Serum Protein Profiling Reveals a Landscape of Inflammation and Immune Signaling in Early-stage COVID-19 Infection

Abstract

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy. Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy. The corona virus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is highly contagious (1Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. Zhao X. Huang B. Shi W. Lu R. Niu P. Zhan F. Ma X. Wang D. Xu W. Wu G. Gao G.F. Tan W China Novel Coronavirus Investigating and Research TeamChina Novel Coronavirus, I., and Research, T. (2020) A Novel Coronavirus from Patients with Pneumonia in China.N Engl. J. Med. 2020; 382: 727-733Crossref PubMed Scopus (16050) Google Scholar, 2Wang C. Horby P.W. Hayden F.G. Gao G.F. A novel coronavirus outbreak of global health concern.The Lancet. 2020; 395: 470-473Abstract Full Text Full Text PDF PubMed Scopus (4317) Google Scholar). As of May 04, 2020, 3,524,429 cases of infection and 247,838 COVID-19 related deaths have been reported worldwide. The most common symptoms of COVID-19 are fever, malaise, fatigue, dry cough, conjunctivitis, diarrhea, and pneumonia (3Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Cheng Z. Yu T. Xia J. Wei Y. Wu W. Xie X. Yin W. Li H. Liu M. Xiao Y. Gao H. Guo L. Xie J. Wang G. Jiang R. Gao Z. Jin Q. Wang J. Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan.China. The Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (11331) Google Scholar). Although 19% of infected patients develop severe pneumonia or multiple organ failure, 81% have only mild symptoms or are asymptomatic. Individuals who are asymptomatic are a major challenge in controlling the COVID-19 pandemic because they are still contagious (4Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China Summary of a Report of 72 314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242Crossref PubMed Scopus (10966) Google Scholar). Recent studies have reported that COVID-19 patients with severe symptoms have elevated plasma levels of IL2, IL6, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα (3Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Cheng Z. Yu T. Xia J. Wei Y. Wu W. Xie X. Yin W. Li H. Liu M. Xiao Y. Gao H. Guo L. Xie J. Wang G. Jiang R. Gao Z. Jin Q. Wang J. Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan.China. The Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (11331) Google Scholar, 5Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. Qiu Y. Wang J. Liu Y. Wei Y. Xia J. Yu T. Zhang X. Zhang L. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in china summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (12585) Google Scholar, 6Ruan Q. Yang K. Wang W. Jiang L. Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan.Intensive Care Med. 2020; 46 (1293): 1294Crossref PubMed Scopus (183) Google Scholar, 7Mehta P. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034Abstract Full Text Full Text PDF PubMed Scopus (5923) Google Scholar), which suggests that the progression of COVID-19 is associated with cytokine storms and immunosuppression. Further profiling of the proteins in serum may help to understand the pathogenesis of COVID-19 and to develop effective treatment (8Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Cheng Z. Yu T. Xia J. Wei Y. Wu W. Xie X. Yin W. Li H. Liu M. Xiao Y. Gao H. Guo L. Xie J. Wang G. Jiang R. Gao Z. Jin Q. Wang J. Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (28324) Google Scholar, 9Zhang W. Zhao Y. Zhang F. Wang Q. Li T. Liu Z. Wang J. Qin Y. Zhang X. Yan X. Zeng X. Zhang S. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China.Clin. Immunol. 2020; 214: 108393Crossref PubMed Scopus (858) Google Scholar). However, to date, there is neither a vaccine to prevent COVID-19 nor an effective medicine to treat COVID-19. In this study, a comprehensive analysis of serological proteins from patients in the early stages of COVID-19 or influenza was performed using an antibody microarray developed in our laboratory (10Xu M. Deng J. Xu K. Zhu T. Han L. Yan Y. Yao D. Deng H. Wang D. Sun Y. Chang C. Zhang X. Dai J. Yue L. Zhang Q. Cai X. Zhu Y. Duan H. Liu Y. Li D. Zhu Y. Radstake T. Balak D.M.W. Xu D. Guo T. Lu C. Yu X. In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.Theranostics. 2019; 9: 2475-2488Crossref PubMed Scopus (51) Google Scholar). Many differentially-expressed proteins were identified that mediates diverse immune signaling pathways related to viral infection, the inflammatory response, and immune cell activation and migration. These data reflect the host response to COVID-19 infection, thus providing insight into COVID-19 pathogenesis and providing potential therapeutic targets. All COVID-19 and influenza patients were enrolled in the outpatient department of the Peking Union Medical College Hospital (Peking, China). Serum samples were collected with written informed consent under the approval of the intuitional review board (IRB) from the Peking Union Medical College Hospital (Ethical number: ZS-2303) and the Beijing Proteome Research Center (Beijing, China). All experiments were performed according to the standards of the Declaration of Helsinki. All COVID-19 patients with mild or moderate symptoms were positively diagnosed in accordance with the Diagnosis and Management Plan of Pneumonia with Novel Coronavirus Infection (trial version 7). The antibody microarrays and sera screening were processed as previously described (10Xu M. Deng J. Xu K. Zhu T. Han L. Yan Y. Yao D. Deng H. Wang D. Sun Y. Chang C. Zhang X. Dai J. Yue L. Zhang Q. Cai X. Zhu Y. Duan H. Liu Y. Li D. Zhu Y. Radstake T. Balak D.M.W. Xu D. Guo T. Lu C. Yu X. In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.Theranostics. 2019; 9: 2475-2488Crossref PubMed Scopus (51) Google Scholar). Briefly, 10 μl of serum were diluted with 90 μl PBS (PBS; pH 7.4) and labeled with 1 μl of NHS-PEG4-Biotin (20 g/L in DMSO) (Thermo Fisher Scientific, MA) for 1 h at room temperature. After removing the excess biotin molecules, the biotinylated proteins were dissolved in 400 μl of PBS containing 5% milk (w/v). In parallel with biotin labeling, antibody microarrays were blocked with 500 μl of PBS with 5% milk (w/v) for 1 h at room temperature. After removing the milk, the arrays were incubated with biotin-labeled proteins at 4 °C overnight. The slides were washed with PBS containing 0.05% (w/v) Tween 20 (PBST). To detect the bound proteins, the arrays were incubated with 2 µg/ml streptavidin-Phycoerythrin (PE) (Jackson Immunoresearch, PA) for 1 h at room temperature in the dark and then washed with PBST. After centrifuging for 2 min at 1000 × g, the slide was scanned using the GenePix 4300A microarray scanner at the wavelength of 532 nm. Functional annotation of protein classes was performed using the PANTHER database (http://pantherdb.org/)(11Mi H. Poudel S. Muruganujan A. Casagrande J.T. Thomas P.D. PANTHER version 10: expanded protein families and functions, and analysis tools.Nucleic Acids Res. 2016; 44: D336-D342Crossref PubMed Scopus (650) Google Scholar). The GO biological process analysis was performed using CluGO and visualized in Cytoscape (version 3.7.2) using two-sided hypergeometric test with a p-value less than 0.01 (12Bindea G. Mlecnik B. Hackl H. Charoentong P. Tosolini M. Kirilovsky A. Fridman W.H. Pages F. Trajanoski Z. Galon J. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks.Bioinformatics. 2009; 25: 1091-1093Crossref PubMed Scopus (3851) Google Scholar, 13Franz M. Lopes C.T. Huck G. Dong Y. Sumer O. Bader G.D. Cytoscape.js: a graph theory library for visualisation and analysis.Bioinformatics. 2016; 32: 309-311Crossref PubMed Scopus (395) Google Scholar). The analyses of signaling pathways, protein domains and cellular components were performed using the STRING database (14Szklarczyk D. Franceschini A. Wyder S. Forslund K. Heller D. Huerta-Cepas J. Simonovic M. Roth A. Santos A. Tsafou K.P. Kuhn M. Bork P. Jensen L.J. von Mering C. STRING v10: protein-protein interaction networks, integrated over the tree of life.Nucleic Acids Res. 2015; 43: D447-D452Crossref PubMed Scopus (6793) Google Scholar). Differentially-expressed proteins were identified using the t-distributed t test (p-value = 0.05). Hierarchical clustering was performed using the Mev software (15Chu V.T. Gottardo R. Raftery A.E. Bumgarner R.E. Yeung K.Y. MeV+R: using MeV as a graphical user interface for Bioconductor applications in microarray analysis.Genome Biol. 2008; 9: R118Crossref PubMed Scopus (77) Google Scholar, 16Yu X. Wallstrom G. Magee D.M. Qiu J. Mendoza D.E. Wang J. Bian X. Graves M. LaBaer J. Quantifying antibody binding on protein microarrays using microarray nonlinear calibration.BioTechniques. 2013; 54: 257-264Crossref PubMed Scopus (24) Google Scholar). The COVID-19 status of twenty-eight patients with similar symptoms (i.e. fever, headache, cough sputum, myalgia) were ascertained via RT-PCR, which detects SARS-CoV-2 RNA. In addition, the patients were tested 2–4 days from symptom onset. Fifteen (15Chu V.T. Gottardo R. Raftery A.E. Bumgarner R.E. Yeung K.Y. MeV+R: using MeV as a graphical user interface for Bioconductor applications in microarray analysis.Genome Biol. 2008; 9: R118Crossref PubMed Scopus (77) Google Scholar) patients were positive for COVID-19 whereas 13 patients were negative for COVID-19; this latter group was classified as influenza (Fig. 1A, Table I, and supplemental Table S1). The proteins in the serum were measured using an antibody microarray containing 532 antibodies developed in-house and as previously described (supplemental Table S2, Fig. 1B) (10Xu M. Deng J. Xu K. Zhu T. Han L. Yan Y. Yao D. Deng H. Wang D. Sun Y. Chang C. Zhang X. Dai J. Yue L. Zhang Q. Cai X. Zhu Y. Duan H. Liu Y. Li D. Zhu Y. Radstake T. Balak D.M.W. Xu D. Guo T. Lu C. Yu X. In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.Theranostics. 2019; 9: 2475-2488Crossref PubMed Scopus (51) Google Scholar). The antibodies on the array target intercellular signaling molecules, protein-binding activity modulators, protein modifying enzymes and metabolite interconversion enzymes (Fig. 1C). The intra- and inter-reproducibility of the microarray are 0.9976 and 0.999, respectively (Fig. 1D).Table ICharacteristics of early-stage COVID-19 patientsInfluenza Patients (n = 13)COVID-19 Patients (n = 15)Male8 (61.5%)7 (46.7%)Female5 (38.5%)8 (53.3%)Age, year57.0 (20.0-90.0)41.0 (6.0-68.0)SARS-CoV-2 (+)015 (100%)FluA-RNA (+)6 (46.2%)0FluB RNA (+)3 (23%)0RSV RNA (+)4 (30.8%)0Disease stageMild5 (38.5%)4 (26.7%)Moderate/11 (73.3%)Severe7 (53.8%)0Critical1 (7.7%)0Exposure history4 (30.8%)14 (93.3%)SymptomsFever13 (100%)11 (73.3%)Headache4 (30.8%)1 (6.7%)Cough6 (46.2%)7 (46.7%)Sputum3 (23.1%)2 (13.3%)Myalgia7 (53.8%)2 (13.3%)Fatigue6 (46.2%)0Dyspnea1 (7.7%)2 (13.3%)Nasal congestion/Rhinorrhoea4 (30.8%)4 (26.7%)Sore (7.7%)2 or of are or in a are or a t-distributed t and proteins COVID-19 and influenza group patients were identified (p-value (Fig. and supplemental Table the elevation of cytokines IL6, and were reported in mild and severe COVID-19 patients (Fig. (8Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Cheng Z. Yu T. Xia J. Wei Y. Wu W. Xie X. Yin W. Li H. Liu M. Xiao Y. Gao H. Guo L. Xie J. Wang G. Jiang R. Gao Z. Jin Q. Wang J. Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (28324) Google Scholar, G. M. COVID-19: for cytokine in inflammatory Immunol. 2020; PubMed Scopus Google Scholar, D. Yang in cytokine storm of COVID-19: target of Immunol. 2020; PubMed Scopus Google Scholar). These that the microarray is in serum proteins from COVID-19 patients. Many differentially expressed proteins reported to associated with COVID-19 infection were and (Fig. All the COVID-19 patients were from influenza patients using analysis of the differentially-expressed proteins (Fig. These data that proteins potential biomarkers for early COVID-19 A large to biological were identified from GO analysis of the differentially-expressed proteins in early-stage COVID-19 (Fig. supplemental Table The biological are into immune cell activation and cellular protein signaling that viral infection, and blood the of biological The of biological cellular as protein The of biological signaling pathways that the viral infection, the and The of biological is blood inflammation response, and the and signaling pathways in early SARS-CoV-2 infection were using STRING by for differentially-expressed proteins (n and a p-value less than 0.01 (Fig. supplemental Table pathways that were the most were cytokine signaling in immune and signaling and pathways the most group were associated with viral infection, the and signaling In neutrophil and were in early COVID-19 infection. The most protein domains the differentially-expressed proteins were from the cytokine and protein the cytokine and (Fig. The most protein domains were from and In addition, the domains of protein and were identified. the domains of proteins were the and Functional annotation of the cellular components that the proteins were in cell of plasma plasma of plasma of plasma and cellular was in the the (Fig. To the of cytokines in COVID-19 infection, or are in the and viral protein interaction with cytokine and cytokine pathways (Fig. These cytokines IL6, and A comprehensive analysis of the differentially-expressed proteins and clinical in early-stage COVID-19 patients was performed (Fig. supplemental Table was positively with clinical the acute I, and inflammation and infection (Fig. the of proteins a negative with the lymphocyte and (Fig. clinical and have the correlations with and proteins in COVID-19 respectively (Fig. and The annotation of proteins using database that the proteins are in the and cytokine signaling pathways, respectively (Fig. and supplemental Table the response to SARS-CoV-2 infection is crucial to a therapeutic to the SARS-CoV-2 virus and Y. Wang Y. C. Huang J. J. Huang X. E. M. G. G. COVID-19 the on immune 2020; PubMed Scopus Google Scholar). of that cytokines an important in the severity of COVID-19 symptoms (8Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Cheng Z. Yu T. Xia J. Wei Y. Wu W. Xie X. Yin W. Li H. Liu M. Xiao Y. Gao H. Guo L. Xie J. Wang G. Jiang R. Gao Z. Jin Q. Wang J. Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Abstract Full Text Full Text PDF PubMed Scopus (28324) Google Scholar, Y. Wang Y. C. Huang J. J. Huang X. E. M. G. G. COVID-19 the on immune 2020; PubMed Scopus Google Scholar, G. Wu D. Guo W. Cao Y. Huang D. Wang H. Wang T. Zhang X. H. Yu H. Zhang X. Zhang M. Wu S. Song J. T. Han M. Li S. X. Zhao J. Q. Clinical and features of severe and moderate coronavirus 2020; Scholar). However, the protein changes in serum early SARS-CoV-2 infection is unknown. To this we a high-density antibody microarray to the of 532 serological proteins of early-stage COVID-19 and influenza patients (Fig. of antibody arrays with protein is that of proteins is and is a proteins in serum identified with antibody arrays with (10Xu M. Deng J. Xu K. Zhu T. Han L. Yan Y. Yao D. Deng H. Wang D. Sun Y. Chang C. Zhang X. Dai J. Yue L. Zhang Q. Cai X. Zhu Y. Duan H. Liu Y. Li D. Zhu Y. Radstake T. Balak D.M.W. Xu D. Guo T. Lu C. Yu X. In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.Theranostics. 2019; 9: 2475-2488Crossref PubMed Scopus (51) Google Scholar). All antibodies for microarray been by the using or Furthermore, antibodies and were and to the target using a protein array in our of psoriasis disease (10Xu M. Deng J. Xu K. Zhu T. Han L. Yan Y. Yao D. Deng H. Wang D. Sun Y. Chang C. Zhang X. Dai J. Yue L. Zhang Q. Cai X. Zhu Y. Duan H. Liu Y. Li D. Zhu Y. Radstake T. Balak D.M.W. Xu D. Guo T. Lu C. Yu X. In-depth serum proteomics reveals biomarkers of psoriasis severity and response to traditional Chinese medicine.Theranostics. 2019; 9: 2475-2488Crossref PubMed Scopus (51) Google Scholar). We that differentially-expressed proteins (n = p-value (Fig. participate in a of biological associated with viral infection, immune cell activation and and the and (Fig. in the and have been identified in early SARS-CoV-2 infection and severe COVID-19 patients T. M. T. of for cytokine 2016; PubMed Scopus Google Scholar, N. Li D. Wang X. Sun Z. are associated with in patients with novel coronavirus 2020; PubMed Scopus Google Scholar, R. the target in 2020; Scholar, M. D. C. F. as a target in Immunol. 2020; 20 PubMed Scopus Google Scholar). data that activation of viral infection pathways in acute COVID-19 infection. studies have that the signaling pathway is a major immune response to SARS-CoV-2 infection, and that the and signaling pathways a in and pathogenesis L. Shi Y. Gong B. Jiang L. Liu X. Yang J. J. C. Jiang Q. B. Zeng T. M. Zeng F. Zeng F. Wang S. Yang X. Yang Z. cell immune profiling reveals the pathway mediated immune response for 2020; Scholar, J. B. S. D. J. Kuhn potential of and signaling for respiratory syndrome coronavirus infection as identified by 2015; PubMed Scopus Google Scholar, T. S. M. S. and signaling pathways are for infection in PubMed Scopus Google Scholar). We that signaling pathways are the major of pathways in early SARS-CoV-2 infection (Fig. and Fig. These pathways in infection R. R. M. Zhao J. S. and inflammatory pneumonia in 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). The changes of cytokines (i.e. IL6, that may in early stages of SARS-CoV-2 infection (Fig. 1A, Table In addition, our identified of which are by cytokines and as for from the blood to of infection or The and cytokine signaling pathways, which are to in viral were in a of differentially-expressed proteins in early SARS-CoV-2 infection (Fig. CCL2 is a that and and is associated with inflammatory acute respiratory and inflammatory and are associated with the respiratory and of patients Chang Wu Yu Wei S. Chang of the 2 via a severe acute respiratory syndrome coronavirus signaling PubMed Scopus Google Scholar). Furthermore, CCL2 as an that viral in infected and CCL2 in M. C. A. M. Lu J. M. R. Z. A. S. S. M. L. CCL2 in human by viral 2015; PubMed Scopus Google Scholar). a novel of inflammation caused by and by CCL2 in A. G. C. A. A. S. of and in a by treatment with an of 2009; PubMed Scopus Google Scholar, A. S. A. S. from and in a of acute virus disease by an of PubMed Scopus Google Scholar). CXCL10 is a for the the activation of which in the of and the of a from been to CCL2 and CXCL10 in human T. H. K. T. E. A. H. Y. A. CCL2 and CXCL10 via the of activation in human J. Med. PubMed Scopus Google Scholar). All the that CCL2 and CXCL10 may have the potential to as anti-inflammation for COVID-19 W. Zhao Y. Zhang F. Wang Q. Li T. Liu Z. Wang J. Qin Y. Zhang X. Yan X. Zeng X. Zhang S. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China.Clin. Immunol. 2020; 214: 108393Crossref PubMed Scopus (858) Google Scholar, M. Guo S. J.M. N. in pathogenesis and potential therapeutic PubMed Scopus Google Scholar). in Fig. there are of COVID-19 patients in the clustering The group of patients were whereas the patients were in the may in the immune SARS-CoV-2 infection. The are to the in which patients plasma levels of immune cytokines and the is a for the severity of COVID-19 T. P. M. C. J. B. J. J. T. M. Lu P. A. A. Liu F. A. Sun J. Wang E. R. S. A. A. C. J. C. S. N. W. A. A. S. A. in immune to SARS-CoV-2 that disease 2020; Scholar, J. C. biological immune and COVID-19 Immunol. 2020; PubMed Scopus Google Scholar). are in this the of serum samples was the biomarkers identified in our in a large clinical protein on the and of the antibodies on the serological proteins of early-stage COVID-19 patients were only with early-stage influenza patients. In the protein profiling of COVID-19 patients over the of infection. In addition, the with patients and patients infected with the serological proteins of early a understanding of the inflammation and immune signaling that data identified potential biomarkers that to COVID-19 patients and effective We for review and of this with Coronavirus disease 2019 severe acute respiratory syndrome coronavirus

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