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Since 2019, Coronavirus Disease 2019(COVID-19) has affected millions of people worldwide. Except for acute respiratory distress syndrome, dysgeusis is also a common symptom of COVID-19 that burdens patients for weeks or permanently. However, the mechanisms underlying taste dysfunctions remain unclear. Here, we performed complete autopsies of five patients who died of COVID-19. Integrated tongue samples, including numerous taste buds, salivary glands, vessels, and nerves were collected to map the pathology, distribution, cell tropism, and receptor distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the tongue. Our results revealed that all patients had moderate lymphocyte infiltration around the salivary glands and in the lamina propria adjacent to the mucosa, and pyknosis in the epithelia of taste buds and salivary glands. This may be because the serous acini, salivary gland ducts, and taste buds are the primary sites of SARS-CoV-2 infection. Multicolor immunofluorescence showed that SARS-CoV-2 readily infects Keratin (KRT) 7+ taste receptor cells in taste buds, secretory cells in serous acini, and inner epithelial cells in the ducts. The major receptors, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), were both abundantly expressed in these cells. Viral antigens and receptor were both rarely detected in vessels and nerves. This indicates that SARS-CoV-2 infection triggers pathological injury in the tongue, and that dysgeusis may be directly related to viral infection and cellular damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ma, Liu, Wang, Liu, Hu, Zhou and Liu.)

The high risk of SARS-CoV-2 infection and reinfection and the occurrence of post-acute pulmonary sequelae have highlighted the importance of understanding the mechanism underlying lung repair after injury. To address this concern, comparative and systematic analyses of SARS-CoV-2 infection in COVID-19 patients and animals were conducted. In the lungs of nine patients who died of COVID-19 and one recovered from COVID-19 but died of unrelated disease in early 2020, damage-related transient progenitor (DATP) cells expressing CK8 marker proliferated significantly. These CK8 + DATP cells were derived from bronchial CK5 + basal cells. However, they showed different cell fate toward differentiation into type I alveolar cells in the deceased and convalescent patients, respectively. By using a self-limiting hamster infection model mimicking the dynamic process of lung injury remodeling in mild COVID-19 patients, the accumulation and regression of CK8 + cell marker were found to be closely associated with the disease course. Finally, we examined the autopsied lungs of two patients who died of infection by the recent Omicron variant and found that they only exhibited mild pathological injury with no CK8 + cell proliferation. These results indicate a clear pulmonary cell remodeling route and suggest that CK8 + DATP cells play a primary role in mediating alveolar remodeling, highlighting their potential applications as diagnostic markers and therapeutic targets., Competing Interests: Conflict of interest Prof. Fei Deng is an editorial board member for ​Virologica Sinica ​and was not involved in the editorial review or the decision to publish this article. ​All the authors declare no conflicts of interests., (Copyright © 2024 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike (S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the wild-type, B.1.1.7, B.1.351, B.1.617.2, and the newly emerging Omicron variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. Furthermore, our safety assessment of RQ3013 in NHP showed no observable adverse effects. These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants., Competing Interests: Conflict of interest Jinzhong Lin is a co-founder of RNACure and serves on the advisory board of RNACure. Jing Lu is now an employee at RNACure. The other authors declare that they have no conflict of interest., (Copyright © 2023 Science China Press. Published by Elsevier B.V. All rights reserved.)

Background: The ongoing coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on our societies. Moreover, the disease's extensive and sustained symptoms are now becoming a nonnegligible medical challenge. In this respect, data indicate that heart failure is one of the most common readmission diagnoses among COVID-19 patients., Methods: In this study, we used human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes to develop an in vitro model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and studied the dynamic changes occurring in cardiomyocytes after SARS-CoV-2 infection., Results: To this end, we have created an effective time series SARS-CoV-2 infection model exhibiting different functional patterns of up- and downregulated proteins, and demonstrating that SARS-CoV-2 mainly affects (i) the lipid and the energy metabolism of hiPSC-derived cardiomyocytes during the early infection stage, and (ii) the DNA repair ability of cardiomyocytes during the late infection stage. By analyzing the proteome changes occurring at different infection timepoints, we were able to observe that the simulated disease (COVID-19) course developed rapidly, and that each of the studied timepoints was characterized by a distinct protein expression pattern., Conclusions: Our findings highlight the importance of early detection and personalized treatment based on the disease stage. Finally, by combing the proteomics data with virus-host interaction network analysis, we were able to identify several potential drug targets for the disease., (© 2023. The Author(s).)

Neutralizing monoclonal antibodies (mAb) are a major therapeutic strategy for the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The continuous emergence of new SARS-CoV-2 variants worldwide has increased the urgency for the development of new mAbs. In this study, we immunized mice with the receptor-binding domain (RBD) of the SARS-CoV-2 prototypic strain (WIV04) and screened 35 RBD-specific mAbs using hybridoma technology. Results of the plaque reduction neutralization test showed that 25 of the mAbs neutralized authentic WIV04 strain infection. The 25 mAbs were divided into three categories based on the competitive enzyme-linked immunosorbent assay results. A representative mAb was selected from each category (RD4, RD10, and RD14) to determine the binding kinetics and median inhibitory concentration (IC 50 ) of WIV04 and two variants of concern (VOC): B.1.351 (Beta) and B.1.617.2 (Delta). RD4 neutralized the B.1.617.2 variant with an IC 50 of 2.67 ​ng/mL; however, it completely lost neutralizing activity against the B.1.351 variant. RD10 neutralized both variants with an IC 50 exceeding 100 ​ng/mL; whereas RD14 neutralized two variants with a higher IC 50 (>1 ​mg/mL). Animal experiments were performed to evaluate the protective effects of RD4 and RD10 against various VOC infections. RD4 could protect Adv-hACE2 transduced mice from B.1.617.2 infection at an antibody concentration of 25 ​mg/kg, while RD10 could protect mice from B.1.351 infection at an antibody concentration of 75 ​mg/kg. These results highlight the potential for future modifications of the mAbs for practical use., Competing Interests: Conflict of interest All authors have declared no conflict of interest., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The ongoing COVID-19 pandemic has caused over six million deaths and huge economic burdens worldwide. Antivirals against its causative agent, SARS-CoV-2, are in urgent demand. Previously, we reported that heterocylic compounds, i.e., chloroquine (CQ) and hydroxychloroquine (HCQ), are potent in inhibiting SARS-CoV-2 replication in vitro . In this study, we discussed the syntheses of two novel heterocylic compounds: tert -butyl rel -4-(((3 R ,4 S )-3-(1 H -indol-3-yl)-1-oxo-2-propyl-1,2,3,4-tetrahydroisoquinolin-4-yl)methyl)piperazine-1-carboxylate ( trans - 1 ) and rel -(3 R ,4 S )-3-(1 H -indol-3-yl)-4-(piperazin-1-ylmethyl)-2-propyl-3,4-dihydroisoquinolin-1(2 H )-one ( trans - 2 ), which effectively suppressed authentic SARS-CoV-2 replication in Vero E6 cells. Compound trans - 1 showed higher anti-SARS-CoV-2 activity than trans - 2 , with a half maximal effective concentration (EC 50 ) of 3.15 μM and a selective index (SI) exceeding 63.49, which demonstrated comparable potency to CQ or HCQ. Additional anti-SARS-CoV-2 tests on Calu-3 human lung cells showed that trans - 1 efficiently inhibited viral replication (EC 50 = 2.78 μM; SI: > 71.94) and performed better than CQ (EC 50 = 44.90 μM; SI = 2.94). The time of an addition assay showed that the action mechanism of trans - 1 differed from that of CQ, as it mainly inhibited the post-entry viral replication in both Vero E6 and Calu-3 cells. In addition, the differences between the antiviral mechanisms of these novel compounds and CQ were discussed.

Viral infection often causes severe damage to the lungs, leading to the appearance of ectopic basal cells (EBCs) and tuft cells in the lung parenchyma. Thus far, the roles of these ectopic epithelial cells in alveolar regeneration remain controversial. Here, we confirm that the ectopic tuft cells are originated from EBCs in mouse models and COVID-19 lungs. The differentiation of tuft cells from EBCs is promoted by Wnt inhibition while suppressed by Notch inhibition. Although progenitor functions have been suggested in other organs, pulmonary tuft cells don't proliferate or give rise to other cell lineages. Consistent with previous reports, Trp63 CreERT2 and KRT5-CreERT2 -labeled ectopic EBCs do not exhibit alveolar regeneration potential. Intriguingly, when tamoxifen was administrated post-viral infection, Trp63 CreERT2 but not KRT5-CreERT2 labels islands of alveolar epithelial cells that are negative for EBC biomarkers. Furthermore, germline deletion of Trpm5 significantly increases the contribution of Trp63 CreERT2 -labeled cells to the alveolar epithelium. Although Trpm5 is known to regulate tuft cell development, complete ablation of tuft cell production fails to improve alveolar regeneration in Pou2f3 -/- mice, implying that Trpm5 promotes alveolar epithelial regeneration through a mechanism independent of tuft cells., Competing Interests: HH, YF, MJ, YZ, JB, JM, JD, YY, LQ, JL, YZ, MW, ZH, TW, AS, JS, IM, WC, CE, JZ, BI, HM, JQ No competing interests declared, (© 2022, Huang et al.)

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

B cell response plays a critical role against SARS-CoV-2 infection. However, little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection. Here, we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients, and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses. Via linking BCR to antigen specificity through sequencing (LIBRA-seq), we identified a distinct activated memory B cell subgroup (CD11c high CD95 high ) had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells. Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection. The public antibody clonotypes were shared by distinct convalescent individuals. Moreover, several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain (RBD) or nucleoprotein (NP) via ELISA assay. Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro. Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Y.G., Z.R., L.L., J.W., Z.L., D.F., X.W. and C.N. are inventors in a pending patent application filed on the reported antibodies. L.L., J.W., Z.L., X.W., C.N., C.D., L.Z., G.G. and N.S. are employees of Harbour Biomed (Suzhou) Co. Ltd. Other authors declare no competing interests. All reagents and information presented in this study are available from corresponding authors upon reasonable request.

Only a few studies investigated the impact of quarantine on anxiety of general population during a second wave of COVID-19 breakout. We aimed to compare anxiety levels of quarantined and non-quarantined people and investigate factors affecting anxiety during the second COVID-19 pandemic. A total of 1837 participants were included in this cross-sectional study. Anxiety was measured by the State-Trait Anxiety Inventory (STAI). Participants were divided into the quarantined group (QG) and non-quarantined group (Non-QG). The mean STAI-S score in the QG was significantly higher than Non-QG (41.8 ± 11.2 vs 40.01 ± 9.9), so was the proportion of severe state anxiety (11.6% vs 5.5%). Males in the QG were significantly more anxious than females evaluated by both STAI-S and STAI-T. High income was independent protective factors while moderate or bad health status and high trait anxiety level were independent risk factors for severe state anxiety. In conclusion, the COVID-19 confinement could significantly increase anxiety of quarantined people. Males were more vulnerable to the quarantine of COVID-19 with significantly increased anxiety level than females. The results suggest that attention should be paid to anxiety during a second round of quarantine due to COVID-19 and are of help in planning psychological interventions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: This study aimed to investigate and monitor the mental health status of pregnant women during the COVID-19 pandemic., Materials and Methods: The meta-analysis was used to study the literatures on the psychology of pregnant women in four databases until Sep 27, 2020., Results: A total of 19 articles were included in the final meta-analysis. The overall prevalence of anxiety was 42 % (95 %CI 26 %-57 %) with substantial heterogeneity (I 2  = 99.6 %). The overall prevalence of depression was 25 % (95 %CI 20 %-31 %) with substantial heterogeneity (I 2  = 97.9 %). Age, family economic status, social support, and physical activity seem to correlate with the mental health status of pregnant women., Conclusion: The prevalence of anxiety and depression among pregnant women increased significantly during the COVID-19 epidemic. Pregnant women are more concerned about others than themselves during COVID-19, and younger pregnant women seem to be more prone to anxiety, while social support and physical activity can reduce the likelihood of anxiety and depression. It is necessary to take some psychological intervention measures for pregnant women to help them go through this special period safely and smoothly., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The COVID-19 epidemic has generated great stress throughout healthcare workers (HCWs). The situation of HCWs should be fully and timely understood. The aim of this meta-analysis is to determine the psychological impact of COVID-19 pandemic on health care workers. Method: We searched the original literatures published from 1 Nov 2019 to 20 Sep 2020 in electronic databases of PUBMED, EMBASE and WEB OF SCIENCE. Forty-seven studies were included in the meta-analysis with a combined total of 81,277 participants. Results: The pooled prevalence of anxiety is 37% (95% CI 0.31–0.42, I2 = 99.9%) from 44 studies. Depression is estimated in 39 studies, and the pooled prevalence of depression is 36% (95% CI 0.31–0.41, I2 = 99.6%). There are 10 studies reported the prevalence of insomnia, and the overall prevalence of insomnia is 32% (95% CI 0.23–0.42, I2 = 99.5%). The subgroup analysis showed a higher incidence of anxiety and depression among women and the frontline HCWs compared to men and non-frontline HCWs respectively. Conclusions: The COVID-19 pandemic has caused heavy psychological impact among healthcare professionals especially women and frontline workers. Timely psychological counseling and intervention ought to be implemented for HCWs in order to alleviate their anxiety and improve their general mental health. [ABSTRACT FROM AUTHOR]