jobst Roehmel
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
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11
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Druzak S, Iffrig E, Roberts BR, Zhang T, Fibben KS, Sakurai Y, Verkerke HP, Rostad CA, Chahroudi A, Schneider F, Wong AKH, Roberts AM, Chandler JD, Kim SO, Mosunjac M, Mosunjac M, Geller R, Albizua I, Stowell SR, Arthur CM, Anderson EJ, Ivanova AA, Ahn J, Liu X, Maner-Smith K, Bowen T, Paiardini M, Bosinger SE, Roback JD, Kulpa DA, Silvestri G, Lam WA, Ortlund EA, Maier CL. Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19. Nat Commun 2023; 14:1638. [PMID: 37015925 PMCID: PMC10073144 DOI: 10.1038/s41467-023-37269-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 03/08/2023] [Indexed: 04/06/2023] Open
Abstract
The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.
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Grants
- T32 GM142617 NIGMS NIH HHS
- P51 OD011132 NIH HHS
- R35 HL145000 NHLBI NIH HHS
- K99 HL150626 NHLBI NIH HHS
- T32 GM135060 NIGMS NIH HHS
- F31 DK126435 NIDDK NIH HHS
- R01 DK115213 NIDDK NIH HHS
- R38 AI140299 NIAID NIH HHS
- A F31 training fellowship from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), F31DK126435, supported S.A.D during the duration of this work. Stimulating Access to Research in Residency of the National Institutes of Health under Award Number R38AI140299 supported E.I. R35HL145000 supported E.I, Y.S, K.S.F and W.A.L. National Institutes of Health National Heart, Lung, and Blood Institute (NIH/NHLBI) HL150658, awarded to J.D.C. A training grant supported by the Biochemistry and Cell Developmental Biology program (BCDB) at Emory university, T32GM135060-02S1, to S.O.K. NIH/NIDDK Grant R01-DK115213 and Winship Synergy Award to E.A.O. NIH/NHLBI K99 HL150626-01 awarded to C.L.M. The lipidomics and metabolomics experiments were supported by the Emory Integrated Metabolomics and Lipidomics Core, which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.
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Affiliation(s)
- Samuel Druzak
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Elizabeth Iffrig
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Blaine R Roberts
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Tiantian Zhang
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Kirby S Fibben
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Yumiko Sakurai
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Hans P Verkerke
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Christina A Rostad
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Ann Chahroudi
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Frank Schneider
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Andrew Kam Ho Wong
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Emory National Primate Research Center, Atlanta, GA, USA
| | - Anne M Roberts
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - Joshua D Chandler
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Susan O Kim
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Mario Mosunjac
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Marina Mosunjac
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Rachel Geller
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Georgia Bureau of Investigation, Decatur, GA, USA
| | - Igor Albizua
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Sean R Stowell
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Connie M Arthur
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Evan J Anderson
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Anna A Ivanova
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Jun Ahn
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Xueyun Liu
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Kristal Maner-Smith
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Thomas Bowen
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA
| | - Mirko Paiardini
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Emory National Primate Research Center, Atlanta, GA, USA
| | - Steve E Bosinger
- Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Emory National Primate Research Center, Atlanta, GA, USA
- Emory Vaccine Center, Atlanta, GA, USA
| | - John D Roback
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Deanna A Kulpa
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Emory National Primate Research Center, Atlanta, GA, USA
- Center for AIDS Research, Emory University, Atlanta, GA, USA
| | - Guido Silvestri
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Emory National Primate Research Center, Atlanta, GA, USA
- Emory Vaccine Center, Atlanta, GA, USA
- Center for AIDS Research, Emory University, Atlanta, GA, USA
| | - Wilbur A Lam
- Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
- Children's Healthcare of Atlanta, Atlanta, GA, USA.
| | - Eric A Ortlund
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
- Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA.
| | - Cheryl L Maier
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
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12
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Sahin AT, Yurtseven A, Dadmand S, Ozcan G, Akarlar BA, Kucuk NEO, Senturk A, Ergonul O, Can F, Tuncbag N, Ozlu N. Plasma proteomics identify potential severity biomarkers from COVID-19 associated network. Proteomics Clin Appl 2023; 17:e2200070. [PMID: 36217943 PMCID: PMC9874836 DOI: 10.1002/prca.202200070] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/27/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022]
Abstract
PURPOSE Coronavirus disease 2019 (COVID-19) continues to threaten public health globally. Severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection-dependent alterations in the host cell signaling network may unveil potential target proteins and pathways for therapeutic strategies. In this study, we aim to define early severity biomarkers and monitor altered pathways in the course of SARS-CoV-2 infection. EXPERIMENTAL DESIGN We systematically analyzed plasma proteomes of COVID-19 patients from Turkey by using mass spectrometry. Different severity grades (moderate, severe, and critical) and periods of disease (early, inflammatory, and recovery) are monitored. Significant alterations in protein expressions are used to reconstruct the COVID-19 associated network that was further extended to connect viral and host proteins. RESULTS Across all COVID-19 patients, 111 differentially expressed proteins were found, of which 28 proteins were unique to our study mainly enriching in immunoglobulin production. By monitoring different severity grades and periods of disease, CLEC3B, MST1, and ITIH2 were identified as potential early predictors of COVID-19 severity. Most importantly, we extended the COVID-19 associated network with viral proteins and showed the connectedness of viral proteins with human proteins. The most connected viral protein ORF8, which has a role in immune evasion, targets many host proteins tightly connected to the deregulated human plasma proteins. CONCLUSIONS AND CLINICAL RELEVANCE Plasma proteomes from critical patients are intrinsically clustered in a distinct group than severe and moderate patients. Importantly, we did not recover any grouping based on the infection period, suggesting their distinct proteome even in the recovery phase. The new potential early severity markers can be further studied for their value in the clinics to monitor COVID-19 prognosis. Beyond the list of plasma proteins, our disease-associated network unravels altered pathways, and the possible therapeutic targets in SARS-CoV-2 infection by connecting human and viral proteins. Follow-up studies on the disease associated network that we propose here will be useful to determine molecular details of viral perturbation and to address how the infection affects human physiology.
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Affiliation(s)
- Ayse Tugce Sahin
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.,Graduate School of Science and Engineering, Koc University, Istanbul, Turkey
| | - Ali Yurtseven
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.,Graduate School of Science and Engineering, Koc University, Istanbul, Turkey
| | - Sina Dadmand
- Graduate School of Science and Engineering, Koc University, Istanbul, Turkey.,Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey
| | - Gulin Ozcan
- Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.,Graduate School of Health Sciences, Koc University, Istanbul, Turkey
| | - Busra A Akarlar
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.,Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey
| | - Nazli Ezgi Ozkan Kucuk
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.,Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey
| | - Aydanur Senturk
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey
| | - Onder Ergonul
- Graduate School of Health Sciences, Koc University, Istanbul, Turkey.,Koc University Is Bank Research Center for Infectious Diseases (KUISCID), Istanbul, Turkey
| | - Fusun Can
- Graduate School of Health Sciences, Koc University, Istanbul, Turkey.,Department of Infectious Diseases, School of Medicine, Koc University, Istanbul, Turkey
| | - Nurcan Tuncbag
- Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.,Department of Medical Microbiology, School of Medicine, Koc University, Istanbul, Turkey.,Department of Medical Biology, School of Medicine, Koc University, Istanbul, Turkey
| | - Nurhan Ozlu
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.,Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey.,Department of Medical Biology, School of Medicine, Koc University, Istanbul, Turkey
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13
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Bruzzone C, Conde R, Embade N, Mato JM, Millet O. Metabolomics as a powerful tool for diagnostic, pronostic and drug intervention analysis in COVID-19. Front Mol Biosci 2023; 10:1111482. [PMID: 36876049 PMCID: PMC9975567 DOI: 10.3389/fmolb.2023.1111482] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
COVID-19 currently represents one of the major health challenges worldwide. Albeit its infectious character, with onset affectation mainly at the respiratory track, it is clear that the pathophysiology of COVID-19 has a systemic character, ultimately affecting many organs. This feature enables the possibility of investigating SARS-CoV-2 infection using multi-omic techniques, including metabolomic studies by chromatography coupled to mass spectrometry or by nuclear magnetic resonance (NMR) spectroscopy. Here we review the extensive literature on metabolomics in COVID-19, that unraveled many aspects of the disease including: a characteristic metabotipic signature associated to COVID-19, discrimination of patients according to severity, effect of drugs and vaccination treatments and the characterization of the natural history of the metabolic evolution associated to the disease, from the infection onset to full recovery or long-term and long sequelae of COVID.
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Affiliation(s)
- Chiara Bruzzone
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bilbao, Bizkaia, Spain
| | - Ricardo Conde
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bilbao, Bizkaia, Spain
| | - Nieves Embade
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bilbao, Bizkaia, Spain
| | - José M. Mato
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bilbao, Bizkaia, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Oscar Millet
- Precision Medicine and Metabolism Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bilbao, Bizkaia, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
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14
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Tang L, Zhang S, Zhang M, Wang PJ, Liang GY, Gao XL. Integrated Proteomics and Metabolomics Analysis to Explore the Amelioration Mechanisms of Rosa roxburghii Tratt Fruit Polyphenols on Lipopolysaccharide-Induced Acute Lung Injury Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:3079-3092. [PMID: 36745194 DOI: 10.1021/acs.jafc.2c04344] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Acute lung injury (ALI) is the main cause of death for the elderly and children due to its high morbidity and mortality rates. Plant-derived functional foods are becoming increasingly important to the healthcare and food industries for adjunctive and alternative treatments of ALI. Polyphenols have been regarded to be beneficial to the prevention and amelioration of ALI. Rosa roxburghii Tratt fruit polyphenols (RRTP) has potential to prevent ALI, but mechanism remains unclear. This study was set up to systematically analyze the RRTP extract active ingredients, comprehensively evaluate its protective effects via lung histopathological examination, protein concentration, and cytokines production in ALI mice induced by lipopolysaccharide (LPS), and finally revealed alleviation mechanisms of the regulatory effects of RRTP by proteomics and metabolomics approach. The results demonstrated RRTP could synergistically exert significant preventive effects against ALI by notably ameliorating lung histopathological damage and pulmonary capillary permeability in ALI mice, inhibiting lung tissue inflammatory response and acute phase proteins and S-100 calcium binding proteins, suppressing excessive activation of complement and coagulation cascades, and regulating disordered lipids metabolism and amino acid metabolism. This study illustrated that RRTP has obvious advantages in ALI adjunctive therapy and revealed the complicated amelioration mechanisms, which provides a breakthrough for the development and demonstration of RRTP as a nutritional compound additive for complementary therapy of ALI.
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Affiliation(s)
- Li Tang
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China
- School of Chinese Ethnic Medicine, Guizhou Minzu University, Guiyang, 550025, China
| | - Shuo Zhang
- School of Basic Medical Sciences & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang 550025, China
| | - Min Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Peng-Jiao Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences & Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Gui-You Liang
- Translational Medicine Research Center & State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China
| | - Xiu-Li Gao
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025, China
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15
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Wildman E, Mickiewicz B, Vogel HJ, Thompson GC. Metabolomics in pediatric lower respiratory tract infections and sepsis: a literature review. Pediatr Res 2023; 93:492-502. [PMID: 35778499 PMCID: PMC9247944 DOI: 10.1038/s41390-022-02162-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/19/2022] [Accepted: 05/23/2022] [Indexed: 11/09/2022]
Abstract
Lower respiratory tract infections (LRTIs) are a leading cause of morbidity and mortality in children. The ability of healthcare providers to diagnose and prognose LRTIs in the pediatric population remains a challenge, as children can present with similar clinical features regardless of the underlying pathogen or ultimate severity. Metabolomics, the large-scale analysis of metabolites and metabolic pathways offers new tools and insights that may aid in diagnosing and predicting the outcomes of LRTIs in children. This review highlights the latest literature on the clinical utility of metabolomics in providing care for children with bronchiolitis, pneumonia, COVID-19, and sepsis. IMPACT: This article summarizes current metabolomics approaches to diagnosing and predicting the course of pediatric lower respiratory infections. This article highlights the limitations to current metabolomics research and highlights future directions for the field.
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Affiliation(s)
- Emily Wildman
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Beata Mickiewicz
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Hans J Vogel
- Bio-NMR Centre, Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Graham C Thompson
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. .,Department of Emergency Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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16
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Wang D, Zhao P, Lv Y, Ming J, Wang Z, Yang E, Li Y, Wang M, Niu J, Zhang Y, Sun Y, Chen Y, Chen K, Chen Z, Liu W, Hu X. Proteomic-Based Platelet Activation-Associated Protein SELP May Be a Novel Biomarker for Coagulation and Prognostic in Essential Thrombocythemia. J Clin Med 2023; 12:jcm12031078. [PMID: 36769725 PMCID: PMC9917633 DOI: 10.3390/jcm12031078] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/26/2023] [Accepted: 01/28/2023] [Indexed: 01/31/2023] Open
Abstract
Abnormal platelet activation can lead to thrombosis in essential thrombocythemia (ET) and thus impact patient prognosis. Platelet activation-associated proteins are key molecules for platelet activation. However, it is unclear which proteins are most closely associated with the disease's prognosis. To determine which platelet activation-related proteins can be employed as ET patient prognosis predictors, we used label-free quantification (LFQ) and parallel reaction monitoring (PRM) technology and first determined the serum proteomic expression levels and the differential proteins of ET patients. Then, based on the IPSET (International Prognostic Score for ET), the differential protein associated with the prognostic score was found. To investigate potential processes affecting prognosis, the connection of this protein with prognostic markers, such as thrombotic history, age, white blood cell count, coagulation factors, and inflammatory factors, were further examined. The levels of platelet activation-related proteins GPIbα, SELP, PF4, MMP1, and FLNA were significantly higher in ET patients, according to LFQ and PRM analyses (p < 0.01). Based on regression analysis of the IPSET prognostic score, it is suggested that the SELP level was positively correlated with the prognostic score and prognostic risk factor analysis (p < 0.05). Further regression analysis of SELP with coagulation factors showed that antithrombin (AT-III) was negatively correlated with SELP levels (p < 0.05). Further regression analysis of the inflammatory factors with AT-III and SELP revealed that IL-10, IL-12P70, and IL-31 were negatively correlated with AT-III and SELP (p < 0.01). Platelet activation pathway-related proteins are expressed more frequently in ET patients, and serum SELP may be a prognostic marker for these individuals by encouraging leukocyte increase and inflammatory factor expression and causing aberrant coagulation.
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Affiliation(s)
- Dehao Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Pei Zhao
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yan Lv
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Jing Ming
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Ziqing Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Erpeng Yang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yumeng Li
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Mingjing Wang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Jicong Niu
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yanyu Zhang
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yan Sun
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yi Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Ke Chen
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Postdoctoral Research Programme of China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Zhuo Chen
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Weiyi Liu
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Correspondence: (W.L.); (X.H.); Tel.: +86-10-6283-5361 (W.L. & X.H.); Fax: +86-010-6286-0397 (W.L. & X.H.)
| | - Xiaomei Hu
- Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- Correspondence: (W.L.); (X.H.); Tel.: +86-10-6283-5361 (W.L. & X.H.); Fax: +86-010-6286-0397 (W.L. & X.H.)
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17
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Mechanisms of NO-Mediated Protein S-Nitrosylation in the Lens-Induced Myopia. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8296043. [DOI: 10.1155/2022/8296043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/01/2022] [Indexed: 11/17/2022]
Abstract
Background. Myopia is a chronic ocular disease, emerging as the most common type of refractive error. This study intends to preliminarily explore the roles of protein S-nitrosylation of nitric oxide (NO) in the regulation of myopia by detecting the expression of neuronal nitric oxide synthase (nNOS) and downstream S-nitrosylation, using the animal model of lens-induced myopia (LIM) in mice. Methods. The 3-week-old C57BL/6 J mice were divided into three groups: group I, lens-induced 0-week group (take eyeballs at the age of 3 weeks); group II, self-control eyes of experimental group (take eyeballs at the age of 7 weeks); and group III, lens-induced 4-week group (take eyeballs at the age of 7 weeks). The diopter and axial length of each group were measured by streak retinoscopes and optical coherence tomography (OCT) before and after model establishment. The protein expressions and locations of nNOS and S-nitrosylated proteins (PSNOs) were measured by western blot and immunofluorescence staining. Site-specific proteomic for protein S-nitrolysation was used to detect the existence and location of S-nitrosylation proteins in the retina of myopic and nonmyopic mice. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and motif enrichment analyses were performed. The differential sites were analyzed by GO, KEGG, and motif. Irreversible biotinylation procedure combined with protein purification and western blot was used to detect the protein expression of α-enolase (ENO1), a key player in the hypoxia-related signal pathway. Results. The expressions of nNOS and PSNOs were significantly lower in the retina of experimental eyes than that in self-control eyes and 3-week-old baseline group. A total of 595 S-nitrosylated proteins, 709 S-nitrosylated peptides, and 708 S-nitrosylated sites were identified by site-specific S-nitrolysation proteomics in the retina of myopic and control eyes. A total of 19 differentiation loci were screened, of which 13 sites were downregulated and 6 sites were upregulated in experimental eyes compared with the self-control group. Specifically, the expression of SNO-ENO1 was significantly lower in the retina of experimental eyes than that in self-control eyes and 3-week-old baseline group. Conclusion. LIM induces the decrease of nNOS and PSNO protein levels in the retina of myopic mice. NO-mediated nonclassical protein S-nitrosylation modification may play an important role in the regulation of lens-induced myopia. ENO1 may be a key factor in the regulation of S-nitrosylation modification of myopia.
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18
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He B, Huang Z, Huang C, Nice EC. Clinical applications of plasma proteomics and peptidomics: Towards precision medicine. Proteomics Clin Appl 2022; 16:e2100097. [PMID: 35490333 DOI: 10.1002/prca.202100097] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/16/2022] [Accepted: 04/28/2022] [Indexed: 02/05/2023]
Abstract
In the context of precision medicine, disease treatment requires individualized strategies based on the underlying molecular characteristics to overcome therapeutic challenges posed by heterogeneity. For this purpose, it is essential to develop new biomarkers to diagnose, stratify, or possibly prevent diseases. Plasma is an available source of biomarkers that greatly reflects the physiological and pathological conditions of the body. An increasing number of studies are focusing on proteins and peptides, including many involving the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), and proteomics and peptidomics techniques are emerging as critical tools for developing novel precision medicine preventative measures. Excitingly, the emerging plasma proteomics and peptidomics toolbox exhibits a huge potential for studying pathogenesis of diseases (e.g., COVID-19 and cancer), identifying valuable biomarkers and improving clinical management. However, the enormous complexity and wide dynamic range of plasma proteins makes plasma proteome profiling challenging. Herein, we summarize the recent advances in plasma proteomics and peptidomics with a focus on their emerging roles in COVID-19 and cancer research, aiming to emphasize the significance of plasma proteomics and peptidomics in clinical applications and precision medicine.
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Affiliation(s)
- Bo He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, P. R. China.,Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
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19
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Zhang F, Luna A, Tan T, Chen Y, Sander C, Guo T. COVIDpro: Database for mining protein dysregulation in patients with COVID-19. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2022:2022.09.27.509819. [PMID: 36203550 PMCID: PMC9536031 DOI: 10.1101/2022.09.27.509819] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Background The ongoing pandemic of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has limited treatment options partially due to our incomplete understanding of the molecular dysregulations of the COVID-19 patients. We aimed to generate a repository and data analysis tools to examine the modulated proteins underlying COVID-19 patients for the discovery of potential therapeutic targets and diagnostic biomarkers. Methods We built a web server containing proteomic expression data from COVID-19 patients with a toolset for user-friendly data analysis and visualization. The web resource covers expert-curated proteomic data from COVID-19 patients published before May 2022. The data were collected from ProteomeXchange and from select publications via PubMed searches and aggregated into a comprehensive dataset. Protein expression by disease subgroups across projects was compared by examining differentially expressed proteins. We also visualize differentially expressed pathways and proteins. Moreover, circulating proteins that differentiated severe cases were nominated as predictive biomarkers. Findings We built and maintain a web server COVIDpro ( https://www.guomics.com/covidPro/ ) containing proteomics data generated by 41 original studies from 32 hospitals worldwide, with data from 3077 patients covering 19 types of clinical specimens, the majority from plasma and sera. 53 protein expression matrices were collected, for a total of 5434 samples and 14,403 unique proteins. Our analyses showed that the lipopolysaccharide-binding protein, as identified in the majority of the studies, was highly expressed in the blood samples of patients with severe disease. A panel of significantly dysregulated proteins was identified to separate patients with severe disease from non-severe disease. Classification of severe disease based on these proteomic signatures on five test sets reached a mean AUC of 0.87 and ACC of 0.80. Interpretation COVIDpro is an online database with an integrated analysis toolkit. It is a unique and valuable resource for testing hypotheses and identifying proteins or pathways that could be targeted by new treatments of COVID-19 patients. Funding National Key R&D Program of China: Key PDPM technologies (2021YFA1301602, 2021YFA1301601, 2021YFA1301603), Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars (LR19C050001), Hangzhou Agriculture and Society Advancement Program (20190101A04), National Natural Science Foundation of China (81972492) and National Science Fund for Young Scholars (21904107), National Resource for Network Biology (NRNB) from the National Institute of General Medical Sciences (NIGMS-P41 GM103504). Research in context Evidence before this study: Although an increasing number of therapies against COVID-19 are being developed, they are still insufficient, especially with the rise of new variants of concern. This is partially due to our incomplete understanding of the disease’s mechanisms. As data have been collected worldwide, several questions are now worth addressing via meta-analyses. Most COVID-19 drugs function by targeting or affecting proteins. Effectiveness and resistance to therapeutics can be effectively assessed via protein measurements. Empowered by mass spectrometry-based proteomics, protein expression has been characterized in a variety of patient specimens, including body fluids (e.g., serum, plasma, urea) and tissue (i.e., formalin-fixed and paraffin-embedded (FFPE)). We expert-curated proteomic expression data from COVID-19 patients published before May 2022, from the largest proteomic data repository ProteomeXhange as well as from literature search engines. Using this resource, a COVID-19 proteome meta-analysis could provide useful insights into the mechanisms of the disease and identify new potential drug targets.Added value of this study: We integrated many published datasets from patients with COVID-19 from 11 nations, with over 3000 patients and more than 5434 proteome measurements. We collected these datasets in an online database, and generated a toolbox to easily explore, analyze, and visualize the data. Next, we used the database and its associated toolbox to identify new proteins of diagnostic and therapeutic value for COVID-19 treatment. In particular, we identified a set of significantly dysregulated proteins for distinguishing severe from non-severe patients using serum samples.Implications of all the available evidence: COVIDpro will support the navigation and analysis of patterns of dysregulated proteins in various COVID-19 clinical specimens for identification and verification of protein biomarkers and potential therapeutic targets.
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20
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Kumar R, Kumar V, Arya R, Anand U, Priyadarshi RN. Association of COVID-19 with hepatic metabolic dysfunction. World J Virol 2022; 11:237-251. [PMID: 36188741 PMCID: PMC9523326 DOI: 10.5501/wjv.v11.i5.237] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/25/2022] [Accepted: 06/20/2022] [Indexed: 02/05/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic continues to be a global problem with over 438 million cases reported so far. Although it mostly affects the respiratory system, the involvement of extrapulmonary organs, including the liver, is not uncommon. Since the beginning of the pandemic, metabolic com-orbidities, such as obesity, diabetes, hypertension, and dyslipidemia, have been identified as poor prognostic indicators. Subsequent metabolic and lipidomic studies have identified several metabolic dysfunctions in patients with COVID-19. The metabolic alterations appear to be linked to the course of the disease and inflammatory reaction in the body. The liver is an important organ with high metabolic activity, and a significant proportion of COVID-19 patients have metabolic comorbidities; thus, this factor could play a key role in orchestrating systemic metabolic changes during infection. Evidence suggests that metabolic dysregulation in COVID-19 has both short- and long-term metabolic implications. Furthermore, COVID-19 has adverse associations with metabolic-associated fatty liver disease. Due to the ensuing effects on the renin-angiotensin-aldosterone system and ammonia metabolism, COVID-19 can have significant implications in patients with advanced chronic liver disease. A thorough understanding of COVID-19-associated metabolic dysfunction could lead to the identification of important plasma biomarkers and novel treatment targets. In this review, we discuss the current understanding of metabolic dysfunction in COVID-19, focusing on the liver and exploring the underlying mechanistic pathogenesis and clinical implications.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Vijay Kumar
- Department of Medicine, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rahul Arya
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna, Patna 801507, Bihar, India
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21
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Bennet S, Kaufmann M, Takami K, Sjaarda C, Douchant K, Moslinger E, Wong H, Reed DE, Ellis AK, Vanner S, Colautti RI, Sheth PM. Small-molecule metabolome identifies potential therapeutic targets against COVID-19. Sci Rep 2022; 12:10029. [PMID: 35705626 PMCID: PMC9200216 DOI: 10.1038/s41598-022-14050-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 05/31/2022] [Indexed: 11/09/2022] Open
Abstract
Respiratory viruses are transmitted and acquired via the nasal mucosa, and thereby may influence the nasal metabolome composed of biochemical products produced by both host cells and microbes. Studies of the nasal metabolome demonstrate virus-specific changes that sometimes correlate with viral load and disease severity. Here, we evaluate the nasopharyngeal metabolome of COVID-19 infected individuals and report several small molecules that may be used as potential therapeutic targets. Specimens were tested by qRT-PCR with target primers for three viruses: Influenza A (INFA), respiratory syncytial virus (RSV), and SARS-CoV-2, along with unaffected controls. The nasopharyngeal metabolome was characterized using an LC–MS/MS-based screening kit capable of quantifying 141 analytes. A machine learning model identified 28 discriminating analytes and correctly categorized patients with a viral infection with an accuracy of 96% (R2 = 0.771, Q2 = 0.72). A second model identified 5 analytes to differentiate COVID19-infected patients from those with INFA or RSV with an accuracy of 85% (R2 = 0.442, Q2 = 0.301). Specifically, Lysophosphatidylcholines-a-C18:2 (LysoPCaC18:2) concentration was significantly increased in COVID19 patients (P < 0.0001), whereas beta-hydroxybutyric acid, Methionine sulfoxide, succinic acid, and carnosine concentrations were significantly decreased (P < 0.0001). This study demonstrates that COVID19 infection results in a unique nasopharyngeal metabolomic signature with carnosine and LysoPCaC18:2 as potential therapeutic targets.
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Affiliation(s)
- Sean Bennet
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada
| | - Martin Kaufmann
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada
| | - Kaede Takami
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada
| | - Calvin Sjaarda
- Department of Psychiatry, Queen's University, Kingston, ON, Canada
| | - Katya Douchant
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada
| | - Emily Moslinger
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada.,Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - Henry Wong
- Division of Microbiology, Kingston Health Sciences Centre, Kingston, ON, Canada
| | - David E Reed
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada
| | - Anne K Ellis
- Division of Allergy and Immunology, Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Stephen Vanner
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada
| | | | - Prameet M Sheth
- Gastrointestinal Diseases Research Unit (GIDRU), Kingston Health Sciences Centre, 76 Stuart St., Kingston, ON, K7L 2V7, Canada. .,Division of Microbiology, Kingston Health Sciences Centre, Kingston, ON, Canada. .,Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
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22
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Gu M, Pan H, Yuan Y, Zhou X, Chen L, Wang X, Fang F, Hu L, Xie Y, Shen C. Sera Metabolomics Characterization of Patients at Different Stages in Wuhan Identifies Critical Biomarkers of COVID-19. Front Cell Infect Microbiol 2022; 12:882661. [PMID: 35586248 PMCID: PMC9108257 DOI: 10.3389/fcimb.2022.882661] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/28/2022] [Indexed: 12/15/2022] Open
Abstract
We have witnessed the 2-year-long global rampage of COVID-19 caused by the wide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, knowledge about biomarkers of the entire COVID-19 process is limited. Identification of the systemic features of COVID-19 will lead to critical biomarkers and therapeutic targets for early intervention and clinical disease course prediction. Here, we performed a comprehensive analysis of clinical measurements and serum metabolomics in 199 patients with different stages of COVID-19. In particular, our study is the first serum metabolomic analysis of critical rehabilitation patients and critical death patients. We found many differential metabolites in the comparison of metabolomic results between ordinary, severe, and critical patients and uninfected patients. Through the metabolomic results of COVID-19 patients in various stages, and critical rehabilitation patients and critical death patients, we identified a series of differential metabolites as biomarkers, a separate queue and precise distinction, and predicted COVID-19 verification. These differentially expressed metabolites, included 1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate, propylparaben, 20-hydroxyeicosatetraenoic acid, triethanolamine, chavicol, disialosyl galactosyl globoside, 1-arachidonoylglycerophosphoinositol, and alpha-methylstyrene, all of which have been identified for the first time as biomarkers in COVID-19 progression. These biomarkers are involved in many pathological and physiological pathways of COVID-19, for example, immune responses, platelet degranulation, and metabolism which might result in pathogenesis. Our results showed valuable information about metabolites obviously altered in COVID-19 patients with different stages, which could shed light on the pathogenesis as well as serve as potential therapeutic agents of COVID-19.
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Affiliation(s)
- Meijia Gu
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China
| | - Huaqin Pan
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University; Clinical Research Center of Hubei Critical Care Medicine, Wuhan, China
| | - Yuncong Yuan
- College of Life Sciences, Wuhan University, Wuhan, China
- China Center for Type Culture Collection, Wuhan University, Wuhan, China
| | - Xuemin Zhou
- Shanghai BIOTREE Biological Technology Co., Ltd, Shanghai, China
| | - Luojia Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China
| | - Xingran Wang
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Fang Fang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Liu Hu
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Yaxuan Xie
- School of Health Sciences, Wuhan University, Wuhan, China
| | - Chao Shen
- College of Life Sciences, Wuhan University, Wuhan, China
- China Center for Type Culture Collection, Wuhan University, Wuhan, China
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23
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COVID-19 and One-Carbon Metabolism. Int J Mol Sci 2022; 23:ijms23084181. [PMID: 35456998 PMCID: PMC9026976 DOI: 10.3390/ijms23084181] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 12/31/2022] Open
Abstract
Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B12 deficiency (pernicious anemia). The metabolism of a cell infected by the SARS-CoV-2 virus is reshaped to fulfill the need for massive viral RNA synthesis, which requires de novo purine biosynthesis involving folate and one-carbon metabolism. Many aspects of host sulfur amino acid metabolism, particularly glutathione metabolism underlying antioxidant defenses, are also taken over by the SARS-CoV-2 virus. The purpose of this review is to summarize recent findings related to one-carbon metabolism and sulfur metabolites in COVID-19 and discuss how they inform strategies to combat the disease.
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24
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Li H, Li X, Wu Q, Wang X, Qin Z, Wang Y, He Y, Wu Q, Li L, Chen H. Plasma proteomic and metabolomic characterization of COVID-19 survivors 6 months after discharge. Cell Death Dis 2022; 13:235. [PMID: 35288537 PMCID: PMC8919172 DOI: 10.1038/s41419-022-04674-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/11/2022] [Accepted: 02/18/2022] [Indexed: 02/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19) has gained prominence as a global pandemic. Studies have suggested that systemic alterations persist in a considerable proportion of COVID-19 patients after hospital discharge. We used proteomic and metabolomic approaches to analyze plasma samples obtained from 30 healthy subjects and 54 COVID-19 survivors 6 months after discharge from the hospital, including 30 non-severe and 24 severe patients. Through this analysis, we identified 1019 proteins and 1091 metabolites. The differentially expressed proteins and metabolites were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Among the patients evaluated, 41% of COVID-19 survivors reported at least one clinical symptom and 26.5% showed lung imaging abnormalities at 6 months after discharge. Plasma proteomics and metabolomics analysis showed that COVID-19 survivors differed from healthy control subjects in terms of the extracellular matrix, immune response, and hemostasis pathways. COVID-19 survivors also exhibited abnormal lipid metabolism, disordered immune response, and changes in pulmonary fibrosis-related proteins. COVID-19 survivors show persistent proteomic and metabolomic abnormalities 6 months after discharge from the hospital. Hence, the recovery period for COVID-19 survivors may be longer.
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Affiliation(s)
- Hongwei Li
- Department of Respiratory Medicine, Haihe Hospital, Tianjin University, Tianjin, China
| | - Xue Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China
| | - Qian Wu
- Department of Respiratory Medicine, Haihe Hospital, Tianjin University, Tianjin, China
| | - Xing Wang
- Department of Respiratory Medicine, Haihe Hospital, Tianjin University, Tianjin, China
| | - Zhonghua Qin
- Department of Laboratory Medicine, Haihe Hospital, Tianjin University, Tianjin, China
| | - Yaguo Wang
- Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Yanbin He
- Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Qi Wu
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China.
| | - Li Li
- Department of Respiratory Medicine, Haihe Hospital, Tianjin University, Tianjin, China.
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China.
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China.
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Tianjin, China.
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Tianjin, China.
- Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China.
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25
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Costanzo M, Caterino M, Fedele R, Cevenini A, Pontillo M, Barra L, Ruoppolo M. COVIDomics: The Proteomic and Metabolomic Signatures of COVID-19. Int J Mol Sci 2022; 23:ijms23052414. [PMID: 35269564 PMCID: PMC8910221 DOI: 10.3390/ijms23052414] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/04/2022] [Accepted: 02/18/2022] [Indexed: 02/06/2023] Open
Abstract
Omics-based technologies have been largely adopted during this unprecedented global COVID-19 pandemic, allowing the scientific community to perform research on a large scale to understand the pathobiology of the SARS-CoV-2 infection and its replication into human cells. The application of omics techniques has been addressed to every level of application, from the detection of mutations, methods of diagnosis or monitoring, drug target discovery, and vaccine generation, to the basic definition of the pathophysiological processes and the biochemical mechanisms behind the infection and spread of SARS-CoV-2. Thus, the term COVIDomics wants to include those efforts provided by omics-scale investigations with application to the current COVID-19 research. This review summarizes the diverse pieces of knowledge acquired with the application of COVIDomics techniques, with the main focus on proteomics and metabolomics studies, in order to capture a common signature in terms of proteins, metabolites, and pathways dysregulated in COVID-19 disease. Exploring the multiomics perspective and the concurrent data integration may provide new suitable therapeutic solutions to combat the COVID-19 pandemic.
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Affiliation(s)
- Michele Costanzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.C.); (A.C.)
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
| | - Marianna Caterino
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.C.); (A.C.)
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
| | - Roberta Fedele
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
| | - Armando Cevenini
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.C.); (A.C.)
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
| | - Mariarca Pontillo
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
| | - Lucia Barra
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.C.); (A.C.)
- CEINGE–Biotecnologie Avanzate s.c.ar.l., 80145 Naples, Italy; (R.F.); (M.P.); (L.B.)
- Correspondence:
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