Current advance of basic and clinical medical virology

Coronavirus disease 2019 (COVID-19), which is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become the worst pandemic and public health crisis across the globe once a century. This pandemic has caused huge losses in both human lives and global economy. Innate immunity is the first line of defense against pathogenic invasions. Extensive studies by scientists in China and the world have reported that SARS-CoV-2 can employ multiple strategies to evade host innate immunity, and such immune evasion mechanisms have become critical contributing factors for the pathogenicity of SARS-CoV-2. On the other hand, the pathogenesis of COVID-19 has been found to be closely relevant with the pro-inflammatory responses induced by SARS-CoV-2 infection in humans. This paper provides a brief review to the relationship between SARS-CoV-2 infection and innate immunity as well as inflammation.

[The Clinical Characteristics and Influencing Factors of Patients with Severe COVID-19].

OBJECTIVE: To investigate the clinical characteristic of coagulation, possible causes and countermeasures of patients with severe corona virus disease 2019 (COVID-19). METHODS: The clinical data of the 142 patients diagnosed as COVID-19 at Wuhan Third Hospital in Wuhan, China, from February 10 to February 16, 2020 were collected and analyzed retrospective. Among the patients, 17 cases of dead patients were divided into observe group, and 125 cases of cured patients were divided into control group. The clinical characteristics, laboratory tests, influencing factors, anticoagulant therapy, embolization and bleeding events of the two groups were observed. RESULTS: The average hospital stay time in 142 patients was 22 d. For the 17 dead patients in the observe group, the average hospital stay time was 9.9 d, and the D-dimer, prothrombin time, WBC count and Padua score of the patients in the observe group were significantly higher as compared with the patients in the control group. PT(OR=1.064, 95%CI 1.012-1.119) and D-D(OR=1.045, 95%CI 1.027-1.064) were the independent risk factors that causing the death of COVID-19 patients. Among the patients, 36(25.4%) patients received low-molecular-weight heparin for anticoagulant therapy, with the average course of 9.6 d. The cumulative incidence of the embolism of the patients in the observe group was 7（41.2%）, while 2(11.8%) patients developed to deep vein thrombosis (DVT) and pulmonary embolism (PE), 3 (17.6%) patients occurred acute cerebral infarction and 2 (11.8%) patients occurred acute myocardial infarction. 3 (17.6%) dead patients revealed dominant disseminated intravascular coagulation (DIC). CONCLUSION: Most patients with severe COVID-19 shows a variety of risk factors for thrombus, and those with coagulation dysfunction shows a high dead rate and rapid disease progression. Therefore, coagulation indicators should be dynamically monitored, and mechanical and drug prevention should be actively carried out.

Multi-Omic Profiling of Plasma Identify Biomarkers and Pathogenesis of COVID-19 in Children (preprint)

Background: Children usually develop less severe disease responding to COVID-19 than adults. However, little is known about the detailed mechanism and pathogenesis of children with COVID-19 (CC), and its difference to adults with COVID-19 (AC).Methods: We conducted a plasma proteomic and metabolomic profiling, using the blood samples of 30 children including 18 CC cases and 12 healthy children (HC). By comparing the multi-omic data of AC, standard statistical tests were used to identify differentially expressed proteins (DEPs) and metabolites (DEMs) exclusively altered in CC. Enrichment analyses were conducted to identify biological processes/pathways specifically enriched in CC. To identify potential CC-specific biomarkers, we developed a new machine learning-based method named inference of biomarker combinations with minimal bias (iBM). Further experiments were conducted to validate the predicted metabolic markers.Findings: By quantifying 757 proteins and 1174 metabolites, we identified 44 DEPs and 249 DEMs exclusively altered in CC. Enrichment analyses demonstrated that in CC both deleterious immune response/inflammation processes and protective anti-inflammatory processes were strongly induced in the proteomic level, whereas protective anabolism-related processes were enriched in the metabolomic level. Using iBM, we prioritized two CC-specific biomarker combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish CC from HC or AC. Further experiments showed that the identified metabolites not only inhibited the expression of pro-inflammatory factors, but also suppressed coronaviral replication, implying that these factors played key roles in protecting pediatric patients from both viral infection and infection-induced inflammation.Interpretation: The finding of a strong antagonism of deleterious and protective effects provided new insights on the mechanism and pathogenesis of CC cases that mostly undergo mild symptoms. The identified CC-specific biomarkers could serve as candidate drug targets or therapeutic agents of COVID-19.Funding Statement: This work was supported by the Strategic Priority Research Program of CAS (XDB29010300 to X.Z.), the National Science and Technology Major Project (2018ZX10101004 to X.Z.), National Natural Science Foundation of China (81873964 to Y.Q., 31930021, 31970633 and 34671360 to Y.X., and 31670161 to X.Z.), Grant from the CAS Youth Innovation Promotion Association (2020332 to Y.Q.), the program for HUST Academic Frontier Youth Team (Y.X.).Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: All work performed in this study was approved by the Guangzhou Women and Children's Medical Center Ethics Committee and Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious diseases.

Multi-Omic Profiling of Plasma Identify Biomarkers and Pathogenesis of COVID-19 in Children (preprint)

Although children usually develop less severe disease responding to COVID-19 than adults, little is known about the pathogenesis of COVID-19 in children. Herein, we conducted the plasma proteomic and metabolomic profiling of a cohort of COVID-19 pediatric patients with mild symptoms. Our data show that numerous proteins and metabolites involved in immune as well as anti-inflammatory processes were up-regulated on a larger scale in children than in adults. By developing a machine learning-based pipeline, we prioritized two sets of biomarker combinations, and identified 5 proteins and 5 metabolites as potential children-specific COVID-19 biomarkers. Further study showed that these identified metabolites not only inhibited the expression of pro-inflammatory factors, but also suppressed coronaviral replication, implying that these factors played key roles in protecting pediatric patients from both viral infection and infection-induced inflammation. Together, our study uncovered a protective mechanism responding to COVID-19 in children, and sheds light on potential therapies. Teaser Anti-inflammatory metabolites were highly elevated in the plasma of COVID-19 pediatric patients with mild symptoms.

Postmortem Tissue Proteomics Reveals the Pathogenesis of Multiorgan Injuries of COVID-19 (preprint)

Multiorgan injuries are a major complication of severe COVID-19; however, its pathogenesis is barely understood. Herein, we profiled the host responses to SARS-CoV-2 infection by performing quantitative proteomics of COVID-19 postmortem samples, and provided a comprehensive proteome map covering the protein alterations in eight different organs/tissues. Our results revealed that lung underwent the most abundant protein alterations mainly enriched in immune-/inflammation-related or morphology-related processes, while surprisingly, other organs/tissues exhibited significant protein alterations mainly enriched in processes related with organ movement, respiration, and metabolism. These results indicate that the major cause of lung injury was excessive inflammatory response, and subsequent intravascular thrombosis and pulmonary architecture/function destruction, while other organs/tissues were mainly injured by hypoxia and functional impairment. Therefore, our findings demonstrate the significant pathophysiological alternations of host proteins/pathways associated with multiorgan injuries of COVID-19, which provides invaluable knowledge about COVID-19-associated host responses and sheds light on the pathogenesis of COVID-19. 

Plasma Metabolomic and Lipidomic Alterations Associated with COVID-19 (preprint)

The pandemic of the coronavirus disease 2019 (COVID-19) has become a global public health crisis. COVID-19 is marked by its rapid progression from mild to severe conditions, particularly in the absence of adequate medical care. However, the physiological changes associated with COVID-19 are barely understood. In this study, we performed untargeted metabolomic and lipidomic analyses of plasma from a cohort of COVID-19 patients who had experienced different symptoms. We found the metabolite and lipid alterations exhibit apparent correlation with the course of disease in these COVID-19 patients, indicating that the development of COVID-19 affected patient metabolism. Moreover, many of the metabolite and lipid alterations, particularly ones associated with hepatic functions, have been found to align with the progress and severity of COVID-19. This work provides valuable knowledge about blood biomarkers associated with COVID-19 and potential therapeutic targets, and presents important resource for further studies of COVID-19 pathogenesis.

Epidemiological and Clinical Characteristics of 99 Cases of 2019-Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China (preprint)

Background: Since December 2019, a novel coronavirus (2019-nCoV) associated pneumonia has emerged in Wuhan, China. The study aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia.Methods: 99 cases admitted to Wuhan Jinyintan Hospital during January 1 to 20, 2020 and confirmed by real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) test were analyzed for epidemiological, demographic, clinical, radiological features, and laboratory data. Findings: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the South China Seafood Wholesale Market. The average age of the patients was 62.85 ± 11.99 years, including 67 males and 32 females. 2019-nCoV was detected in all patients by RT-PCR, and some of them also by serological testing, and metagenomics sequencing analysis. 50 cases (50.51%) had chronic basic diseases. Patients had clinical manifestations of fever (83%), cough (82%), shortness of breath (31%), muscle aches (11%), headache (8%), fuzzy confusion (7%), chest pain (2%), and diarrhea (2%). According to imaging examination, 74 patients showed bilateral pneumonia (74.75%), 25 patients showed multiple mottled and ground-glass opacity, and 1 patient had pneumothorax. Most patients received antiviral, antibiotics, supportive treatments, continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO), and had good prognosis. 17 patients developed acute Respiratory Distress Syndrome (ARDS) and among them, 2 patients worsened in a short period of time and died of multiple organ failure.Interpretation: The infection of the 2019-nCoV can result in severe and even fatal respiratory disease like ARDS. It is very important to actively prevent complications and secondary infections, treat underlying diseases, and provide timely organ function support. Early diagnosis, early isolation, multiple treatment, and intervention of CRRT and ECMO when necessary can effectively reduce mortality caused by severe coronavirus pneumonia.Funding: National Key R&D Program of China (No. 2017YFC1309700)Declaration of Interest: The author reports no conflicts of interest in this work.Ethical Approval: The study was approved by Jinyintan Hospital Ethics Committee and written informed consent was obtained from all patients involved before enrolment.