Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux.

Chemokine production by epithelial cells is crucial for neutrophil recruitment to sites of inflammation during viral infection. However, the effect of chemokine on epithelia and how chemokine is involved in coronavirus infection remains to be fully understood. Here, we identified an inducible chemokine interleukin-8 (CXCL8/IL-8), which could promote coronavirus porcine epidemic diarrhea virus (PEDV) infection in African green monkey kidney epithelial cells (Vero) and Lilly Laboratories cell-porcine kidney 1 epithelial cells (LLC-PK1). IL-8 deletion restrained cytosolic calcium (Ca2+), whereas IL-8 stimulation improved cytosolic Ca2+. The consumption of Ca2+ restricted PEDV infection. PEDV internalization and budding were obvious reductions when cytosolic Ca2+ was abolished in the presence of Ca2+ chelators. Further study revealed that the upregulated cytosolic Ca2+ redistributes intracellular Ca2+. Finally, we identified that G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-store-operated Ca2+ (SOC) signaling was crucial for enhancive cytosolic Ca2+ and PEDV infection. To our knowledge, this study is the first to uncover the function of chemokine IL-8 during coronavirus PEDV infection in epithelia. PEDV induces IL-8 expression to elevate cytosolic Ca2+, promoting its infection. Our findings reveal a novel role of IL-8 in PEDV infection and suggest that targeting IL-8 could be a new approach to controlling PEDV infection. IMPORTANCE Coronavirus porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that caused severe economic losses worldwide, and more effort is needed to develop economical and efficient vaccines to control or eliminate this disease. The chemokine interleukin-8 (CXCL8/IL-8) is indispensable for the activation and trafficking of inflammatory mediators and tumor progression and metastasis. This study evaluated the effect of IL-8 on PEDV infection in epithelia. We found that IL-8 expression improved cytosolic Ca2+ in epithelia, facilitating PEDV rapid internalization and egress. G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-SOC signaling was activated by IL-8, releasing the intracellular Ca2+ stores from endoplasmic reticulum (ER). These findings provide a better understanding of the role of IL-8 in PEDV-induced immune responses, which will help develop small-molecule drugs for coronavirus cure.

Smart Nanostructured Materials for SARS-CoV-2 and Variants Prevention, Biosensing and Vaccination.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised great concerns about human health globally. At the current stage, prevention and vaccination are still the most efficient ways to slow down the pandemic and to treat SARS-CoV-2 in various aspects. In this review, we summarize current progress and research activities in developing smart nanostructured materials for COVID-19 prevention, sensing, and vaccination. A few established concepts to prevent the spreading of SARS-CoV-2 and the variants of concerns (VOCs) are firstly reviewed, which emphasizes the importance of smart nanostructures in cutting the virus spreading chains. In the second part, we focus our discussion on the development of stimuli-responsive nanostructures for high-performance biosensing and detection of SARS-CoV-2 and VOCs. The use of nanostructures in developing effective and reliable vaccines for SARS-CoV-2 and VOCs will be introduced in the following section. In the conclusion, we summarize the current research focus on smart nanostructured materials for SARS-CoV-2 treatment. Some existing challenges are also provided, which need continuous efforts in creating smart nanostructured materials for coronavirus biosensing, treatment, and vaccination.

Evaluating the Response and Safety of Inactivated COVID-19 Vaccines in Liver Transplant Recipients.

Purpose: To evaluate the response and safety of an inactivated vaccine (Sinovac Life Sciences Co., Ltd., Beijing, China) for coronavirus disease 2019 (COVID-19) in liver transplant (LTx) recipients from China. Patients and Methods: Thirty-five recipients post LTx from the First Affiliated Hospital of Zhejiang University School of Medicine who received inactivated vaccine from June to October 2021 were screened. Information regarding vaccine side effects and clinical data were collected. Results: Thirty-five LTx recipients were enrolled, with a mean age of 46 years, and most patients were male (30, 85.71%). All the participants had a negative history of COVID-19 infection. Predictors for negative response in the recipients were interleukin-2 receptor (IL-2R) induction during LTx, shorter time post LTx and application of a derivative from mycophenolate acid (MPA). No serious adverse events were observed during the progress of vaccination or after the vaccination. Conclusion: LTx recipients have a substantially partial immunological response to the inactivated vaccine for COVID-19. IL-2R induction during LTx, a shorter time post LTx and the application of a derivative from MPA seem to be predictors for a negative serological immunoglobulin G (IgG) antibody response in recipients. The findings require booster vaccination in these LTx recipients.

Design of a Recombinant Multivalent Epitope Vaccine Based on SARS-CoV-2 and Its Variants in Immunoinformatics Approaches.

The development of an effective multivalent vaccine against SARS-CoV-2 variants is an important means to improve the global public health situation caused by COVID-19. In this study, we identified the antigen epitopes of the main global epidemic SARS-CoV-2 and mutated virus strains using immunoinformatics approach, and screened out 8 cytotoxic T lymphocyte epitopes (CTLEs), 17 helper T lymphocyte epitopes (HTLEs), 9 linear B-cell epitopes (LBEs) and 4 conformational B-cell epitopes (CBEs). The global population coverage of CTLEs and HTLEs was 93.16% and 99.9% respectively. These epitopes were spliced together by corresponding linkers and recombined into multivalent vaccine. In silico tests, the vaccine protein was a non-allergen and the docking with TLR-3 molecule showed a strong interaction. The results of immune simulation showed that the vaccine may be helpful to initiate both cellular and humoral immunity against all VOC. The optimistic immunogenicity of the vaccine was confirmed in vivo and in vitro finally. Therefore, our vaccine may have potential protection against SARS-CoV-2 and its variants.

The Effect of the COVID-19 Vaccine on Daily Cases and Deaths Based on Global Vaccine Data.

BACKGROUND: Coronavirus disease 2019 (COVID-19), a global pandemic, has caused over 216 million cases and 4.50 million deaths as of 30 August 2021. Vaccines can be regarded as one of the most powerful weapons to eliminate the pandemic, but the impact of vaccines on daily COVID-19 cases and deaths by country is unclear. This study aimed to investigate the correlation between vaccines and daily newly confirmed cases and deaths of COVID-19 in each country worldwide. METHODS: Daily data on firstly vaccinated people, fully vaccinated people, new cases and new deaths of COVID-19 were collected from 187 countries. First, we used a generalized additive model (GAM) to analyze the association between daily vaccinated people and daily new cases and deaths of COVID-19. Second, a random effects meta-analysis was conducted to calculate the global pooled results. RESULTS: In total, 187 countries and regions were included in the study. During the study period, 1,011,918,763 doses of vaccine were administered, 540,623,907 people received at least one dose of vaccine, and 230,501,824 people received two doses. For the relationship between vaccination and daily increasing cases of COVID-19, the results showed that daily increasing cases of COVID-19 would be reduced by 24.43% [95% CI: 18.89, 29.59] and 7.50% [95% CI: 6.18, 8.80] with 10,000 fully vaccinated people per day and at least one dose of vaccine, respectively. Daily increasing deaths of COVID-19 would be reduced by 13.32% [95% CI: 3.81, 21.89] and 2.02% [95% CI: 0.18, 4.16] with 10,000 fully vaccinated people per day and at least one dose of vaccine, respectively. CONCLUSIONS: These findings showed that vaccination can effectively reduce the new cases and deaths of COVID-19, but vaccines are not distributed fairly worldwide. There is an urgent need to accelerate the speed of vaccination and promote its fair distribution across countries.

Association between temperature and COVID-19 transmission in 153 countries.

The WHO characterized coronavirus disease 2019 (COVID-19) as a global pandemic. The influence of temperature on COVID-19 remains unclear. The objective of this study was to investigate the correlation between temperature and daily newly confirmed COVID-19 cases by different climate regions and temperature levels worldwide. Daily data on average temperature (AT), maximum temperature (MAXT), minimum temperature (MINT), and new COVID-19 cases were collected from 153 countries and 31 provinces of mainland China. We used the spline function method to preliminarily explore the relationship between R0 and temperature. The generalized additive model (GAM) was used to analyze the association between temperature and daily new cases of COVID-19, and a random effects meta-analysis was conducted to calculate the pooled results in different regions in the second stage. Our findings revealed that temperature was positively related to daily new cases at low temperature but negatively related to daily new cases at high temperature. When the temperature was below the smoothing plot peak, in the temperate zone or at a low temperature level (e.g., <25th percentiles), the RRs were 1.09 (95% CI: 1.04, 1.15), 1.10 (95% CI: 1.05, 1.15), and 1.14 (95% CI: 1.06, 1.23) associated with a 1°C increase in AT, respectively. Whereas temperature was above the smoothing plot peak, in a tropical zone or at a high temperature level (e.g., >75th percentiles), the RRs were 0.79 (95% CI: 0.68, 0.93), 0.60 (95% CI: 0.43, 0.83), and 0.48 (95% CI: 0.28, 0.81) associated with a 1°C increase in AT, respectively. The results were confirmed to be similar regarding MINT, MAXT, and sensitivity analysis. These findings provide preliminary evidence for the prevention and control of COVID-19 in different regions and temperature levels.

The spatial clustering analysis of COVID-19 and its associated factors in mainland China at the prefecture level

Coronavirus disease 2019 (COVID-19) has become a worldwide public health threat. Many associated factors including population movement, meteorological parameters, air quality and socioeconomic conditions can affect COVID-19 transmission. However, no study has combined these various factors in a comprehensive analysis. We collected data on COVID-19 cases and the factors of interest in 340 prefectures of mainland China from 1 December 2019 to 30 April 2020. Moran's I statistic, Getis-Ord Gi⁎ statistic and Kulldorff's space-time scan statistics were used to identify spatial clusters of COVID-19, and the geographically weighted regression (GWR) model was applied to investigate the effects of the associated factors on COVID-19 incidence. A total of 67,449 laboratory-confirmed cases were reported during the study period. Wuhan city as well as its surrounding areas were the cluster areas, and January 25 to February 21, 2020, was the clustering time of COVID-19. The population outflow from Wuhan played a significant role in COVID-19 transmission, with the local coefficients varying from 14.87 to 15.02 in the 340 prefectures. Among the meteorological parameters, relative humidity and precipitation were positively associated with COVID-19 incidence, while the average wind speed showed a negative correlation, but the relationship of average temperature with COVID-19 incidence inconsistent between northern and southern China. NO2 was positively associated, and O3 was negatively associated, with COVID-19 incidence. Environment with high levels of inbound migration or travel, poor ventilation, high humidity or heavy rainfall, low temperature, and high air pollution may be favorable for the growth, reproduction and spread of SARS-CoV-2. Therefore, applying appropriate lockdown measures and travel restrictions, strengthening the ventilation of living and working environments, controlling air pollution and making sufficient preparations for a possible second wave in the relatively cold autumn and winter months may be helpful for the control and prevention of COVID-19.

Modeling and analysis of COVID-19 based on a time delay dynamic model.

The new type of coronavirus pneumonia is caused by the new type of coronavirus which appeared at the end of 2019. Because of its strong contagiousness, rapid spread and great harm, it has already given countries around the world serious effects. So far there is no clear specific drug. Scientifically grasping the development law of epidemics is extremely important for preventing and controlling epidemics. Since the latent of this epidemic are also highly contagious, traditional infectious disease models cannot accurately describe the regularity of this epidemic transmission. Based on the traditional infectious disease model, an infectious disease model with a time delay is proposed. The time difference is used to characterize the cycle of viral infection and treatment time. Using the epidemic data released in real time, firstly, through the numerical simulation parameter inversion, the minimum error is obtained; then we simulate the development trend of the epidemic according to the dynamics system; finally, we compare and analyze the effectiveness of isolation measures. This article has simulated COVID-19 and analyzed the development of the epidemic in Beijing and Wuhan. By comparing the severity of the epidemic in the two regions, early detection and isolation are still the top priority of epidemic prevention and control.

Shorter incubation period is associated with severe disease progression in patients with COVID-19.

The diagnosed COVID-19 cases revealed that the incubation periods (IP) varied a lot among patients. However, few studies had emphasized on the different clinical features and prognosis of patients with different IP. A total of 330 patients with laboratory-confirmed COVID-19 were enrolled and classified into immediate onset group(IP<3 days, I group, 57 cases) and late onset group(IP>10 days, L group, 75 cases) based on IP. The difference of clinical characteristics and prognosis of the two groups were compared. There were more patients with fever in I group than in L group(P = 0.003), and counts of all the total lymphocytes, total T lymphocytes, CD4 + and CD8 + T lymphocytes were significantly different between the two groups(all P < 0.01). Besides, patients in L group had more GGOs in CT scan than I group and there were more patients in I group receiving antibiotic treatment than in L group(P < 0.001). For disease aggravation, the median CT scores were comparable between the two groups, but individually, there were more patients with increased CT score during hospitalization in I group than in L group. The aggravation incidence of CT presentation was 21.1% in I group, significantly higher than L group(8.0%, P = 0.042). Multivariable COX models suggested that IP was the only independent factors for CT aggravation. Conclusively, patients with different IP were different in clinical symptoms, laboratory tests, and CT presentations. Shorter IP was associated with the aggravation of lung involvement in CT scan.

Porcine epidemic diarrhea virus: Molecular mechanisms of attenuation and vaccines.

Porcine epidemic diarrhea virus (PEDV) causes an emerging and re-emerging coronavirus disease characterized by vomiting, acute diarrhea, dehydration, and up to 100% mortality in neonatal suckling piglets, leading to huge economic losses in the global swine industry. Vaccination remains the most promising and effective way to prevent and control PEDV. However, effective vaccines for PEDV are still under development. Understanding the genomic structure and function of PEDV and the influence of the viral components on innate immunity is essential for developing effective vaccines. In the current review, we systematically describe the recent developments in vaccine against PEDV and the roles of structural proteins, non-structural proteins and accessory proteins of PEDV in affecting viral virulence and regulating innate immunity, which will provide insight into the rational design of effective and safe vaccines for PEDV or other coronaviruses.

Reverse genetic systems: Rational design of coronavirus live attenuated vaccines with immune sequelae.

Since the end of 2019, the global COVID-19 outbreak has once again made coronaviruses a hot topic. Vaccines are hoped to be an effective way to stop the spread of the virus. However, there are no clinically approved vaccines available for coronavirus infections. Reverse genetics technology can realize the operation of RNA virus genomes at the DNA level and provide new ideas and strategies for the development of new vaccines. In this review, we systematically describe the role of reverse genetics technology in studying the effects of coronavirus proteins on viral virulence and innate immunity, cell and tissue tropism and antiviral drug screening. An efficient reverse genetics platform is useful for obtaining the ideal attenuated strain to prepare an attenuated live vaccine.

COVID-19: Abnormal liver function tests.

BACKGROUND & AIMS: Recent data on the coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has begun to shine light on the impact of the disease on the liver. But no studies to date have systematically described liver test abnormalities in patients with COVID-19. We evaluated the clinical characteristics of COVID-19 in patients with abnormal liver test results. METHODS: Clinical records and laboratory results were obtained from 417 patients with laboratory-confirmed COVID-19 who were admitted to the only referral hospital in Shenzhen, China from January 11 to February 21, 2020 and followed up to March 7, 2020. Information on clinical features of patients with abnormal liver tests were collected for analysis. RESULTS: Of 417 patients with COVID-19, 318 (76.3%) had abnormal liver test results and 90 (21.5%) had liver injury during hospitalization. The presence of abnormal liver tests became more pronounced during hospitalization within 2 weeks, with 49 (23.4%), 31 (14.8%), 24 (11.5%) and 51 (24.4%) patients having alanine aminotransferase, aspartate aminotransferase, total bilirubin and gamma-glutamyl transferase levels elevated to more than 3× the upper limit of normal, respectively. Patients with abnormal liver tests of hepatocellular type or mixed type at admission had higher odds of progressing to severe disease (odds ratios [ORs] 2.73; 95% CI 1.19-6.3, and 4.44, 95% CI 1.93-10.23, respectively). The use of lopinavir/ritonavir was also found to lead to increased odds of liver injury (OR from 4.44 to 5.03, both p <0.01). CONCLUSION: Patients with abnormal liver tests were at higher risk of progressing to severe disease. The detrimental effects on liver injury mainly related to certain medications used during hospitalization, which should be monitored and evaluated frequently. LAY SUMMARY: Data on liver tests in patients with COVID-19 are scarce. We observed a high prevalence of liver test abnormalities and liver injury in 417 patients with COVID-19 admitted to our referral center, and the prevalence increased substantially during hospitalization. The presence of abnormal liver tests and liver injury were associated with the progression to severe pneumonia. The detrimental effects on liver injury were related to certain medications used during hospitalization, which warrants frequent monitoring and evaluation for these patients.

Response to the COVID-19 epidemic: a report from Shenzhen, China.

The whole world is now facing an unprecedented pandemic with over 1.8 million confirmed cases and more than one hundred thousand deaths. To counter the pandemic, Shenzhen created a central command and control structure based on the only designated hospital- Shenzhen Third People's Hospital which is a large general hospital specialized on infectious diseases in the bay area. The hospital has taken many decisive and effective actions to respond to the epidemic. Here, we will describe and share healthcare experiences from Shenzhen and call for international cooperation and collaboration.

COVID-19 in a designated infectious diseases hospital outside Hubei Province, China.

BACKGROUND: The clinical characteristics of novel coronavirus disease (COVID-2019) patients outside the epicenter of Hubei Province are less understood. METHODS: We analyzed the epidemiological and clinical features of all COVID-2019 cases in the only referral hospital in Shenzhen City, China, from January 11, 2020, to February 6, 2020, and followed until March 6, 2020. RESULTS: Among the 298 confirmed cases, 233 (81.5%) had been to Hubei, while 42 (14%) did not have a clear travel history. Only 218 (73.15%) cases had a fever as the initial symptom. Compared with the nonsevere cases, severe cases were associated with older age, those with underlying diseases, and higher levels of C-reactive protein, interleukin-6, and erythrocyte sedimentation rate. Slower clearance of the virus was associated with a higher risk of progression to critical condition. As of March 6, 2020, 268 (89.9%) patients were discharged and the overall case fatality ratio was 1.0%. CONCLUSIONS: In a designated hospital outside Hubei Province, COVID-2019 patients could be effectively managed by properly using the existing hospital system. Mortality may be lowered when cases are relatively mild, and there are sufficient medical resources to care and treat the disease.