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Life science Shanghai Jiao Tong University School of Medicine/Shanghai Institute of Immunology Researcher Liang Qiming team and Fudan University Affiliated Public Health Clinical Center Zhu Tongyu team, Chinese Academy of Sciences Shanghai Institutes for Advanced Study of National Protein Science (Shanghai) Facility Mass Spectrometry System Peng Chao team Published original research results in the Med journal under Cell Press.
This paper entitled "Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis" comprehensively constructed SARS-CoV-2 The interaction network with host proteins and quantitative proteomic analysis of PBMC samples of COVID-19 patients have further deepened our understanding of the molecular mechanism of SARS-CoV-2.
▲Long press the picture to identify the QR code to read the original paper.
The COVID-19 pandemic caused by SARS-CoV-2 is a zoonotic disease, which is spread mainly through droplets and direct contact with infected or virus carriers.
Although the activation and recruitment of neutrophils and cytokine response contribute to the pathogenesis of COVID-19, how SARS-CoV-2 triggers these immunological changes, especially the enhancement of neutrophil chemotaxis and activation, in It is still largely unknown.
In addition, people know little about the function of viral proteins, which limits the understanding of the immune escape and pathogenesis of SARS-CoV-2, and further hinders the development of antiviral drugs and treatments.
To this end, Professor Liang Qiming from Shanghai Jiaotong University and others have characterized the SARS-CoV-2 virus-virus and virus-host interaction network in human cells through whole-genome screening and quantitative proteome analysis, and determined 286 potential host targets.
The study found that compared with mild patients, the levels of IL-6 and IL-8 in peripheral blood mononuclear cells of severe COVID-19 patients increased, and the functional annotation of differentially expressed proteins indicated that it was related to neutrophil activation and T cell activation.
Pathways related to body signaling and the coagulation cascade are activated.
In addition, the authors found that the viral nsp10 interacts with NF-κB inhibitory factor (NKRF) to mediate the expression of IL-8, which provides a potential molecule for the cytokine storm and excessive inflammation induced by SARS-CoV-2 Mechanism explanation reveals new therapeutic targets.
In summary, this study integrates the virus-host interaction network and quantitative proteomics methods, and deeply analyzes the mechanism by which SARS-CoV-2 regulates basic host cell processes and escapes the host immune system.
Establishing a virus-virus and virus-host interaction network is conducive to understanding the host's response to SARS-CoV-2 infection, and it also provides valuable information for future research on the pathogenesis of COVID-19 or the nature of the virus, as well as guidance The design of COVID-19 drug candidates or the reuse of existing drugs provides unique insights.
The author explained that SARS-CoV-2 was first reported in Wuhan, China in 2019, and widespread transmission and infection broke out worldwide, causing more than 2.
5 million deaths worldwide.
The virus is mainly spread through breathing, is highly contagious, and can enhance its own pathogenicity during the transmission process and eventually lead to severe respiratory syndrome, renal failure, and even death in patients, which is extremely harmful to public health safety , Especially in severely ill patients, the disease develops rapidly in the later stage of infection, and the treatment is extremely difficult.
Therefore, in order to clarify the mechanism of the interaction between SARS-CoV-2 and the host, we constructed 28 viral protein-viral protein interaction maps and viral protein-host protein interaction maps, and analyzed the PBMCs of patients with mild and severe COVID-19.
Sample proteome, and explored that nsp10 interacts with NKRF to specifically induce IL-8 expression, initially reveals the potential mechanism of SARS-CoV-2 triggering cytokine storm, and provides important basic data for the prevention and treatment of COVID-19 . The complexes formed between viral proteins play different key functions at different stages of the virus life cycle.
SARS-CoV-2 encodes a total of 28 viral proteins.
Through yeast two-hybrid screening and immunoprecipitation experiments, a total of 58 viral protein interactions (PPIs) were found in this study.
Some viral proteins, such as M, E, ORF6, etc.
, can form dimers or oligomers.
4 structural proteins form 3 PPIs.
The interaction of structural proteins may be crucial to the assembly of virus particles, while non-structural proteins are important for viral RNA replication and protein translation.
Enzymatic activity is a virulence factor that inhibits the host immune system.
Non-structural protein formation complexes play an important role in the virus life cycle.
For example, nsp10-nsp16 can promote the methyltransferase activity of nsp16.
Although the biological functions of most PPIs are still to be verified, the interaction between these viral proteins has important significance in the immune escape and pathogenesis of virus replication and infection.
Among them, 20 PPIs also exist in SARS-CoV, including M-ORF6 and nsp2-nsp15.
It can be seen that these interactions play a key role in maintaining the basic functions of the SARS coronavirus family.
In order to further understand the role of SARS-CoV-2 virus protein in its life cycle, the SARS-CoV-2 encoding gene plasmid with 3xflag at the N-terminus was overexpressed in HEK293T cells, combined with affinity purification of AP and LC-MS/MS After analysis, after statistical analysis, a total of 286 host proteins that interact with the virus were identified and 295 high-confidence PPIs were formed.
We found that the host cell pathways that the SARS-CoV-2 virus protein mainly affects are ATP biosynthesis and metabolism (M protein), mRNA transport (N protein), protein methylation and alkylation (nsp5 protein), and reactive oxygen metabolism.
(Nsp14 protein) and endoplasmic reticulum stress (orf3a), etc.
, which are also consistent with the proteomic analysis results of SARS-CoV-2 infected cells. It is worth noting that our AP-LC-MS/MS analysis results have identified unique host targets related to inflammation and innate immunity of SARS-CoV-2 infected hosts, including NKRF-nsp10, TBK1-ORF6, TANK-ORF6 , TRAF2-ORF6 and KIT-ORF3a, these PPIs may be the key cause of SARS-CoV-2.
Among them, NKRF is a transcriptional repressor protein that can induce the expression of IL-8 to stimulate neutrophil chemotaxis and recruit to the site of infection.
This study confirmed that nsp10 regulates the expression of IL-8 by targeting NKRF, which may be caused The underlying cause of the unique immune response to COVID-19.
In order to clarify the pathogenesis of SARS-CoV-2 infection, we collected healthy clinical samples, PBMCs from mild patients and severe patients, and found that compared with healthy samples, there were 726 differentially expressed proteins in mild patients, of which 333 protein expression increased.
While the expression of 393 proteins was reduced, functional analysis revealed that patients with mild COVID-19 mainly showed abnormalities in blood coagulation.
Furthermore, we found that compared with mild patients, severe patients had 366 differentially expressed proteins, of which 209 proteins were up-regulated.
Functional analysis revealed that these proteins were mainly concentrated in neutrophil activation and degranulation, gas transport, and bicarbonate.
Transport, differentiation of myeloid cells, and blood coagulation.
The expression of IL-6 and IL-8 in critically ill patients is up-regulated.
It may be that SARS-CoV-2 triggered the release of cytokines, leading to the infiltration of neutrophils at the site of infection And activation, and eventually develop into cytokine storm and respiratory distress.
In addition, coagulation-related gene clusters in critically ill patients are significantly up-regulated, which may be the cause of death in clinically severe COVID-19 patients due to abnormal coagulation.
The down-regulated protein expression in critically ill patients is mainly related to T cell activation and T cell receptor signaling, including the down-regulation of T cell surface molecules CD4 and CD8a, MHC class II molecules HLA-DRA and T cell signal kinase CARD11, suggesting that critically ill patients The activation of T cells in the body fails, and the patient's adaptive immune function is down-regulated.
In summary, this study systematically explored the interaction network map of viral proteins and host proteins, especially the quantitative proteomic analysis of PBMC samples from severely ill patients, which filled the host caused by SARS-CoV-2 infection at the protein level.
The blank response mechanism provides important basic data for the research on the pathogenic mechanism of SARS-CoV-2 and the research and development of antiviral drugs in the later stage.
The research results of related paper information are published in the Med journal under Cell Press.
Click "Read Full Text" or scan the QR code below to view the paper.
▌Paper title: Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis▌Paper URL: https://▌ DOI: https://doi.
org/10.
1016/j.
medj.
2020.
07.
002▲Long press the picture to identify the QR code to read the original text Recommended reading Med review: The new coronavirus neutralizing antibody still exists stably after 6 months of patient infection| Cell Press paper express ▲
This paper entitled "Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis" comprehensively constructed SARS-CoV-2 The interaction network with host proteins and quantitative proteomic analysis of PBMC samples of COVID-19 patients have further deepened our understanding of the molecular mechanism of SARS-CoV-2.
▲Long press the picture to identify the QR code to read the original paper.
The COVID-19 pandemic caused by SARS-CoV-2 is a zoonotic disease, which is spread mainly through droplets and direct contact with infected or virus carriers.
Although the activation and recruitment of neutrophils and cytokine response contribute to the pathogenesis of COVID-19, how SARS-CoV-2 triggers these immunological changes, especially the enhancement of neutrophil chemotaxis and activation, in It is still largely unknown.
In addition, people know little about the function of viral proteins, which limits the understanding of the immune escape and pathogenesis of SARS-CoV-2, and further hinders the development of antiviral drugs and treatments.
To this end, Professor Liang Qiming from Shanghai Jiaotong University and others have characterized the SARS-CoV-2 virus-virus and virus-host interaction network in human cells through whole-genome screening and quantitative proteome analysis, and determined 286 potential host targets.
The study found that compared with mild patients, the levels of IL-6 and IL-8 in peripheral blood mononuclear cells of severe COVID-19 patients increased, and the functional annotation of differentially expressed proteins indicated that it was related to neutrophil activation and T cell activation.
Pathways related to body signaling and the coagulation cascade are activated.
In addition, the authors found that the viral nsp10 interacts with NF-κB inhibitory factor (NKRF) to mediate the expression of IL-8, which provides a potential molecule for the cytokine storm and excessive inflammation induced by SARS-CoV-2 Mechanism explanation reveals new therapeutic targets.
In summary, this study integrates the virus-host interaction network and quantitative proteomics methods, and deeply analyzes the mechanism by which SARS-CoV-2 regulates basic host cell processes and escapes the host immune system.
Establishing a virus-virus and virus-host interaction network is conducive to understanding the host's response to SARS-CoV-2 infection, and it also provides valuable information for future research on the pathogenesis of COVID-19 or the nature of the virus, as well as guidance The design of COVID-19 drug candidates or the reuse of existing drugs provides unique insights.
The author explained that SARS-CoV-2 was first reported in Wuhan, China in 2019, and widespread transmission and infection broke out worldwide, causing more than 2.
5 million deaths worldwide.
The virus is mainly spread through breathing, is highly contagious, and can enhance its own pathogenicity during the transmission process and eventually lead to severe respiratory syndrome, renal failure, and even death in patients, which is extremely harmful to public health safety , Especially in severely ill patients, the disease develops rapidly in the later stage of infection, and the treatment is extremely difficult.
Therefore, in order to clarify the mechanism of the interaction between SARS-CoV-2 and the host, we constructed 28 viral protein-viral protein interaction maps and viral protein-host protein interaction maps, and analyzed the PBMCs of patients with mild and severe COVID-19.
Sample proteome, and explored that nsp10 interacts with NKRF to specifically induce IL-8 expression, initially reveals the potential mechanism of SARS-CoV-2 triggering cytokine storm, and provides important basic data for the prevention and treatment of COVID-19 . The complexes formed between viral proteins play different key functions at different stages of the virus life cycle.
SARS-CoV-2 encodes a total of 28 viral proteins.
Through yeast two-hybrid screening and immunoprecipitation experiments, a total of 58 viral protein interactions (PPIs) were found in this study.
Some viral proteins, such as M, E, ORF6, etc.
, can form dimers or oligomers.
4 structural proteins form 3 PPIs.
The interaction of structural proteins may be crucial to the assembly of virus particles, while non-structural proteins are important for viral RNA replication and protein translation.
Enzymatic activity is a virulence factor that inhibits the host immune system.
Non-structural protein formation complexes play an important role in the virus life cycle.
For example, nsp10-nsp16 can promote the methyltransferase activity of nsp16.
Although the biological functions of most PPIs are still to be verified, the interaction between these viral proteins has important significance in the immune escape and pathogenesis of virus replication and infection.
Among them, 20 PPIs also exist in SARS-CoV, including M-ORF6 and nsp2-nsp15.
It can be seen that these interactions play a key role in maintaining the basic functions of the SARS coronavirus family.
In order to further understand the role of SARS-CoV-2 virus protein in its life cycle, the SARS-CoV-2 encoding gene plasmid with 3xflag at the N-terminus was overexpressed in HEK293T cells, combined with affinity purification of AP and LC-MS/MS After analysis, after statistical analysis, a total of 286 host proteins that interact with the virus were identified and 295 high-confidence PPIs were formed.
We found that the host cell pathways that the SARS-CoV-2 virus protein mainly affects are ATP biosynthesis and metabolism (M protein), mRNA transport (N protein), protein methylation and alkylation (nsp5 protein), and reactive oxygen metabolism.
(Nsp14 protein) and endoplasmic reticulum stress (orf3a), etc.
, which are also consistent with the proteomic analysis results of SARS-CoV-2 infected cells. It is worth noting that our AP-LC-MS/MS analysis results have identified unique host targets related to inflammation and innate immunity of SARS-CoV-2 infected hosts, including NKRF-nsp10, TBK1-ORF6, TANK-ORF6 , TRAF2-ORF6 and KIT-ORF3a, these PPIs may be the key cause of SARS-CoV-2.
Among them, NKRF is a transcriptional repressor protein that can induce the expression of IL-8 to stimulate neutrophil chemotaxis and recruit to the site of infection.
This study confirmed that nsp10 regulates the expression of IL-8 by targeting NKRF, which may be caused The underlying cause of the unique immune response to COVID-19.
In order to clarify the pathogenesis of SARS-CoV-2 infection, we collected healthy clinical samples, PBMCs from mild patients and severe patients, and found that compared with healthy samples, there were 726 differentially expressed proteins in mild patients, of which 333 protein expression increased.
While the expression of 393 proteins was reduced, functional analysis revealed that patients with mild COVID-19 mainly showed abnormalities in blood coagulation.
Furthermore, we found that compared with mild patients, severe patients had 366 differentially expressed proteins, of which 209 proteins were up-regulated.
Functional analysis revealed that these proteins were mainly concentrated in neutrophil activation and degranulation, gas transport, and bicarbonate.
Transport, differentiation of myeloid cells, and blood coagulation.
The expression of IL-6 and IL-8 in critically ill patients is up-regulated.
It may be that SARS-CoV-2 triggered the release of cytokines, leading to the infiltration of neutrophils at the site of infection And activation, and eventually develop into cytokine storm and respiratory distress.
In addition, coagulation-related gene clusters in critically ill patients are significantly up-regulated, which may be the cause of death in clinically severe COVID-19 patients due to abnormal coagulation.
The down-regulated protein expression in critically ill patients is mainly related to T cell activation and T cell receptor signaling, including the down-regulation of T cell surface molecules CD4 and CD8a, MHC class II molecules HLA-DRA and T cell signal kinase CARD11, suggesting that critically ill patients The activation of T cells in the body fails, and the patient's adaptive immune function is down-regulated.
In summary, this study systematically explored the interaction network map of viral proteins and host proteins, especially the quantitative proteomic analysis of PBMC samples from severely ill patients, which filled the host caused by SARS-CoV-2 infection at the protein level.
The blank response mechanism provides important basic data for the research on the pathogenic mechanism of SARS-CoV-2 and the research and development of antiviral drugs in the later stage.
The research results of related paper information are published in the Med journal under Cell Press.
Click "Read Full Text" or scan the QR code below to view the paper.
▌Paper title: Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis▌Paper URL: https://▌ DOI: https://doi.
org/10.
1016/j.
medj.
2020.
07.
002▲Long press the picture to identify the QR code to read the original text Recommended reading Med review: The new coronavirus neutralizing antibody still exists stably after 6 months of patient infection| Cell Press paper express ▲
