SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication.

Viral infection in respiratory tract usually leads to cell death, impairing respiratory function to cause severe disease. However, the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention, and especially the high-frequency asymptomatic infection increases the risk of virus transmission. Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection. Here, we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein. We found SARS-CoV-2 virus-like particles (trVLP) suppressed cell apoptosis, but the trVLP lacking N protein didn't. Further study verified that N protein repressed cell apoptosis in cultured cells, human lung organoids and mice. Mechanistically, N protein specifically interacted with anti-apoptotic protein MCL-1, and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1, which stabilized this protein and promoted it to hijack Bak in mitochondria. Importantly, N protein promoted the replications of IAV, DENV and ZIKV, and exacerbated death of IAV-infected mice, all of which could be blocked by a MCL-1 specific inhibitor, S63845. Altogether, we identifed a distinct anti-apoptotic function of the N protein, through which it promoted viral replication. These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction, and indicate a risk of enhanced coinfection with other viruses. We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.

The roles of critical pro-inflammatory cytokines in the drive of cytokine storm during SARS-CoV-2 infection.

In patients with severe COVID-19, acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and even mortality can result from cytokine storm, which is a hyperinflammatory medical condition caused by the excessive and uncontrolled release of pro-inflammatory cytokines. High levels of numerous crucial pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-α, interferon (IFN)-γ, IFN-induced protein 10 kDa, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and IL-10 and so on, have been found in severe COVID-19. They participate in cascade amplification pathways of pro-inflammatory responses through complex inflammatory networks. Here, we review the involvements of these critical inflammatory cytokines in SARS-CoV-2 infection and discuss their potential roles in triggering or regulating cytokine storm, which can help to understand the pathogenesis of severe COVID-19. So far, there is rarely effective therapeutic strategy for patients with cytokine storm besides using glucocorticoids, which is proved to result in fatal side effects. Clarifying the roles of key involved cytokines in the complex inflammatory network of cytokine storm will help to develop an ideal therapeutic intervention, such as neutralizing antibody of certain cytokine or inhibitor of some inflammatory signal pathways.

Ferroptosis: A mixed blessing for infectious diseases.

To date, it has been confirmed that the occurrence and development of infectious diseases are tightly associated with regulatory cell death processes, such as apoptosis, autophagy, and necroptosis. Ferroptosis, as a newly discovered form of regulatory cell death characterized by iron-dependent lipid peroxidation, is not only closely associated with tumor progression, but is also found to be tightly related to the regulation of infectious diseases, such as Tuberculosis, Cryptococcal meningitis, Malaria and COVID-2019. The emerging critical roles of ferroptosis that has been found in infectious disease highlight ferroptosis as a potential therapeutic target in this field, which is therefore widely expected to be developed into new therapy strategy against infectious diseases. Here, we summarized the underlying mechanisms of ferroptosis and highlighted the intersections between host immunity and ferroptosis. Moreover, we illuminated the roles of ferroptosis in the occurrence and progression of different infectious diseases, which might provide some unique inspiration and thought-provoking perspectives for the future research of these infectious diseases, especially for the development of ferroptosis-based therapy strategy against infectious diseases.

ZDHHC11 Suppresses Zika Virus Infections by Palmitoylating the Envelope Protein.

Zika virus (ZIKV) is an RNA-enveloped virus that belongs to the Flavivirus genus, and ZIKV infections potentially induce severe neurodegenerative diseases and impair male fertility. Palmitoylation is an important post-translational modification of proteins that is mediated by a series of DHHC-palmitoyl transferases, which are implicated in various biological processes and viral infections. However, it remains to be investigated whether palmitoylation regulates ZIKV infections. In this study, we initially observed that the inhibition of palmitoylation by 2-bromopalmitate (2-BP) enhanced ZIKV infections, and determined that the envelope protein of ZIKV is palmitoylated at Cys308. ZDHHC11 was identified as the predominant enzyme that interacts with the ZIKV envelope protein and catalyzes its palmitoylation. Notably, ZDHHC11 suppressed ZIKV infections in an enzymatic activity-dependent manner and ZDHHC11 knockdown promoted ZIKV infection. In conclusion, we proposed that the envelope protein of ZIKV undergoes a novel post-translational modification and identified a distinct mechanism in which ZDHHC11 suppresses ZIKV infections via palmitoylation of the ZIKV envelope protein.

A vaccine delivery system promotes strong immune responses against SARS-CoV-2 variants.

Global coronavirus disease 2019 (COVID-19) pandemics highlight the need of developing vaccines with universal and durable protection against emerging SARS-CoV-2 variants. Here we developed an extended-release vaccine delivery system (GP-diABZI-RBD), consisting the original SARS-CoV-2 WA1 strain receptor-binding domain (RBD) as the antigen and diABZI stimulator of interferon genes (STING) agonist in conjunction with yeast ß-glucan particles (GP-diABZI) as the platform. GP-diABZI-RBD could activate STING pathway and inhibit SARS-CoV-2 replication. Compared to diABZI-RBD, intraperitoneal injection of GP-diABZI-RBD elicited robust cellular and humoral immune responses in mice. Using SARS-CoV-2 GFP/ΔN transcription and replication-competent virus-like particle system (trVLP), we demonstrated that GP-diABZI-RBD-prototype vaccine exhibited the strongest and durable humoral immune responses and antiviral protection; whereas GP-diABZI-RBD-Omicron displayed minimum neutralization responses against trVLP. By using pseudotype virus (PsVs) neutralization assay, we found that GP-diABZI-RBD-Prototype, GP-diABZI-RBD-Delta, and GP-diABZI-RBD-Gamma immunized mice sera could efficiently neutralize Delta and Gamma PsVs, but had weak protection against Omicron PsVs. In contrast, GP-diABZI-RBD-Omicron immunized mice sera displayed the strongest neutralization response to Omicron PsVs. Taken together, the results suggest that GP-diABZI can serve as a promising vaccine delivery system for enhancing durable humoral and cellular immunity against broad SARS-CoV-2 variants. Our study provides important scientific basis for developing SARS-CoV-2 VOC-specific vaccines.

Ferroptosis: A mixed blessing for infectious diseases

To date, it has been confirmed that the occurrence and development of infectious diseases are tightly associated with regulatory cell death processes, such as apoptosis, autophagy, and necroptosis. Ferroptosis, as a newly discovered form of regulatory cell death characterized by iron-dependent lipid peroxidation, is not only closely associated with tumor progression, but is also found to be tightly related to the regulation of infectious diseases, such as Tuberculosis, Cryptococcal meningitis, Malaria and COVID-2019. The emerging critical roles of ferroptosis that has been found in infectious disease highlight ferroptosis as a potential therapeutic target in this field, which is therefore widely expected to be developed into new therapy strategy against infectious diseases. Here, we summarized the underlying mechanisms of ferroptosis and highlighted the intersections between host immunity and ferroptosis. Moreover, we illuminated the roles of ferroptosis in the occurrence and progression of different infectious diseases, which might provide some unique inspiration and thought-provoking perspectives for the future research of these infectious diseases, especially for the development of ferroptosis-based therapy strategy against infectious diseases.

Urban greenspace helps ameliorate people's negative sentiments during the COVID-19 pandemic: The case of Beijing.

The COVID-19 pandemic has had negative effects on people's mental health worldwide, especially for those who live in large cities. Studies have reported that urban greenspace may help lessen these adverse effects, but more research that explicitly considers urban landscape pattern is needed to understand the underlying processes. Thus, this study was designed to examine whether the resident sentiments in Beijing, China changed before and during the pandemic, and to investigate what urban landscape attributes - particularly greenspace - might contribute to the sentiment changes. We conducted sentiment analysis based on 25,357 geo-tagged microblogs posted by residents in 51 neighborhoods. We then compared the resident sentiments in 2019 (before the COVID-19) with those in 2020 (during the COVID-19) using independent sample t-tests, and examined the relationship between resident sentiments and urban greenspace during the COVID-19 pandemic phases using stepwise regression. We found that residents' sentiments deteriorated significantly from 2019 to 2020 in general, and that urban sentiments during the pandemic peak times showed an urban-suburban trend that was determined either by building density or available greenspace. Although our analysis included several other environmental and socioeconomic factors, none of them showed up as a significant factor. Our study suggests the effects of urban greenspace and building density on residents' sentiments increased during the COVID-19 pandemic and that not all green spaces are equal. Increasing greenspace, especially within and near neighborhoods, seems critically important to helping urban residents to cope with public health emergencies such as global pandemics.

Altered Lipid Profile in COVID-19 Patients and Metabolic Reprogramming.

Background: Coronavirus disease 2019 (COVID-19) is a global pandemic. Previous studies have reported dyslipidemia in patients with COVID-19. Herein, we conducted a retrospective study and a bioinformatics analysis to evaluate the essential data of the lipid profile as well as the possible mechanism in patients with COVID-19. Methods: First of all, the retrospective study included three cohorts: patients with COVID-19, a healthy population, and patients with chronic obstructive pulmonary disease (COPD). For each subject, serum lipid profiles in the biochemical data were compared, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Furthermore, bioinformatics analyses were performed for exploring the biological or immunological mechanisms. Results: In line with the biochemical data of the three cohorts, the statistical result displayed that patients with COVID-19 were more likely to have lower levels of TC and HDL-C as compared with healthy individuals. The differential proteins associated with COVID-19 are involved in the lipid pathway and can target and regulate cytokines and immune cells. Additionally, a heatmap revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were possibly involved in lipid metabolic reprogramming. The viral proteins, such as spike (S) and non-structural protein 2 (Nsp2) of SARS-CoV-2, may be involved in metabolic reprogramming. Conclusion: The metabolic reprogramming after SARS-CoV-2 infections is probably associated with the immune and clinical phenotype of patients. Hence, metabolic reprogramming may be targeted for developing antivirals against COVID-19.

七例2019冠状病毒病(COVID-19)普通型患者出院后病毒核酸随访结果 Follow-up testing of viral nucleic acid in discharged patients with moderate type of COVID-19

目的 随访研究2019冠状病毒病（COVID-19）患者在达到出院标准后病毒核酸检测结果，为医疗机构对出院患者随访管理提供决策依据。 方法 对浙江大学医学院附属第四医院经治疗后已符合出院标准的COVID-19患者采取院内继续隔离观察7 d，再居家隔离4周，期间记录患者每日临床体征，定期送检痰液行病毒核酸检测，评估患者病情变化。 结果 已符合现有出院标准的7例患者中有3例在5~7 d后再次出现痰液病毒核酸检测阳性，持续阳性2~6 d后再次转阴；复查患者血常规、C反应蛋白、血生化以及胸部CT结果均无明显异常，也无明显临床症状。其余4例患者随访4周，痰液病毒核酸检测均为阴性，未出现COVID-19相关临床症状，实验室和影像学检查结果无异常。 结论 COVID-19患者按现有标准出院后复阳的比例较高，建议有条件的医疗机构对满足现行出院标准的患者继续院内隔离观察7 d并进行连续的病毒核酸监测。

DNA Based Vaccine Expressing SARS-CoV-2 Spike-CD40L Fusion Protein Confers Protection Against Challenge in a Syrian Hamster Model.

SARS-CoV-2 infections present a tremendous threat to public health. Safe and efficacious vaccines are the most effective means in preventing the infections. A variety of vaccines have demonstrated excellent efficacy and safety around the globe. Yet, development of alternative forms of vaccines remains beneficial, particularly those with simpler production processes, less stringent storage conditions, and the capability of being used in heterologous prime/boost regimens which have shown improved efficacy against many diseases. Here we reported a novel DNA vaccine comprised of the SARS-CoV-2 spike protein fused with CD40 ligand (CD40L) serving as both a targeting ligand and molecular adjuvant. A single intramuscular injection in Syrian hamsters induced significant neutralizing antibodies 3-weeks after vaccination, with a boost substantially improving immune responses. Moreover, the vaccine also reduced weight loss and suppressed viral replication in the lungs and nasal turbinates of challenged animals. Finally, the incorporation of CD40L into the DNA vaccine was shown to reduce lung pathology more effectively than the DNA vaccine devoid of CD40L. These results collectively indicate that this DNA vaccine candidate could be further explored because of its efficacy and known safety profile.

Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events.

The current pandemic of COVID-19 is fueled by more infectious emergent Omicron variants. Ongoing concerns of emergent variants include possible recombinants, as genome recombination is an important evolutionary mechanism for the emergence and re-emergence of human viral pathogens. In this study, we identified diverse recombination events between two Omicron major subvariants (BA.1 and BA.2) and other variants of concern (VOCs) and variants of interest (VOIs), suggesting that co-infection and subsequent genome recombination play important roles in the ongoing evolution of SARS-CoV-2. Through scanning high-quality completed Omicron spike gene sequences, 18 core mutations of BA.1 (frequency >99%) and 27 core mutations of BA.2 (nine more than BA.1) were identified, of which 15 are specific to Omicron. BA.1 subvariants share nine common amino acid mutations (three more than BA.2) in the spike protein with most VOCs, suggesting a possible recombination origin of Omicron from these VOCs. There are three more Alpha-related mutations in BA.1 than BA.2, and BA.1 is phylogenetically closer to Alpha than other variants. Revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1. Most notably, multiple characteristic amino acid mutations in the Delta spike protein have been also identified in the "Deltacron"-like Omicron Variants isolated since November 11, 2021 in South Africa, which implies the recombination events occurring between the Omicron and Delta variants. Monitoring the evolving SARS-CoV-2 genomes especially for recombination is critically important for recognition of abrupt changes to viral attributes including its epitopes which may call for vaccine modifications.

Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants.

Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in late 2019, the coronavirus disease 2019 (COVID-19) pandemic has challenged public health around the world. Currently, there is an urgent need to explore antiviral therapeutic targets and effective clinical drugs. In this study, we systematically summarized two main therapeutic strategies against COVID-19, namely drugs targeting the SARS-CoV-2 life cycle and SARS-CoV-2-induced inflammation in host cells. The development of above two strategies is implemented by repurposing drugs and exploring potential targets. A comprehensive summary of promising drugs, especially cytokine inhibitors, and traditional Chinese medicine (TCM), provides recommendations for clinicians as evidence-based medicine in the actual clinical COVID-19 treatment. Considering the emerging SARS-CoV-2 variants greatly impact the effectiveness of drugs and vaccines, we reviewed the appearance and details of SARS-CoV-2 variants for further perspectives in drug design, which brings updating clues to develop therapeutical agents against the variants. Based on this, the development of broadly antiviral drugs, combined with immunomodulatory, or holistic therapy in the host, is prior to being considered for therapeutic interventions on mutant strains of SARS-CoV-2. Therefore, it is highly acclaimed the requirements of the concerted efforts from multi-disciplinary basic studies and clinical trials, which improves the accurate treatment of COVID-19 and optimizes the contingency measures to emerging SARS-CoV-2 variants.

Optimization of loop-mediated isothermal amplification (LAMP) assay for robust visualization in SARS-CoV-2 and emerging variants diagnosis.

Loop-mediated isothermal amplification (LAMP) is widely used in detection of pathogenic microorganisms including SARS-CoV-2. However, the performance of LAMP assay needs further exploration in the emerging SARS-CoV-2 variants test. Here, we design serials of primers and select an optimal set for LAMP-based on SARS-CoV-2 N gene for a robust and visual assay in SARS-CoV-2 diagnosis. The limit of detectable template reaches 10 copies of N gene per 25 µL reaction at isothermal 58℃ within 40 min. Importantly, the primers for LAMP assay locate at 12 to 213 nt of N gene, a highly conservative region, which serves as a compatible test in emerging SARS-CoV-2 variants. Comparison to a commercial qPCR assay, this LAMP assay exerts the high viability in diagnosis of 41 clinical samples. Our study optimizes an advantageous LAMP assay for colorimetric detection of SARS-CoV-2 and emerging variants, which is hopeful to be a promising test in COVID-19 surveillance.

DNA Based Vaccine Expressing SARS-CoV-2 Spike-CD40L Fusion Protein Confers Protection Against Challenge in a Syrian Hamster Model

SARS-CoV-2 infections present a tremendous threat to public health. Safe and efficacious vaccines are the most effective means in preventing the infections. A variety of vaccines have demonstrated excellent efficacy and safety around the globe. Yet, development of alternative forms of vaccines remains beneficial, particularly those with simpler production processes, less stringent storage conditions, and the capability of being used in heterologous prime/boost regimens which have shown improved efficacy against many diseases. Here we reported a novel DNA vaccine comprised of the SARS-CoV-2 spike protein fused with CD40 ligand (CD40L) serving as both a targeting ligand and molecular adjuvant. A single intramuscular injection in Syrian hamsters induced significant neutralizing antibodies 3-weeks after vaccination, with a boost substantially improving immune responses. Moreover, the vaccine also reduced weight loss and suppressed viral replication in the lungs and nasal turbinates of challenged animals. Finally, the incorporation of CD40L into the DNA vaccine was shown to reduce lung pathology more effectively than the DNA vaccine devoid of CD40L. These results collectively indicate that this DNA vaccine candidate could be further explored because of its efficacy and known safety profile.

SARS-CoV-2 N Protein Induces Acute Kidney Injury via Smad3-Dependent G1 Cell Cycle Arrest Mechanism.

COVID-19 is infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and can cause severe multiple organ injury and death. Kidney is one of major target organs of COVID-19 and acute kidney injury (AKI) is common in critically ill COVID-19 patients. However, mechanisms through which COVID-19 causes AKI remain largely unknown and treatment remains unspecific and ineffective. Here, the authors report that normal kidney-specifically overexpressing SARS-CoV-2 N develops AKI, which worsens in mice under ischemic condition. Mechanistically, it is uncovered that SARS-CoV-2 N-induced AKI is Smad3-dependent as SARS-CoV-2 N protein can interact with Smad3 and enhance TGF-ß/Smad3 signaling to cause tubular epithelial cell death and AKI via the G1 cell cycle arrest mechanism. This is further confirmed in Smad3 knockout mice and cells in which deletion of Smad3 protects against SARS-CoV-2 N protein-induced cell death and AKI in vivo and in vitro. Most significantly, it is also found that targeting Smad3 with a Smad3 pharmacological inhibitor is able to inhibit SARS-CoV-2 N-induced AKI. In conclusion, the authors identify that SARS-CoV-2 N protein is a key mediator for AKI and induces AKI via the Smad3-dependent G1 cell cycle arrest mechanism. Targeting Smad3 may represent as a novel therapy for COVID-19-asscoaited AKI.

Low Humoral Immune Response and Ineffective Clearance of SARS-Cov-2 in a COVID-19 Patient With CLL During a 69-Day Follow-Up

Background: A recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), which began in Wuhan, China, with a high level of human-to-human transmission has been reported. There are limited data available on Coronavirus Disease 2019 (COVID-19) patients with hematological malignancies with more than 60 days of follow-up. This study describes the clinical characteristics, including multiple recurrences of COVID-19, in a patient with chronic lymphocytic leukemia (CLL) during 69 days of follow-up. Case Presentation: A 72-year-old female was admitted to hospital isolation after being infected with COVID-19 as part of a family cluster on January 30, 2020. Apart from SARS-Cov-2 virus infection, laboratory results revealed lymphocytosis of uncertain etiology and abnormal distribution of T lymphocytes. On blood smears, small blue lymphocytes with scant cytoplasm were observed, and the presence of high levels of circulating clonal B cells was also demonstrated by flow cytometry. The patient was diagnosed with COVID-19 and CLL. Among her family members, she had the highest viral loads and the fastest progression on lung injury and developed severe pneumonia. Serological results showed she had both 2019-nCoV-specific IgM and IgG antibodies;however, only IgG antibodies were detected in her husband's plasma. Results: A combination regimen of antiviral therapy and high-dose intravenous immunoglobulin (IVIG) in the early stage seemed to be effective for treating CLL and SARS-Cov-2 infection. Because of the low humoral immune response, the CLL patient could not effectively clear the SARS-Cov-2 infection and suffered from recurrence twice during the 69-day follow-up. Conclusion: In CLL, a neoplastic antigen-specific B-cell clone proliferates, and the progeny cells accumulate and outgrow other B cells, leading to immune deficiency. Considering the low humoral immune response and ineffective clearance of SARS-Cov-2 in CLL patients, the follow-up and home quarantine period should be extended. We need further studies to clarify suspending or continuing CLL therapy during COVID infection. For those patients who are prone to progression to severe disease, administering humoral immunity therapies can help to prevent disease progression and quickly meet the cure criteria.

V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity.

The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.

Etiological and epidemiological features of acute respiratory infections in China.

Nationwide prospective surveillance of all-age patients with acute respiratory infections was conducted in China between 2009‒2019. Here we report the etiological and epidemiological features of the 231,107 eligible patients enrolled in this analysis. Children <5 years old and school-age children have the highest viral positivity rate (46.9%) and bacterial positivity rate (30.9%). Influenza virus, respiratory syncytial virus and human rhinovirus are the three leading viral pathogens with proportions of 28.5%, 16.8% and 16.7%, and Streptococcus pneumoniae, Mycoplasma pneumoniae and Klebsiella pneumoniae are the three leading bacterial pathogens (29.9%, 18.6% and 15.8%). Negative interactions between viruses and positive interactions between viral and bacterial pathogens are common. A Join-Point analysis reveals the age-specific positivity rate and how this varied for individual pathogens. These data indicate that differential priorities for diagnosis, prevention and control should be highlighted in terms of acute respiratory tract infection patients' demography, geographic locations and season of illness in China.