Genomic representation predicts an asymptotic host adaptation of bat coronaviruses using deep learning.

Introduction: Coronaviruses (CoVs) are naturally found in bats and can occasionally cause infection and transmission in humans and other mammals. Our study aimed to build a deep learning (DL) method to predict the adaptation of bat CoVs to other mammals. Methods: The CoV genome was represented with a method of dinucleotide composition representation (DCR) for the two main viral genes, ORF1ab and Spike. DCR features were first analyzed for their distribution among adaptive hosts and then trained with a DL classifier of convolutional neural networks (CNN) to predict the adaptation of bat CoVs. Results and discussion: The results demonstrated inter-host separation and intra-host clustering of DCR-represented CoVs for six host types: Artiodactyla, Carnivora, Chiroptera, Primates, Rodentia/Lagomorpha, and Suiformes. The DCR-based CNN with five host labels (without Chiroptera) predicted a dominant adaptation of bat CoVs to Artiodactyla hosts, then to Carnivora and Rodentia/Lagomorpha mammals, and later to primates. Moreover, a linear asymptotic adaptation of all CoVs (except Suiformes) from Artiodactyla to Carnivora and Rodentia/Lagomorpha and then to Primates indicates an asymptotic bats-other mammals-human adaptation. Conclusion: Genomic dinucleotides represented as DCR indicate a host-specific separation, and clustering predicts a linear asymptotic adaptation shift of bat CoVs from other mammals to humans via deep learning.

SARS-CoV-2 viral protein ORF3A injures renal tubules by interacting with TRIM59 to induce STAT3 activation.

Acute kidney injury occurs frequently in COVID-19 patients infected by the coronavirus SARS-CoV-2, and infection of kidney cells by this virus has been reported. However, little is known about the direct impact of the SARS-CoV-2 infection upon the renal tubular cells. We report that SARS-CoV-2 activated signal transducer and activator of transcription 3 (STAT3) signaling and caused cellular injury in the human renal tubular cell line. Mechanistically, the viral protein ORF3A of SARS-CoV-2 augmented both NF-κB and STAT3 signaling and increased the expression of kidney injury molecule 1. SARS-CoV-2 infection or expression of ORF3A alone elevated the protein level of tripartite motif-containing protein 59 (TRIM59), an E3 ubiquitin ligase, which interacts with both ORF3A and STAT3. The excessive TRIM59 in turn dissociated the phosphatase TCPTP from binding to STAT3 and hence inhibited the dephosphorylation of STAT3, leading to persistent STAT3 activation. Consistently, ORF3A induced renal injury in zebrafish and mice. In addition, expression of TRIM59 was elevated in the kidney autopsies of COVID-19 patients with acute kidney injury. Thus, the aberrant activation of STAT3 signaling by TRIM59 plays a significant role in the renal tubular cell injury caused by SARS-CoV-2, which suggests a potential targeted therapy for the renal complications of COVID-19.

Associations between trait and state perceived stress and daily moods: COVID-19 stressful experiences as a moderator.

Drastically disrupting daily routines, the global pandemic of COVID-19 has posed critical mental health threats to adolescents and young adults worldwide. Many of the extant empirical findings, however, have focused on individuals' psychological adjustment during the initial phase of the pandemic. It is less clear how COVID-19 stressful experiences impact young people's daily lives in the post-pandemic "new normal." Drawing on 7-day diary reports, the present study fills this gap by examining: (1) how daily perceived stress impacted daily emotional adjustment; and (2) the moderating effects of COVID-19 stressful experiences on these associations among 582 Chinese young adults (M age = 18.12, SD = .65; 69% females). Results indicated that higher levels of both trait (i.e., average levels) and state (i.e., daily fluctuations) perceived stress were associated with greater negative and anxious moods, and that prior pandemic-related experiences exacerbated the adverse impact of both trait and state perceived stress on daily moods. Specifically, young adults reporting greater COVID-19 stressful experiences demonstrated poorer emotional adjustment (i.e., lower levels of positive mood and higher levels of negative mood) on days when they had more fluctuations in perceived stress; the aggravating impact was stronger when the average levels of perceived stress were higher. By illuminating the moderating effects of COVID-19 stressful experiences, this study contributes to the limited, but burgeoning, research examining the prolonged impact of the COVID-19 health crisis on daily emotional adjustment in post-pandemic life.

Rational development of a combined mRNA vaccine against COVID-19 and influenza (preprint)

As the world continues to experience the COVID-19 pandemic, seasonal influenza remain a cause of severe morbidity and mortality globally. Worse yet, coinfection with SARS-CoV-2 and influenza A virus (IAV) leads to more severe clinical outcomes. The development of a combined vaccine against both COVID-19 and influenza is thus of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we developed and characterized a novel mRNA vaccine encoding the HA antigen of influenza A (H1N1) virus, termed ARIAV. Then, ARIAV was combined with our COVID-19 mRNA vaccine ARCoV, which encodes the receptor binding domain (RBD) of the SARS-CoV-2 S protein, to formulate the final combined vaccine, AR-CoV/IAV. Further characterization demonstrated that immunization with two doses of AR-CoV/IAV elicited robust protective antibodies as well as antigen-specific cellular immune responses against SARS-CoV-2 and IAV. More importantly, AR-CoV/IAV immunization protected mice from coinfection with IAV and the SARS-CoV-2 Alpha and Delta variants. Our results highlight the potential of the LNP-mRNA vaccine platform in preventing COVID-19 and influenza, as well as other respiratory diseases.

Risk assessment of public health emergencies concerned in the mainland of China, August 2021

Objective: To assess the risk of public health emergencies, both the indigenous ones and the imported ones, which might occur in the mainland of China in August 2021.

Both Simulation and Sequencing Data Reveal Multiple SARS-CoV-2 Variants Coinfection in COVID-19 Pandemic (preprint)

SARS-CoV-2 is a single-stranded RNA betacoronavirus with a high mutation rate. The rapidly emerged SARS-CoV-2 variants could increase the transmissibility, aggravate the severity, and even fade the vaccine protection. Although the coinfections of SARS-CoV-2 with other respiratory pathogens have been reported, whether multiple SARS-CoV-2 variants coinfection exists remains controversial. This study collected 12,986 and 4,113 SARS-CoV-2 genomes from the GISAID database on May 11, 2020 (GISAID20May11) and April 1, 2021 (GISAID21Apr1), respectively. With the single-nucleotide variants (SNV) and network clique analysis, we constructed the single-nucleotide polymorphism (SNP) coexistence networks and noted the SNP number of the maximal clique as the coinfection index. The coinfection indices of GISAID20May11 and GISAID21Apr1 datasets were 16 and 34, respectively. Simulating the transmission routes and the mutation accumulations, we discovered the linear relationship between the coinfection index and the coinfected variant number. Based on the linear relationship, we deduced that the COVID-19 cases in the GISAID20May11 and GISAID21Apr1 datasets were coinfected with 2.20 and 3.42 SARS-CoV-2 variants on average. Additionally, we performed Nanopore sequencing on 42 COVID-19 patients to explore the virus mutational characteristics. We found the heterozygous SNPs in 41 COVID-19 cases, which support the coinfection of SARS-CoV-2 variants and challenge the accuracy of phylogenetic analysis. In conclusion, our findings reported the coinfection of SARS-CoV-2 variants in COVID-19 patients, demonstrated the increased coinfected variants number in the epidemic, and provided clues for the prolonged viral shedding and severe symptoms in some cases.

Sleep disparities during the COVID-19 pandemic: An investigation of AIAN, Asian, Black, Latinx, and White young adults.

OBJECTIVES: This study investigates race-related disparities in sleep duration and quality among diverse young adults during the coronavirus 2019 (COVID-19) pandemic. DESIGN & SETTING: Online cross-sectional study of young adults in the United States in April 2020. PARTICIPANTS: About 547 American Indian/Alaskan Native (AIAN), Asian, Black, Latinx, and White young adults ages 18-25 years. MEASUREMENTS: Participants completed measures of sleep duration and quality, coronavirus victimization distress, depression, age, sex/gender, employment status, essential worker status, student status, residential region, socioeconomic status, concerns about contracting coronavirus and CDC health risks. RESULTS: Black young adults reported the largest disparity in sleep duration and quality. For sleep duration, AIAN, Asian, White, and Latinx young adults reported approximately one additional hour of sleep compared to Black respondents. Mediation analyses suggest that disparities in sleep duration between Asian and Black young adults may be explained by the higher likelihood of Black respondents being essential workers. For sleep quality, Latinx, White, AIAN, and Asian young adults reported higher levels than Black respondents. Including coronavirus victimization distress as an intervening pathway decreased the effect for Asian and White respondents on sleep quality, suggesting that coronavirus victimization distress partially explains Black and Asian, as well as Black and White differences in sleep quality. CONCLUSIONS: Black young adults reported the shortest sleep duration and lowest levels of sleep quality relative to AIAN, Asian, Latinx and White peers. Interpersonal experiences of coronavirus victimization and structural inequities may partially explain disparities during the COVID-19 pandemic.

The global emergence of a novel Streptococcus suis clade associated with human infections.

Streptococcus suis, a ubiquitous bacterial colonizer in pigs, has recently extended host range to humans, leading to a global surge of deadly human infections and three large outbreaks since 1998. To better understand the mechanisms for the emergence of cross-species transmission and virulence in human, we have sequenced 366 S. suis human and pig isolates from 2005 to 2016 and performed a large-scale phylogenomic analysis on 1,634 isolates from 14 countries over 36 years. We show the formation of a novel human-associated clade (HAC) diversified from swine S. suis isolates. Phylogeographic analysis identified Europe as the origin of HAC, coinciding with the exportation of European swine breeds between 1960s and 1970s. HAC is composed of three sub-lineages and contains several healthy-pig isolates that display high virulence in experimental infections, suggesting healthy-pig carriers as a potential source for human infection. New HAC-specific genes are identified as promising markers for pathogen detection and surveillance. Our discovery of a human-associated S. suis clade provides insights into the evolution of this emerging human pathogen and extend our understanding of S. suis epidemics worldwide.

Multi-Epitope Vaccine Design Using an Immunoinformatic Approach for SARS-CoV-2.

Through 4 June 2021, COVID-19 has caused over 172.84 million cases of infection and 3.71 million deaths worldwide. Due to its rapid dissemination and high mutation rate, it is essential to develop a vaccine harboring multiple epitopes and efficacious against multiple variants to prevent the immune escape of SARS-CoV-2. An in silico approach based on the viral genome was applied to identify 19 high-immunogenic B-cell epitopes and 499 human leukocyte antigen (HLA)-restricted T-cell epitopes. Thirty multi-epitope peptide vaccines were designed by iNeo-Suite and manufactured by solid-phase synthesis. Docking analysis confirmed stable hydrogen bonds of epitopes with their corresponding HLA alleles. When four peptide candidates derived from the spike protein of SARS-CoV-2 were selected to immunize mice, a significantly larger amount of total IgG in serum, as well as an increase of CD19+ cells in the inguinal lymph nodes, were observed in the peptide-immunized mice compared to the control. The ratios of IFN-γ-secreting lymphocytes in CD4+ or CD8+ T-cells in the peptide-immunized mice were higher than those in the control mice. There were also a larger number of IFN-γ-secreting T-cells in the spleens of peptide-immunized mice. The peptide vaccines in this study successfully elicited antigen-specific humoral and cellular immune responses in mice. To further validate the safety and efficacy of this vaccine, animal studies using a primate model, as well as clinical trials in humans, are required.

Comparison of acute pneumonia caused by SARS-COV-2 and other respiratory viruses in children: a retrospective multi-center cohort study during COVID-19 outbreak (preprint)

Background: Until July 14, 2020, coronavirus disease-2019 (COVID-19) has infected more than 130 million individuals and has caused a certain degree of panic. Viral pneumonia caused by common viruses such as respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses have been more common in children. However, the incidence of COVID-19 in children was significantly lower than that in adults. The purpose of this study was to describe the clinical manifestations, treatment and outcomes of COVID-19 in children compared to those of other sources of viral pneumonia diagnosed during the COVID-19 outbreak. Methods: Children with COVID-19 and viral pneumonia admitted to 20 hospitals were enrolled in this retrospective multi-center cohort study. A total of 64 children with COVID-19 were defined as the COVID-19 cohort, of which 40 children who developed pneumonia were defined as the COVID-19 pneumonia cohort. Another 284 children with pneumonia caused by other viruses were defined as the viral pneumonia cohort. Results: Compared to the viral pneumonia cohort, children in the COVID-19 cohort were mostly exposed to family members confirmed to have COVID-19 (53/64 vs. 23/284), were of older median age (6.3 vs. 3.2 years), and had a higher proportion of ground-glass opacity (GGO) on computed tomography (18/40 vs. 0/38) (all P ＜0.001). Children in the COVID-19 pneumonia cohort had a lower proportion of severe cases (1/40 vs. 38/284, P =0.048), and lower cases with high fever (3/40 vs 167/284, P ＜0.001), requiring intensive care (1/40 vs 32/284, P ＜0.047) and with shorter symptomatic duration (median 5 vs 8 days, P ＜0.001). The proportion of cases with evaluated inflammatory indicators, biochemical indicators related to organ or tissue damage, D-dimer and secondary bacterial infection were lower in the COVID-19 pneumonia cohort than in the viral pneumonia cohort (all P ＜0.05). No statistical differences were found in the duration of positive PCR results from pharyngeal swabs in 25 children with COVID-19 who received antiviral drugs (lopinavir-ritonavir, ribavirin, and arbidol) as compared to duration in 39 children without antiviral therapy [median 10 vs. 9 days, P =0.885]. Conclusion: The symptoms and severity of COVID-19 pneumonia in children were no more severe than those in children with other viral pneumonias. Lopinavir-ritonavir, ribavirin and arbidol do not shorten the duration of positive PCR results from pharyngeal swabs in children with COVID-19. During the COVID-19 outbreak, attention also must be given to children with infection by other pathogens infection.

Decrease of exercise endurance in critically ill COVID-19 survivors: 4 case reports (preprint)

Background: The Coronavirus Disease 2019 (COVID-19) already have been as a pandemic. However, knowledge about the sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains limited. Here we descirbe the pulmonary function test (PFT) and cardiopulmonary exercise test (CPET) of critically ill COVID-19 in four cases with sereve acute respiratory distress syndrome (ARDS) after discharge.Case presentation: We introduce four patients who complained of fever, cough, chest tightness and other symptoms, all of them were confirmed as SARS-CoV-2 infection by real-time reverse transcription polymerase chain reaction (RT-PCR). They were treated with mechanical ventilation because of severe ARDS. After respiratory support, antiviral and anti-infective treatment, they were weaned from mechanic ventilation with the improvement of hypoxemia. All patients were discharged from the hospital after completion of treatment and had no mortality. Around 1-month post-discharge, they were followed up for chest computed tomography (CT) scan, and performed PFT and CPET. Peak oxygen uptake of predicted (peakVO2% pred) decreased in all four cases, although spirometry were in the normal range, and only 2 cases had mild decline in carbon monoxide diffusion capacity of predicted (DLCO%pred).Conclusions: We found reduced exercise endurance in all four COVID-19 survivors, even parts of them with normal or slightly abnormal static lung function. We also believe that exercise endurance impairment of COVID-19 convalescents is more likely affected by extrapulmonary factors. Taken the above into consideration, our study highlights that the combination of PFT and CPET are important tests for tracking the development and recovery of COVID-19 survivors.

Quarantine At Home May Not Enough!-From the Epidemiological Data In Shaanxi Province of China (preprint)

Objectives : A pneumonia associated with 2019 novel coronavirus (2019-nCoV, subsequently named SARS-CoV2) emerged worldwide since December, 2019. We aimed to describe the epidemiological characteristics of 2019 coronavirus disease (COVID-19) in Shaanxi province of China.  Results: 1. Among the 245 patients, 132 (53.9%) were males and 113 (46.1%) were females. The average age was 46.15±16.43 years, ranging from 3 to 89 years. 2.  For the clinical type, 1.63% (4/245) patients were mild type , 84.90% (208/245) were moderate type, 7.76% (19/245) were severe type, 5.31% (13/245) were critical type and only 0.41% (1/245) was asymptomatic. 3. Of the 245 patients, 116 (47.35%) were input case, 114 (46.53%) were non-input case , and 15 (6.12%) were unknown exposure. 4. 48.57% (119/245) cases were family cluster , involving 42 families. The most common pattern of COVID-19 family cluster was between husband and wife or between parents and children. 

Characterization of Microbial Co-infections in the Respiratory Tract of hospitalized COVID-19 patients (preprint)

Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, microbial composition of the respiratory tract and other infected tissues, as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Method Between January 27 and February 26, 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients (requiring ICU admission and mechanical ventilation), in the Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. Co-infection rates, the prevalence and abundance of microbial communities in these COVID-19 patients were determined. Findings Notably, respiratory microbial co-infections were exclusively found in 84.6% of severely ill patients (11/13), among which viral and bacterial co-infections were detected by sequencing in 30.8% (4/13) and 69.2% (9/13) of the patients, respectively. In addition, for 23.1% (3/13) of the patients, bacterial co-infections with Burkholderia cepacia complex (BCC) and Staphylococcus epidermidis were also confirmed by bacterial culture. Further, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes in one severely ill patient was demonstrated, which might be the primary cause of his disease deterioration and death one month after ICU admission. Interpretation Our findings identified distinct patterns of co-infections with SARS-CoV-2 and various respiratory pathogenic microbes in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking of BCC-associated nosocomial infections are recommended to improve the pre-emptive treatment regimen and reduce fatal outcomes of hospitalized patients infected with SARS-CoV-2. Funding National Science and Technology Major Project of China, National Major Project for Control and Prevention of Infectious Disease in China, the emergency grants for prevention and control of SARS-CoV-2 of Ministry of Science and Technology and Guangdong province, Guangdong Provincial Key Laboratory of Genome Read and Write, Guangdong Provincial Academician Workstation of BGI Synthetic Genomics, and Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics.

Rapid Screening Diagnosis of SARS-COV-2 Infection With IgM-igG Combined Antibody Test Using Peripheral Blood (preprint)

Background Rapid and convenient screening for identification of SARS-CoV-2 infected individuals are key to prevent and control this pandemic.Methods The peripheral blood samples were collected from coronavirus disease 2019 (COVID-19) patients and asymptomatic carriers to evaluate the test characteristics of the IgM-IgG combined assay for SARS-CoV-2 compared to that of serum samples and enzyme-linked immuno sorbent assay (ELISA). Close contacts, healthcare workers and workforces were recruited and screened using this assay.Results The sensitivity of the rapid IgM-IgG combined antibody test for SARS-CoV-2 using peripheral blood (sued as a POCT) was 97.0% and the specificity was 99.2%, which was consistent with the result obtained using serum sample (consistency is about 100%). Furthermore, this POCT assay also can detect IgM and IgG antibodies of SARS-CoV‐2 in asymptomatic carriers, with 19 of the 20 RT-PCR confirmed asymptomatic carriers testing positive. Therefore, this POCT assay was used for population screening of SARS-CoV-2 infection diagnosis. First, it found 4 positive close contacts among the 10 cases, and there were three IgM positive cases and one IgG positive case among them. It is worth noting that the IgM positive cases also tested positive for the nucleic acid of the SARS-CoV-2. Second, there was one IgM positive assay among the 63 healthcare workers, but RT-PCR of SARS CoV-2 was negative. Third, for workforces screening, there were no positive cases.Conclusions The IgM-IgG combined antibody test of SARS-CoV-2 can be used as a POCT for rapid screening of SARS-CoV-2 infection.

Single-Cell Analysis Reveals Macrophage-Driven T Cell Dysfunction in Severe COVID-19 Patients (preprint)

The vastly spreading COVID-19 pneumonia is caused by SARS-CoV-2. Lymphopenia and cytokine levels are tightly associated with disease severity. However, virus-induced immune dysregulation at cellular and molecular levels remains largely undefined. Here, the leukocytes in the pleural effusion, sputum, and peripheral blood biopsies from severe and mild patients were analyzed at single-cell resolution. Drastic T cell hyperactivation accompanying elevated T cell exhaustion was observed, predominantly in pleural effusion. The mechanistic investigation identified a group of CD14+ monocytes and macrophages highly expressing CD163 and MRC1 in the biopsies from severe patients, suggesting M2 macrophage polarization. These M2-like cells exhibited up-regulated IL10, CCL18, APOE, CSF1 (M-CSF), and CCL2 signaling pathways. Further, SARS-CoV-2-specific T cells were observed in pleural effusion earlier than in peripheral blood. Together, our results suggest that severe SARS-CoV-2 infection causes immune dysregulation by inducing M2 polarization and subsequent T cell exhaustion. This study improves our understanding of COVID-19 pathogenesis.

Comparison of clinical characteristics and risk factors in hospitalized patients with SARS-CoV-2, MERS-CoV, and SARS-CoV infection (preprint)

Herein, we compared the risk factors, clinical presentation of patients hospitalized with SARS-CoV-2, SARS-CoV, or MERS-CoV infection. Our data sources include PubMed, Embase, CNKI, and Ovid/Medline. The proportion of male patients with COVID-19 was higher than who with SARS but lower than who with MERS (p<0.001). More patients with COVID-19 had coexisting chronic medical conditions than those with SARS (p<0.001) but fewer than those with MERS (p<0.001), and the prevalence of hypertension (17%) and smoking history (14%) was higher than in patients with SARS (p<0.001). Furthermore, the symptom of fever (53%), hemoptysis (1%), diarrhea (4%) and vomiting (3%) of COVID-19 were significantly lower than that in patients with SARS or MERS. The level of ALT and AST in COVID-19 was significantly lower (p<0.001), however, thrombocytopenia, high LDH were common. Summary, male, smoking history and hypertension were the most common risk factors for hospitalization with COVID-19; and the clinical feature was less severe in COVID-19.

CovProfile: profiling the viral genome and gene expressions of SARS-COV2 (preprint)

The SARS-CoV-2 virus has infected more than one million people worldwide to date. Knowing its genome and gene expressions is essential to understand the virus mechanism. Here, we propose a computational tool CovProfile to detect the viral genomic variations as well as viral gene expressions from the sequences obtained from Nanopore devices. We applied CovProfile to 11 samples, each from a terminally ill patient, and discovered that all the patients are infected by multiple viral strains, which might affect the reliability of phylogenetic analysis. Moreover, the expression of viral genes ORF1ab gene, S gene, M gene, and N gene are high among most of the samples. While performing the tests, we noticed a consistent abundance of transcript segments of MUC5B, presumably from the host, across all the samples.

Comparison of clinical characteristics and risk factors in hospitalized patients with SARS-CoV-2, MERS-CoV, and SARS-CoV infection (preprint)

Herein, we compared the risk factors, clinical presentation of patients hospitalized with SARS-CoV-2, SARS-CoV, or MERS-CoV infection. The proportion of male patients with COVID-19 was higher than who with SARS but lower than who with MERS (p<0.001). More patients with COVID-19 had coexisting chronic medical conditions than those with SARS (p<0.001) but fewer than those with MERS (p<0.001), and the prevalence of hypertension (17%) and smoking history (14%) was higher than in patients with SARS (p<0.001). Furthermore,the symptom of fever (53%), hemoptysis (1%), diarrhea (4%) and vomiting (3%) of COVID-19 were significantly lower than that in patients with SARS or MERS. The level of ALT and AST in COVID-19 was significantly lower (p<0.001), however, thrombocytopenia, high LDH were common. Summary, male, smoking history and hypertension were the most common risk factors for hospitalization with COVID-19; and the clinical feature was less severe in COVID-19.