Cell deaths: Involvement in the pathogenesis and intervention therapy of COVID-19.

The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has dramatically influenced various aspects of the world. It is urgent to thoroughly study pathology and underlying mechanisms for developing effective strategies to prevent and treat this threatening disease. It is universally acknowledged that cell death and cell autophagy are essential and crucial to maintaining host homeostasis and participating in disease pathogenesis. At present, more than twenty different types of cell death have been discovered, some parts of which have been fully understood, whereas some of which need more investigation. Increasing studies have indicated that cell death and cell autophagy caused by coronavirus might play an important role in virus infection and pathogenicity. However, the knowledge of the interactions and related mechanisms of SARS-CoV-2 between cell death and cell autophagy lacks systematic elucidation. Therefore, in this review, we comprehensively delineate how SARS-CoV-2 manipulates diverse cell death (including apoptosis, necroptosis, pyroptosis, ferroptosis, and NETosis) and cell autophagy for itself benefits, which is simultaneously involved in the occurrence and progression of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells.

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids. Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein. Moreover, histones enhance cell-cell fusion. Finally, treatment with an inhibitor of NETosis, histone H3 or H4, or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model. These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Longitudinal changes of laboratory measurements after discharged from hospital in 268 COVID-19 pneumonia patients.

BACKGROUND AND OBJECTIVE: Monitoring recovery process of coronavirus disease 2019 (COVID-19) patients released from hospital is crucial for exploring residual effects of COVID-19 and beneficial for clinical care. In this study, a comprehensive analysis was carried out to clarify residual effects of COVID-19 on hospital discharged patients. METHODS: Two hundred sixty-eight cases with laboratory measured data at hospital discharge record and five follow-up visits were retrospectively collected to carry out statistical data analysis comprehensively, which includes multiple statistical methods (e.g., chi-square, T-test and regression) used in this study. RESULTS: Study found that 13 of 21 hematologic parameters in laboratory measured dataset and volume ratio of right lung lesions on CT images highly associated with COVID-19. Moderate patients had statistically significant lower neutrophils than mild and severe patients after hospital discharge, which is probably caused by more efforts on severe patients and slightly neglection of moderate patients. COVID-19 has residual effects on neutrophil-to-lymphocyte ratio (NLR) of patients who have hypertension or chronic obstructive pulmonary disease (COPD). After released from hospital, female showed better performance in T lymphocytes subset cells, especially T helper lymphocyte% (16% higher than male). According to this sex-based differentiation of COVID-19, male should be recommended to take clinical test more frequently to monitor recovery of immune system. Patients over 60 years old showed unstable recovery process of immune cells (e.g., CD45 + lymphocyte) within 75 days after discharge requiring longer clinical care. Additionally, right lung was vulnerable to COVID-19 and required more time to recover than left lung. CONCLUSIONS: Criterion of hospital discharge and strategy of clinical care should be flexible in different cases due to residual effects of COVID-19, which depend on several impact factors. Revealing remaining effects of COVID-19 is an effective way to eliminate disorder of mental health caused by COVID-19 infection.

mRNA vaccine: a potential therapeutic strategy.

mRNA vaccines have tremendous potential to fight against cancer and viral diseases due to superiorities in safety, efficacy and industrial production. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. Based on the immunological study, mRNA vaccines are coupled with immunologic adjuvant and various delivery strategies. Except for sequence optimization, the assistance of mRNA-delivering strategies is another method to stabilize mRNAs and improve their efficacy. The understanding of increasing the antigen reactiveness gains insight into mRNA-induced innate immunity and adaptive immunity without antibody-dependent enhancement activity. Therefore, to address the problem, scientists further exploited carrier-based mRNA vaccines (lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particle and cationic nanoemulsion), naked mRNA vaccines and dendritic cells-based mRNA vaccines. The article will discuss the molecular biology of mRNA vaccines and underlying anti-virus and anti-tumor mechanisms, with an introduction of their immunological phenomena, delivery strategies, their importance on Corona Virus Disease 2019 (COVID-19) and related clinical trials against cancer and viral diseases. Finally, we will discuss the challenge of mRNA vaccines against bacterial and parasitic diseases.

Using artificial intelligence to assist radiologists in distinguishing COVID-19 from other pulmonary infections.

BACKGROUND: Accurate and rapid diagnosis of coronavirus disease (COVID-19) is crucial for timely quarantine and treatment. PURPOSE: In this study, a deep learning algorithm-based AI model using ResUNet network was developed to evaluate the performance of radiologists with and without AI assistance in distinguishing COVID-19 infected pneumonia patients from other pulmonary infections on CT scans. METHODS: For model development and validation, a total number of 694 cases with 111,066 CT slides were retrospectively collected as training data and independent test data in the study. Among them, 118 are confirmed COVID-19 infected pneumonia cases and 576 are other pulmonary infection cases (e.g. tuberculosis cases, common pneumonia cases and non-COVID-19 viral pneumonia cases). The cases were divided into training and testing datasets. The independent test was performed by evaluating and comparing the performance of three radiologists with different years of practice experience in distinguishing COVID-19 infected pneumonia cases with and without the AI assistance. RESULTS: Our final model achieved an overall test accuracy of 0.914 with an area of the receiver operating characteristic (ROC) curve (AUC) of 0.903 in which the sensitivity and specificity are 0.918 and 0.909, respectively. The deep learning-based model then achieved a comparable performance by improving the radiologists' performance in distinguish COVOD-19 from other pulmonary infections, yielding better average accuracy and sensitivity, from 0.941 to 0.951 and from 0.895 to 0.942, respectively, when compared to radiologists without using AI assistance. CONCLUSION: A deep learning algorithm-based AI model developed in this study successfully improved radiologists' performance in distinguishing COVID-19 from other pulmonary infections using chest CT images.

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.