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1.
Virologie ; 26(2):186, 2022.
Article in English | EMBASE | ID: covidwho-1912865

ABSTRACT

Bats are natural reservoirs for numerous coronaviruses, including the potential ancestor of SARS-CoV-2. Knowledge concerning the interaction of coronaviruses and bat cells is, however, sparse. There is thus a need to develop bat cellular models to understand cell tropism, viral replication and virus-induced cell responses. Here, we report the first molecular study of SARS-CoV-2 infection in chiropteran cells. We investigated the ability of primary cells from Rhinolophus and Myotis species, as well as of established and novel cell lines from Myotis myotis, Eptesicus serotinus, Tadarida brasiliensis and Nyctalus noctula, to support SARS-CoV-2 replication. None of these cells were permissive to infection, not even the ones expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), which serves as the viral receptor in many mammalian species including humans. The resistance to infection was overcome by expression of human ACE2 (hACE2) in three cell lines, suggesting that the restriction to viral replication was due to a low expression of bat ACE2 (bACE2) or absence of bACE2 binding in these cells. By contrast, multiple restriction factors to viral replication exist in the three N. noctula cells since hACE2 expression was not sufficient to permit infection. Infectious virions were produced but not released from hACE2-transduced M. myotis brain cells. E. serotinus brain cells and M. myotis nasal epithelial cells expressing hACE2 efficiently controlled viral replication, which correlated with a potent interferon response. Together, our data highlight the existence of species-specific molecular barriers to viral replication in bat cells. Our newly developed chiropteran cellular models are useful tools to investigate the interplay between viruses belonging to the SARS-CoV- 2 lineage and their natural reservoir, including the identification of factors responsible for viral restriction.

2.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-338253

ABSTRACT

Rubella is well-controlled due to an effective vaccine, but outbreaks are still occurring without any available antiviral treatments. There is still much to learn about the rubella virus (RUBV) papain-like protease (RubPro) that could be a potential drug target. This protease is crucial to RUBV replication, cleaving the non-structural polyprotein p200 into 2 multi-functional proteins, p150 and p90. Here we report a novel crystal structure of RubPro at 1.64 Å resolution. It has a similar catalytic core structure to that of SARS-CoV-2 and foot-mouth-disease virus (FMDV) proteases. RubPro has well-conserved sequence motifs that are also found in its newly discovered Rubivirus relatives. The RubPro construct was shown to have protease activity in trans against a construct of RUBV protease-helicase and fluorogenic peptide. A protease-helicase construct was also cleaved in E. coli expression. RubPro was demonstrated to possess deubiquitylation activity, suggesting a potential role of RubPro in modulating the host's innate immune responses. The structural and functional insights of the RubPro will advance our current understanding of its function and point to more structure-based research into the RUBV replication machinery, in hopes of developing antiviral therapeutics in the future.

3.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-335108

ABSTRACT

In the face of a long-running pandemic, understanding the drivers of ongoing SARS-CoV-2 transmission is crucial for the rational management of COVID-19 disease burden. Keeping schools open has emerged as a vital societal imperative during the pandemic, but in-school transmission of SARS-CoV-2 can contribute to further prolonging the pandemic. In this context, the role of schools in driving SARS-CoV-2 transmission acquires critical importance. Here we model in-school transmission from first principles to investigate the effectiveness of layered mitigation strategies on limiting in-school spread. We examine the effect of masks and air quality (ventilation, filtration and ionizers) on steady-state viral load in classrooms, as well as on the number of particles inhaled by an uninfected person. The effectiveness of these measures in limiting viral transmission is assessed for variants with different levels of mean viral load (Wuhan, Delta, Omicron). Our results suggest that a layered mitigation strategy can be used effectively to limit in-school transmission, with certain limitations. First, poorly designed strategies (insufficient ventilation, no masks, staying open under high levels of community transmission) will permit in-school spread even if some level of mitigation is ostensibly present. Second, for viral variants that are sufficiently contagious, it may be difficult to construct any set of interventions capable of blocking transmission once an infected individual is present, underscoring the importance of other measures. Our findings provide several practical recommendations: the use of a layered mitigation strategy that is designed to limit transmission, with other measures such as frequent surveillance testing and smaller class sizes (such as by offering remote schooling options to those who prefer it) as needed.

4.
Chinese Journal of Disease Control and Prevention ; 26(1):112-115, 2022.
Article in Chinese | EMBASE | ID: covidwho-1771919

ABSTRACT

Objective An epidemic of COVID-19 caused by an imported Delta variant strain in Guangzhou was investigated, and the transmission chain, transmission characteristics and infection of each case were analyzed, so as to provide a theoretical basis for predicting disease development and epidemic prevention and control. Methods By collecting the information released by Guangzhou government, the confirmed cases with a clear transmission chain were selected, and the infectious disease indicators such as serial interval (SI), basic reproduction number (Rq) and time-dependent reproduction number (Rt) were calculated to analyze the epidemiological characteristics. Results From May 21 to June 20, 2021, a total of 144 cases of indigenous COVID-19 were confirmed in Guangzhou, among which 67 pairs of cases with a clear transmission chain were selected. SI was calculated to follow the Gamma distribution, with a mean of 4. 27 d and a standard deviation of 2.65 d. Rq = 3. 18 (95% CI: 2. 1974.428), and Rt showed an obvious decreasing trend over time. On June 10, Rt = 0.97 (95% CI: 0. 751 -1. 214), which was lower than 1. Since then Rt had been less than 1, and it got smaller and smaller over time. Conclusion In this COVID-19 epidemic, the SI was shorter and the Rq was larger, which indicated that the Delta variant strain had a faster transmission rate and stronger transmissibility than the COVID-19 infected in Wuhan in 2020.

5.
New Journal of Chemistry ; 45(26):11512-11529, 2021.
Article in English | EMBASE | ID: covidwho-1585752

ABSTRACT

The normal expression of the main protease (Mpro) plays a vital role in the life cycle of coronavirus. Highly active inhibitors could inhibit the normal circulation of the main protease to achieve therapeutic effects as anti-coronavirus agents. In the present research, 48 peptide compounds with SARS-CoV Mproinhibition selected from the literature were used to establish robust Topomer CoMFA (q2= 0.743,r2= 0.938, andrpred2= 0.700) and HQSAR (q2= 0.774,r2= 0.955, andrpred2= 0.723) models. Structural modification information was used for designing new Mproinhibitors. The high contribution-value descriptor generated by Topomer CoMFA was used to screen for the fragments that possess significant inhibitory activities from the ZINC drug database, and 24 new compounds with predicted high inhibitory activity at nanomolar concentration were designed by combining the high contribution value fragments. The molecular docking results further justified that these potential inhibitors could form hydrogen bonds with the residues of CYS145, GLN189, GLU166, HIS163, and GLY143 of target Mpro, which well explains their strong inhibitory effects. The molecular dynamics simulation results indicated that four highly active compounds could stably bond with SARS-CoV-2 Mproand might be promising anti-SARS-CoV-2 Mprocandidates. Finally, all the newly designed compounds showed premium ADMET properties as per the predictions by the server in the public domain. This research work not only provides robust QSAR models as valuable screening tools for future anti-coronavirus drug development but also renders the newly designed SARS-CoV-2 Mproinhibitors with activity at nanomolar concentration, which can be used for further characterization to obtain novel anti-coronavirus drugs for both SARS-CoV and SARS-CoV-2.

6.
Chinese Science Bulletin-Chinese ; 66(4-5):453-464, 2021.
Article in Chinese | Web of Science | ID: covidwho-1172860

ABSTRACT

The COVID-19 pandemic has battered the world in more than 100 countries and regions due to its deadly and high transmission. How to control or limit the first and possible second wave of the infection has become an essential problem based on the control strategies implemented globally. This study presented a model to evaluate the efficiency of strategies based on an improved multi-stage SEIR (susceptible-exposed-infectious-recovered) model considering quarantine factor, treatment delay, transmission risk by the exposed, and time. The particle swarm optimization (PSO) algorithm with an adaptive weight strategy is adopted to find the SEIR model's critical parameters associated with the control strategies based on the confirmed cases, the cured cases, and the death cases in the Chinese mainland, Italy, Spain, and Germany. The model was verified by the coefficients of correlation (R-2) between the predicted results using parameters found by PSO and the actual data on the confirmed, the death, and the cured cases. The R(2)s are all greater than 0.93 in the Chinese mainland, Italy, Spain, and Germany, showing a good accuracy of the proposed model. Base on the data of analyzed countries, PSO finds the incubation period of COVID-19 is approximately 5.1 d, which is consistent with other literatures. Besides, the period from exposure to medical care delivery is the most significant for controlling the transmission, followed by the quarantined rate according to our model. The effective reproduction number reduces from 3.9 to 1.4 while the delivery period shortens from 13 to 1 d, even without considering the effect of quarantined rate and crowd protection awareness, indicating the importance of acid testing. Moreover, the effective reproduction number is smaller than 1 when the delivery period is 1 d and the quarantined rate is higher than 0.1, which shows the transmission of COVID-19 can be contained in these conditions. Furthermore, the establishment of Fangcang shelter hospitals and the implication of aided diagnosis guideline of COVID-19 gradually reduce the period to the hospital for patients in Hubei Province from 16 to 1-2 d. In addition, the efficiency of strategies among Italy, Spain, and Germany shows that Germany reached a better condition in comparison with others, and the number of confirmed cases in each country can drop by nearly 1/3 as the protection awareness of the population rises from 0.25 to 0.69, through reducing social activities, keeping social distance, and wearing masks, indicating the importance of government advertisement, education, etc. This study might help the governments to make strategies to limit the spreading of COVID-19 or potential outbreak of emerging infectious diseases in the future.

7.
Zhonghua Bing Li Xue Za Zhi ; 49(5): 418-423, 2020 May 08.
Article in Chinese | MEDLINE | ID: covidwho-589596

ABSTRACT

Objective: To investigate the clinical characteristics and placental pathology of 2019-nCoV infection in pregnancy,and to evaluate intrauterine vertical transmission potential of 2019-nCoV infection. Methods: The placentas delivered from pregnant women with confirmed 2019-nCoV infection which were received in the Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology by February 4, 2020 were retrospectively studied. Their clinical material including placental tissue and lung CT, and laboratory results were collected, meanwhile, nucleic acid detection of 2019-nCoV of the placentas were performed by RT-PCR. Results: Three placentas delivered from pregnant women with confirmed 2019-nCoV infection, who were all in their third trimester with emergency caesarean section. All of the three patients presented with fever (one before caesarean and two in postpartum), and had no significant leukopenia and lymphopenia. Neonatal throat swabs from three newborns were tested for 2019-nCoV, and all samples were negative for the nucleic acid of 2019-nCoV. One premature infant was transferred to Department of Neonatology due to low birth weight. By the end of February 25, 2020, none of the three patients developed severe 2019-nCoV pneumonia or died(two patients had been cured and discharged, while another one had been transferred to a square cabin hospital for isolation treatment). There were various degrees of fibrin deposition inside and around the villi with local syncytial nodule increases in all three placentas. One case of placenta showed the concomitant morphology of chorionic hemangioma and another one with massive placental infarction. No pathological change of villitis and chorioamnionitis was observed in our observation of three cases. All samples from three placentas were negative for the nucleic acid of 2019-nCoV. Conclusions: The clinical characteristics of pregnant women with 2019-nCoV infection in late pregnancy are similar to those of non-pregnant patients, and no severe adverse pregnancy outcome is found in the 3 cases of our observation. Pathological study suggests that there are no morphological changes related to infection in the three placentas. Currently no evidence for intrauterine vertical transmission of 2019-nCoV is found in the three women infected by 2019-nCoV in their late pregnancy.


Subject(s)
Coronavirus Infections , Coronavirus , Pandemics , Placenta , Pneumonia, Viral , Pregnancy Complications, Infectious , Adult , Betacoronavirus , COVID-19 , Cesarean Section , Coronavirus Infections/pathology , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Placenta/pathology , Placenta/virology , Pneumonia, Viral/pathology , Pregnancy , Pregnancy Complications, Infectious/pathology , Retrospective Studies , SARS-CoV-2
8.
Zhonghua Bing Li Xue Za Zhi ; 49(6): 576-582, 2020 Jun 08.
Article in Chinese | MEDLINE | ID: covidwho-548023

ABSTRACT

Objective: To study the pathological changes of the spleen in patients with COVID-19 and to analyze the relationship between the weakened immune system and splenic lesions. Methods: Postmortem needle autopsies from the spleen were carried out on 10 patients who died from COVID-19 in Wuhan. Routine hematoxylin and eosin (HE) staining was used to observe the pathological changes. The changes of lymphocytes were studied further with immunohistochemistry.RT-PCR was used to detect 2019-nCoV RNA in the spleen. In addition,the Epstein-Barr virus (EBV) was detected by in situ hybridization, and coronavirus particles were detected by transmission electron microscopy in 2 cases. Results: There were 7 males and 3 females, with an average age of 68.3 years.Of the 10 cases, 4 had cancer history and another 4 had other underlying diseases respectively.Cough, fever, malaise and dyspnea were the main clinical symptoms.The time from onset to death was 15-45 days.Ten cases patients had normal or slight increase in peripheral blood leukocyte count in the early stage of the disease, 6 cases had significant increase before death. Five patients' peripheral blood lymphocyte count decreased in the early stage of the disease, and 10 patients' peripheral blood lymphocyte count decreased significantly before the disease progressed or died. Seven cases were treated with corticosteroid (methylprednisolone ≤40 mg/d, not more than 5 days). Histopathological examination showed that the cell composition of the spleen decreased, white pulp atrophied at different levels, meanwhile lymphoid follicles decreased or absent;in addition, the ratio of red pulp to white pulp increased with varying degrees. In 7 cases, more neutrophil infiltration was found, and in 5 cases, scattered plasma cell infiltration was found. Macrophage proliferation and hemophagocytic phenomena in a few cells were found in a case. Meanwhile, necrosis and lymphocyte apoptosis were detected in 2 cases, small artery thrombosis and spleen infarction in 1 case, and fungal infection in 1 case. The results of immunohistochemistry showed that the T and B lymphocyte components of the spleen in all cases decreased in varying degrees. CD20(+) B cells were found to accumulate in the lymphoid sheath around the splenic artery in 8 cases. However, CD20 and CD21 immunostaining in 2 cases showed that the number of white pulp was almost normal, and splenic nodules were atrophic. CD3(+), CD4(+) and CD8(+)T cells were decreased. In 9 cases,CD68(+) macrophages were no significant changes in the distribution and quantity. While more CD68(+) cells were found in the medullary sinuses of 1 case (related to fungal infection). Few CD56(+) cells were found. EBV was negative by in situ hybridization. RT-PCR was used to detect the nucleic acid of 2019-nCoV. One of 10 cases was positive, 39 years old,who was the youngest patient in this group, and the other 9 cases were negative. Coronavirus particles were found in the cytoplasm of macrophage under electron microscope in 2 cases. Conclusions: The death of COVID-19 occurs mainly in the elderly, and some cases have no underlying diseases. Spleen may be one of the organs directly attacked by the virus in some patients who died from COVID-19. T and B lymphocyte in the spleen decrease in varying degrees, lymphoid follicles are atrophied, decreased or absent, and the number of NK cells do not change significantly. And the pathological changes of the spleen are not related to the use of low dose corticosteroid, which may be related to the direct attack of virus and the attack of immune system on its own tissues.


Subject(s)
Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Spleen/pathology , Adult , Aged , Autopsy , B-Lymphocytes/cytology , Betacoronavirus , COVID-19 , Female , Humans , Male , Pandemics , SARS-CoV-2 , Spleen/virology , T-Lymphocytes/cytology
9.
Zhonghua Bing Li Xue Za Zhi ; 49(6): 568-575, 2020 Jun 08.
Article in Chinese | MEDLINE | ID: covidwho-505562

ABSTRACT

Objectives: To observe the pulmonary changes with coronavirus disease 2019 (COVID-19) in postmortem needle specimens, to detect the presence of 2019 novel coronavirus(2019-nCoV) in the lung tissues, and to analyze the clinicopathological characteristics. Methods: For 10 decedents with 2019-nCoV infection in Wuhan, bilateral lungs underwent ultrasound-guided percutaneous multi-point puncture autopsy, and pulmonary pathological changes were described in routine hematoxylin-eosin staining (HE) slides. Electron microscopy was also performed. The reverse transcription polymerase chain reaction (RT-PCR) was employed to detect 2019-nCoV nucleic acid in lung tissue, and the pathological characteristics were demonstrated in combination with clinical data analysis. Results: Of the 10 deaths associated with COVID-19, 7 were male and 3 were female. The average age was 70 (39-87) years. Medical record showed that 7 patients had underlying diseases. The average course of disease was 30 (16-36) days. Nine cases showed fibrinous and suppurative exudation in the alveolar cavity accompanied by the formation of hyaline membrane, and fibroblastic proliferation of alveolar septum. Type Ⅱ alveolar epithelial cells showed reactive hyperplasia and desquamation. Many macrophages accumulated in the alveolar cavity. Capillary hyaline thrombus and intravascular mixed thrombus were noted. In some cases, acute bronchiolitis with mucous membrane exfoliation, accumulation of bronchiolar secretions, and bronchiolar epithelial metaplasia occurred. In the cohort, a large number of bacteria (cocci) were detected in 1 case and a large number of fungi (yeast type) were detected in 1 case. Nine cases were positive for the nucleic acids of 2019-nCoV while one case remained negative by RT-PCR. Coronavirus particles were detected in the cytoplasm of type Ⅱ alveolar epithelium. Conclusions: The pulmonary pathological changes of fatal COVID-19 are diffuse alveolar damage (DAD), mainly in the acute exudative stage and the organic proliferative stage. There are fibrinous exudate aggregation in alveolar cavity with hyaline membrane formation, fibroblastic proliferation in alveolar septum, and alveolar epithelial cell injuries with reactive hyperplasia and desquamation of type Ⅱ alveolar epithelial cells. A large amount of neutrophils and monocytes infiltration is present in most cases and bacteria and fungi are detected in some cases, suggesting a serious bacterial or fungal infection secondary to the DAD.


Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Adult , Aged , Aged, 80 and over , Autopsy , COVID-19 , Female , Humans , Lung , Male , Middle Aged , SARS-CoV-2
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