Gut Microbiome Alterations in COVID-19

Since the outset of the coronavirus disease 2019 (COVID-19) pandemic, the gut microbiome in COVID-19 has garnered substantial interest, given its significant roles in human health and pathophysiology. Accumulating evidence is unveiling that the gut microbiome is broadly altered in COVID-19, including the bacterial microbiome, mycobiome, and virome. Overall, the gut microbial ecological network is significantly weakened and becomes sparse in patients with COVID-19, together with a decrease in gut microbiome diversity. Beyond the existence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the gut microbiome of patients with COVID-19 is also characterized by enrichment of opportunistic bacteria, fungi, and eukaryotic viruses, which are also associated with disease severity and presentation. Meanwhile, a multitude of symbiotic bacteria and bacteriophages are decreased in abundance in patients with COVID-19. Such gut microbiome features persist in a significant subset of patients with COVID-19 even after disease resolution, coinciding with ‘long COVID’ (also known as post-acute sequelae of COVID-19). The broadly-altered gut microbiome is largely a consequence of SARS-CoV-2 infection and its downstream detrimental effects on the systemic host immunity and the gut milieu. The impaired host immunity and distorted gut microbial ecology, particularly loss of low-abundance beneficial bacteria and blooms of opportunistic fungi including Candida, may hinder the reassembly of the gut microbiome post COVID-19. Future investigation is necessary to fully understand the role of the gut microbiome in host immunity against SARS-CoV-2 infection, as well as the long-term effect of COVID-19 on the gut microbiome in relation to the host health after the pandemic.     

Clinical Characteristics of 28 Patients with Diabetes and COVID-19 in Wuhan,China

Objective: Previous studies on coronavirus disease 2019 (COVID-19) were based on information from the general population. We aimed to further clarify the clinical characteristics of diabetes with COVID-19.Methods: Twenty-eight patients with diabetes and COVID-19 were enrolled from January 29, 2020, to February 10, 2020, with a final follow-up on February 22, 2020. Epidemiologic, demographic, clinical, laboratory, treatment, and outcome data were analyzed.Results: The average age of the 28 patients was 68.6 ± 9.0 years. Most (75%) patients were male. Only 39.3% of the patients had a clear exposure of COVID-19. Fever (92.9%), dry cough (82.1%), and fatigue (64.3%) were the most common symptoms, followed by dyspnea (57.1%), anorexia (57.1%), diarrhea (42.9%), expectoration (25.0%), and nausea (21.4%). Fourteen patients were admitted to the intensive care unit (ICU). The hemoglobin A1c level was similar between ICU and non-ICU patients. ICU patients had a higher respiratory rate, higher levels of random blood glucose, aspartate transaminase, bilirubin, creatine, N-terminal prohormone of brain natriuretic peptide, troponin I, D-dimers, procalcitonin, C-reactive protein, ferritin, interleukin (IL)-2R, IL-6, and IL-8 than non-ICU patients. Eleven of 14 ICU patients received noninvasive ventilation and 7 patients received invasive mechanical ventilation. Twelve patients died in the ICU group and no patients died in the non-ICU group.Conclusion: ICU cases showed higher rates of organ failure and mortality than non-ICU cases. The poor outcomes of patients with diabetes and COVID-19 indicated that more supervision is required in these patients.Abbreviations: COVID-19 = coronavirus disease 2019; ICU = intensive care unit; MERS-CoV = middle East respiratory syndrome-related coronavirus; 2019- nCoV = 2019 novel coronavirus; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; SARS-CoV = severe acute respiratory syndrome-related coronavirus     

Metformin Use in Diabetes Prior to Hospitalization: Effects on Mortality in Covid-19

Objective: Although type 2 diabetes mellitus (T2DM) has been reported as a risk factor for coronavirus disease 2019 (COVID-19), the effect of pharmacologic agents used to treat T2DM, such as metformin, on COVID-19 outcomes remains unclear. Metformin increases the expression of angiotensin converting enzyme 2, a known receptor for severe acute respiratory syndrome coronavirus 2. Data from people with T2DM hospitalized for COVID-19 were used to test the hypothesis that metformin use is associated with improved survival in this population.Methods: Retrospective analyses were performed on de-identified clinical data from a major hospital in Wuhan, China, that included patients with T2DM hospitalized for COVID-19 during the recent epidemic. One hundred and thirty-one patients diagnosed with COVID-19 and T2DM were used in this study. The primary outcome was mortality. Demographic, clinical characteristics, laboratory data, diabetes medications, and respiratory therapy data were also included in the analysis.Results: Of these 131 patients, 37 used metformin with or without other antidiabetes medications. Among the 37 metformin-taking patients, 35 (94.6%) survived and 2 (5.4%) did not survive. The mortality rates in the metformin-taking group versus the non-metformin group were 5.4% (2/37) versus 22.3% (21/94). Using multivariate analysis, metformin was found to be an independent predictor of survival in this cohort (P = .02).Conclusion: This study reveals a significant association between metformin use and survival in people with T2DM diagnosed with COVID-19. These clinical data are consistent with potential benefits of the use of metformin for COVID-19 patients with T2DM.     

Phenotypes and Functions of SARS-CoV-2-Reactive T Cells

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which is an ongoing pandemic disease. SARS-CoV-2-specific CD4⁺ and CD8⁺ T-cell responses have been detected and characterized not only in COVID-19 patients and convalescents, but also unexposed individuals. Here, we review the phenotypes and functions of SARS-CoV-2-specific T cells in COVID-19 patients and the relationships between SARS-CoV-2-specific T-cell responses and COVID-19 severity. In addition, we describe the phenotypes and functions of SARS-CoV-2-specific memory T cells after recovery from COVID-19 and discuss the presence of SARS-CoV-2-reactive T cells in unexposed individuals and SARS-CoV-2-specific T-cell responses elicited by COVID-19 vaccines. A better understanding of T-cell responses is important for effective control of the current COVID-19 pandemic.     

The Global Landscape of SARS-CoV-2 Genomes,Variants, and Haplotypes in 2019nCoVR

On January 22, 2020, China National Center for Bioinformation (CNCB) released the 2019 Novel Coronavirus Resource (2019nCoVR), an open-access information resource for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 2019nCoVR features a comprehensive integration of sequence and clinical information for all publicly available SARS-CoV-2 isolates, which are manually curated with value-added annotations and quality evaluated by an automated in-house pipeline. Of particular note, 2019nCoVR offers systematic analyses to generate a dynamic landscape of SARS-CoV-2 genomic variations at a global scale. It provides all identified variants and their detailed statistics for each virus isolate, and congregates the quality score, functional annotation, and population frequency for each variant. Spatiotemporal change for each variant can be visualized and historical viral haplotype network maps for the course of the outbreak are also generated based on all complete and high-quality genomes available. Moreover, 2019nCoVR provides a full collection of SARS-CoV-2 relevant literature on the coronavirus disease 2019 (COVID-19), including published papers from PubMed as well as preprints from services such as bioRxiv and medRxiv through Europe PMC. Furthermore, by linking with relevant databases in CNCB, 2019nCoVR offers data submission services for raw sequence reads and assembled genomes, and data sharing with NCBI. Collectively, SARS-CoV-2 is updated daily to collect the latest information on genome sequences, variants, haplotypes, and literature for a timely reflection, making 2019nCoVR a valuable resource for the global research community. 2019nCoVR is accessible at https://bigd.big.ac.cn/ncov/.     

Longitudinal virological changes and underlying pathogenesis in hospitalized COVID-19 patients in Guangzhou,China

Science China Life Sciences - Prolonged viral RNA shedding and recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in coronavirus disease 2019 (COVID-19) patients have been...     

Severe Acute Respiratory Syndrome Coronavirus 2: Manifestations of Disease and Approaches to Treatment and Prevention in Humans

The coronavirus disease 2019 (COVID-19) pandemic was caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus has challenged civilization and modern science in ways that few infectious diseases and natural disasters have previously, causing globally significant human morbidity and mortality and triggering economic downturns across financial markets that will be dealt with for generations. Despite this, the pandemic has also brought an opportunity for humanity to come together and participate in a shared scientific investigation. Clinically, SARS-CoV-2 is associated with lower mortality rates than other recently emerged coronaviruses, such as SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV). However, SARS-CoV-2 exhibits efficient human-to-human spread, with transmission often occurring before symptom recognition; this feature averts containment strategies that had worked previously for SARS-CoV and MERS-CoV. Severe COVID-19 disease is characterized by dysregulated inflammatory responses associated with pulmonary congestion and intravascular coagulopathy leading to pneumonia, vascular insults, and multiorgan disease. Approaches to treatment have combined supportive care with antivirals, such as remdesivir, with immunomodulatory medications, including corticosteroids and cytokine-blocking antibody therapies; these treatments have advanced rapidly through clinical trials. Innovative approaches to vaccine development have facilitated rapid advances in design, testing, and distribution. Much remains to be learned about SARS-CoV-2 and COVID-19, and further biomedical research is necessary, including comparative medicine studies in animal models. This overview of COVID-19 in humans will highlight important aspects of disease, relevant pathophysiology, underlying immunology, and therapeutics that have been developed to date.

In December 2019, a cluster of cases of pneumonia without a clear etiology occurred in Wuhan, China. With remarkable speed and efficiency, the etiology of this illness was soon identified as a novel coronavirus; the complete viral genome was sequenced and published on January 10, 2020.¹⁸² These events introduced the world to coronavirus disease 2019 (COVID-19). The disease, now known to be caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has developed into the most significant pandemic of recent times. In less than a year since the virus was first recognized, multiple candidate vaccines were developed worldwide, and some of them rapidly progressed to clinical trials and widespread administration. As the pandemic continues, a number of sequence variants of the virus have emerged around the world. This continued viral evolution highlights the need for continued biomedical research to facilitate understanding of the pathogenesis of COVID-19, seeking innovative therapeutic and preventative strategies for the current and possibly future pandemics. This article will review aspects of SARS-CoV-2 infection of humans and COVID-19, focusing on important aspects of clinical disease, pathophysiology, immunology, and the development of therapeutic and preventative measures to provide context for discussion of the animal models used to study SARS-CoV-2 and COVID-19.     

The Potential of Nanobodies for COVID-19 Diagnostics and Therapeutics

Molecular Diagnosis & Therapy - The infectious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent for coronavirus disease 2019 (COVID-19). Globally, there have...     

Considerations for Gut Microbiota and Probiotics in Patients with Diabetes Amidst the Covid-19 Pandemic: A Narrative Review

Objective: To review data implicating microbiota influences on Coronavirus Disease 2019 (COVID-19) in patients with diabetes.Methods: Primary literature review included topics: “COVID-19,” “SARS,” “MERS,” “gut micro-biota,” “probiotics,” “immune system,” “ACE2,” and “metformin.”Results: Diabetes was prevalent (~11%) among COVID-19 patients and associated with increased mortality (about 3-fold) compared to patients without diabetes. COVID-19 could be associated with worsening diabetes control and new diabetes diagnosis that could be linked to high expression of angiotensin-converting enzyme 2 (ACE2) receptors (coronavirus point of entry into the host) in the endocrine pancreas. A pre-existing gut microbiota imbalance (dysbiosis) could contribute to COVID-19–related complications in patients with diabetes. The COVID-19 virus was found in fecal samples (~55%), persisted for about 5 weeks, and could be associated with diarrhea, suggesting a role for gut dysbiosis. ACE2 expressed on enterocytes and colonocytes could serve as an alternative route for acquiring COVID-19. Experimental models proposed some probiotics, including Lactobacillus casei, L. plantarum, and L. salivarius, as vectors for delivering or enhancing efficacy of anti-coronavirus vaccines. These Lactobacillus probiotics were also beneficial for diabetes. The potential mechanisms for interconnections between coronavirus, diabetes, and gut microbiota could be related to the immune system, ACE2 pathway, and metformin treatment. There were suggestions but no proof supporting probiotics benefits for COVID-19 infection.Conclusion: The data suggested that the host environment including the gut microbiota could play a role for COVID-19 in patients with diabetes. It is a challenge to the scientific community to investigate the beneficial potential of the gut microbiota for strengthening host defense against coronavirus in patients with diabetes.     

Summary of the Detection Kits for SARS-CoV-2 Approved by the National Medical Products Administration of China and Their Application for Diagnosis of COVID-19

Virologica Sinica - The on-going global pandemic of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been...     

Population Genetics of SARS-CoV-2: Disentangling Effects of Sampling Bias and Infection Clusters

A novel RNA virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the ongoing outbreak of coronavirus disease 2019 (COVID-19). Population genetic analysis could be useful for investigating the origin and evolutionary dynamics of COVID-19. However, due to extensive sampling bias and existence of infection clusters during the epidemic spread, direct applications of existing approaches can lead to biased parameter estimations and data misinterpretation. In this study, we first present robust estimator for the time to the most recent common ancestor (TMRCA) and the mutation rate, and then apply the approach to analyze 12,909 genomic sequences of SARS-CoV-2. The mutation rate is inferred to be 8.69 × 10⁻⁴ per site per year with a 95% confidence interval (CI) of [8.61 × 10⁻⁴, 8.77 × 10⁻⁴], and the TMRCA of the samples inferred to be Nov 28, 2019 with a 95% CI of [Oct 20, 2019, Dec 9, 2019]. The results indicate that COVID-19 might originate earlier than and outside of Wuhan Seafood Market. We further demonstrate that genetic polymorphism patterns, including the enrichment of specific haplotypes and the temporal allele frequency trajectories generated from infection clusters, are similar to those caused by evolutionary forces such as natural selection. Our results show that population genetic methods need to be developed to efficiently detangle the effects of sampling bias and infection clusters to gain insights into the evolutionary mechanism of SARS-CoV-2. Software for implementing VirusMuT can be downloaded at https://bigd.big.ac.cn/biocode/tools/BT007081.     

High-throughput,single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19

Tracking evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within infected individuals will help elucidate coronavirus disease 2019 (COVID-19) pathogenesis and inform use of antiviral interventions. In this study, we developed an approach for sequencing the region encoding the SARS-CoV-2 virion surface proteins from large numbers of individual virus RNA genomes per sample. We applied this approach to the WA-1 reference clinical isolate of SARS-CoV-2 passaged in vitro and to upper respiratory samples from 7 study participants with COVID-19. SARS-CoV-2 genomes from cell culture were diverse, including 18 haplotypes with non-synonymous mutations clustered in the spike NH₂-terminal domain (NTD) and furin cleavage site regions. By contrast, cross-sectional analysis of samples from participants with COVID-19 showed fewer virus variants, without structural clustering of mutations. However, longitudinal analysis in one individual revealed 4 virus haplotypes bearing 3 independent mutations in a spike NTD epitope targeted by autologous antibodies. These mutations arose coincident with a 6.2-fold rise in serum binding to spike and a transient increase in virus burden. We conclude that SARS-CoV-2 exhibits a capacity for rapid genetic adaptation that becomes detectable in vivo with the onset of humoral immunity, with the potential to contribute to delayed virologic clearance in the acute setting.     

In silico investigation of ACE2 and the main protease of SARS-CoV-2 with phytochemicals from Myristica fragrans (Houtt.) for the discovery of a novel COVID-19 drug

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), is a new coronavirus strain that was first reported in December 2019 in Wuhan, China. A specific treatment for COVID-19 has yet to be identified. Potential therapeutic targets include SARS-CoV-2 main protease (Mpro) and the SARS-CoV-2 spike-ACE2 interaction. Molecular docking, molecular dynamics (MD), solvent screening for the extraction of the specified compounds, and prediction of the drug properties of certain molecules were the methods used in this study to investigate compounds from the medicinal plant Myristica fragrans, which is one of twelve herbs in Prasachandaeng remedy (PSD). ArgusLab, AutoDock Vina, and AutoDock were used to perform docking tasks. The examined ligands were compared with panduratin A as a standard (Kanjanasirirat et al., 2020), which is a promising medicinal plant molecule for the treatment of COVID-19. Molecular docking revealed that malabaricones B and C and licarins A, B and C bound to SARS-CoV-2/ACE2 and SARS-CoV-2 Mpro with low binding energies compared to that of the standard ligand. Furthermore, appropriate solvent usage is important. Acetone was selected by COSMOquick software for compound extraction in this investigation because it can extract large amounts of all five of the abovementioned M. fragrans compounds. Furthermore, the drug-like properties of these compounds were studied utilizing the Lipinski, Veber, and Ghose criteria. The results revealed that these M. fragrans compounds have potential as effective medicines to combat the COVID-19 pandemic. However, to assess the therapeutic potential of these ligands, additional research is needed, which will use our findings as a foundation.     

Human Organoids as a Promising Platform for Fighting COVID-19

The coronavirus disease 2019 (COVID-19) global pandemic evoked by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a major public health problem with significant morbidity and mortality. Understanding the pathogenesis and molecular mechanisms underlying this novel virus is crucial for both fundamental research and clinical trials in order to devise effective therapies and vaccination regimens. Basic research on SARS-CoV-2 largely depends on ex vivo models that allow viral invasion and replication. Organoid models are now emerging as a valuable tool to investigate viral biology and disease progression, serving as an efficient platform to investigate potential therapies for COVID-19. Here, we summarize various human stem cell-derived organoid types employed in SARS-CoV-2 studies. We highlight key findings from these models, including cell tropisms and molecular mechanisms in viral infection. We also describe their use in identifying potential therapeutic agents against SARS-CoV-2. As more and more advanced organoids emerge, they will facilitate the understanding of disease pathogenesis for drug development in this dreaded pandemic.     

Identification of intrinsically disorder regions in non-structural proteins of SARS-CoV-2: New insights into drug and vaccine resistance

Molecular and Cellular Biochemistry - The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 2019 and caused coronavirus disease 2019 (COVID-19), which...     

COVID-19疫苗研究现状*

2019年底于中国武汉暴发的新型冠状病毒肺炎疫情来势凶猛,迅速蔓延全球,并被世界卫生组织列为“国际关注的突发公共卫生事件”,给全人类的健康及经济发展造成难以估量的损害。新型冠状病毒对人群普遍易感且传染性强,在无特效药物及治疗手段的情况下,疫苗接种是防控COVID-19疫情最有效且最经济的途径。目前全球疫苗研发正在加速进行,各国之间通力合作,共同应对此次疫情。主要对目前正在研发的针对SARS-CoV-2的灭活疫苗、病毒载体疫苗、基因工程重组亚单位疫苗、核酸疫苗的研究进展进行综述。     

Pituitary Stalk Thickening in a Large Cohort: Toward More Accurate Predictors of Pituitary Dysfunction and Etiology

Objective: To summarize the characteristics of patients with pituitary stalk thickening, analyze the association between pituitary stalk width and hypopituitarism, and develop a diagnostic model to differentiate neoplastic and inflammatory origins.Methods: A total of 325 patients with pituitary stalk thickening in a tertiary teaching hospital between January 2012 and February 2018 were enrolled. Basic characteristics and hormonal status were evaluated. Indicators to predict etiology in patients with histologic diagnoses were analyzed.Results: Of the 325 patients, 62.5% were female. Deficiency in gonadotropin was most common, followed by corticotropin, growth hormone, and thyrotropin. The increase in pituitary stalk width was associated with a risk of central diabetes insipidus (odds ratio &lsqb;OR], 3.57; P<.001) and with a combination of central diabetes insipidus and anterior pituitary deficiency (OR, 2.28; P = .029). The cut-off pituitary stalk width of 4.75 mm had a sensitivity of 69.2% and a specificity of 71.4% for the presence of central diabetes insipidus together with anterior pituitary deficiency. Six indicators (central diabetes insipidus, pattern of pituitary stalk thickening, pituitary stalk width, neutrophilic granulocyte percentage, serum sodium level, and gender) were used to develop a model having an accuracy of 95.7% to differentiate neoplastic from inflammatory causes.Conclusion: Pituitary stalk width could indicate the presence of anterior pituitary dysfunction, especially in central diabetes insipidus patients. With the use of a diagnostic model, the neoplastic and inflammatory causes of pituitary stalk thickening could be preliminarily differentiated.Abbreviations: APD = anterior pituitary dysfunction; AUC = area under the curve; CDI = central diabetes insipidus; GH = growth hormone; MRI = magnetic resonance imaging; OR = odd ratio; PHBS = posterior hypophyseal bright spots; PST = pituitary stalk thickening; PSW = pituitary stalk width     

Beneficial effects exerted by hydroxychloroquine in treating COVID-19 patients via protecting multiple organs

正Dear Editor.The coronavirus disease 2019 (COVID-19) pandemic caused by widespread infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)(Chen et al.,2020;Guan et al.,2020) has led to a global health crisis.More than 3.5 million infections and 246,838 deaths have occurred as of May 4,2020 (Saqrane and El Mhammedi,2020),with a rapid upward trend.Many CO VID-19 patients suffer from complicated systemic injuries such as cardiac(Chen et al.,2020) and hepatic (Huang et al.,2020) damages.There are currently no specific drugs on the market to treat COVID-19-induced systemic injuries (Ni et al.,