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1.
Signal Transduct Target Ther ; 7(1): 7, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1606287

ABSTRACT

Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.


Subject(s)
AIDS Vaccines/immunology , B-Cell Activating Factor/immunology , COVID-19 Vaccines/immunology , Cytidine Deaminase/immunology , HIV-1/immunology , Nanoparticles , SARS-CoV-2/immunology , Signal Transduction/immunology , Ubiquitin Thiolesterase/immunology , Ubiquitination/immunology , AIDS Vaccines/genetics , Animals , B-Cell Activating Factor/genetics , COVID-19 Vaccines/genetics , Cytidine Deaminase/genetics , HEK293 Cells , HIV-1/genetics , Humans , Mice , Mice, Knockout , SARS-CoV-2/genetics , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics
2.
Cell Rep ; 38(3): 110256, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1588136

ABSTRACT

Inoculation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing worldwide. However, the emergence of SARS-CoV-2 variants could cause immune evasion. We developed a bivalent nanoparticle vaccine that displays the receptor binding domains (RBDs) of the D614G and B.1.351 strains. With a prime-boost or a single-dose strategy, this vaccine elicits a robust neutralizing antibody and full protection against infection with the authentic D614G or B.1.351 strain in human angiotensin-converting enzyme 2 transgene mice. Interestingly, 8 months after inoculation with the D614G-specific vaccine, a new boost with this bivalent vaccine potently elicits cross-neutralizing antibodies for SARS-CoV-2 variants in rhesus macaques. We suggest that the D614G/B.1.351 bivalent vaccine could be used as an initial single dose or a sequential enforcement dose to prevent infection with SARS-CoV-2 and its variants.

3.
Signal Transduct Target Ther ; 6(1): 420, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585885

ABSTRACT

COVID-19 is identified as a zoonotic disease caused by SARS-CoV-2, which also can cross-transmit to many animals but not mice. Genetic modifications of SARS-CoV-2 or mice enable the mice susceptible to viral infection. Although neither is the natural situation, they are currently utilized to establish mouse infection models. Here we report a direct contact transmission of SARS-CoV-2 variant B.1.351 in wild-type mice. The SARS-CoV-2 (B.1.351) replicated efficiently and induced significant pathological changes in lungs and tracheas, accompanied by elevated proinflammatory cytokines in the lungs and sera. Mechanistically, the receptor-binding domain (RBD) of SARS-CoV-2 (B.1.351) spike protein turned to a high binding affinity to mouse angiotensin-converting enzyme 2 (mACE2), allowing the mice highly susceptible to SARS-CoV-2 (B.1.351) infection. Our work suggests that SARS-CoV-2 (B.1.351) expands the host range and therefore increases its transmission route without adapted mutation. As the wild house mice live with human populations quite closely, this possible transmission route could be potentially risky. In addition, because SARS-CoV-2 (B.1.351) is one of the major epidemic strains and the mACE2 in laboratory-used mice is naturally expressed and regulated, the SARS-CoV-2 (B.1.351)/mice could be a much convenient animal model system to study COVID-19 pathogenesis and evaluate antiviral inhibitors and vaccines.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/transmission , Host-Pathogen Interactions/genetics , Receptors, Virus/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Disease Models, Animal , Gene Expression , HEK293 Cells , Host-Pathogen Interactions/immunology , Humans , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Binding , Protein Domains , Receptors, Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Virus Replication
4.
Int J Nanomedicine ; 16: 4959-4984, 2021.
Article in English | MEDLINE | ID: covidwho-1334842

ABSTRACT

Antiviral drugs (AvDs) are the primary resource in the global battle against viruses, including the recent fight against corona virus disease 2019 (COVID-19). Most AvDs require multiple medications, and their use frequently leads to drug resistance, since they have poor oral bioavailability and low efficacy due to their low solubility/low permeability. Characterizing the in vivo metabolism and pharmacokinetic characteristics of AvDs may help to solve the problems associated with AvDs and enhance their efficacy. In this review of AvDs, we systematically investigated their structure-based metabolic reactions and related enzymes, their cellular pharmacology, and the effects of metabolism on AvD pharmacodynamics and pharmacokinetics. We further assessed how delivery systems achieve better metabolism and pharmacology of AvDs. This review suggests that suitable nanosystems may help to achieve better pharmacological activity and pharmacokinetic behavior of AvDs by altering drug metabolism through the utilization of advanced nanotechnology and appropriate administration routes. Notably, such AvDs as ribavirin, remdesivir, favipiravir, chloroquine, lopinavir and ritonavir have been confirmed to bind to the severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) receptor and thus may represent anti-COVID-19 treatments. Elucidating the metabolic and pharmacokinetic characteristics of AvDs may help pharmacologists to identify new formulations with high bioavailability and efficacy and help physicians to better treat virus-related diseases, including COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , COVID-19/metabolism , Drug Delivery Systems , SARS-CoV-2/drug effects , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans
5.
Eur J Pharmacol ; 890: 173659, 2021 Jan 05.
Article in English | MEDLINE | ID: covidwho-1071289

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of 2019 novel coronavirus disease (COVID-19), is currently spreading around the world. The WHO declared on January 31 that the outbreak of SARS-CoV-2 was a public health emergency. SARS-Cov-2 is a member of highly pathogenic coronavirus group that also consists of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Although respiratory tract lesions were regarded as main manifestation of SARS-Cov-2 infection, gastrointestinal lesions were also reported. Similarly, patients with SARS-CoV and MERS-CoV were also observed. Common gastrointestinal symptoms of patients mainly included diarrhea, vomiting and abdominal pain. Gastrointestinal lesions could be used as basis for early diagnosis of patients, and at the same time, controlling gastrointestinal lesions better facilitated to cut off the route of fecal-oral transmission. Hence, this review summarizes the characteristics and mechanism of gastrointestinal lesions caused by three highly pathogenic human coronavirus infections including SARS-CoV, MERS-CoV, as well as SARS-CoV-2. Furthermore, it is expected to gain experience from gastrointestinal lesions caused by SARS-CoV and MERS-CoV infections in order to be able to better relieve SARS-CoV-2 epidemic. Targetin gut microbiota to regulate the process of SARS-CoV-2 infection should be a concern. Especially, the application of nanotechnology may provide help for further controlling COVID-19.


Subject(s)
Coronavirus Infections/complications , Gastrointestinal Diseases/etiology , Middle East Respiratory Syndrome Coronavirus , SARS Virus , SARS-CoV-2 , Animals , Humans
6.
Psychiatry Res ; 296: 113654, 2021 02.
Article in English | MEDLINE | ID: covidwho-997443

ABSTRACT

The COVID-19 pandemic put global medical systems under massive pressure for its uncertainty, severity, and persistence. For detecting the prevalence of suicidal and self-harm ideation (SSI) and its related risk factors among hospital staff during the COVID-19 pandemic, this cross-sectional study collected the sociodemographic data, epidemic-related information, the psychological status and need, and perceived stress and support from 11507 staff in 46 hospitals by an online survey from February 14 to March 2, 2020. The prevalence of SSI was 6.47%. Hospital staff with SSI had high family members or relatives infected number and the self-rated probability of infection. Additionally, they had more perceived stress, psychological need, and psychological impact. On the contrary, hospital staff without SSI reported high self-rated health, willingness to work in a COVID-19 ward, confidence in defeating COVID-19, and perceived support. Furthermore, they reported better marital or family relationship, longer sleep hours, and shorter work hours. The infection of family members or relatives, poor marital status, poor self-rated health, the current need for psychological intervention, perceived high stress, perceived low support, depression, and anxiety were independent factors to SSI. A systematic psychological intervention strategy during a public health crisis was needed for the hospital staff's mental well-being.


Subject(s)
Anxiety Disorders/epidemiology , COVID-19/epidemiology , Depressive Disorder/epidemiology , Personnel, Hospital/statistics & numerical data , Self-Injurious Behavior/epidemiology , Suicidal Ideation , Adult , Anxiety Disorders/psychology , COVID-19/psychology , China , Cross-Sectional Studies , Depressive Disorder/psychology , Female , Humans , Incidence , Male , Personnel, Hospital/psychology , Self-Injurious Behavior/psychology , Uncertainty , Young Adult
7.
Chin. Trad. Herbal Drugs ; 6(51): 1412-1426, 20200328.
Article in Chinese | ELSEVIER | ID: covidwho-380343

ABSTRACT

Recently, the epidemic of novel coronavirus pneumonia (COVID-19) in China and other countries in the world is serious. There are at present no effective treatments for COVID-19. The safety and effectiveness of western anti-coronavirus drugs are under investigation. In many places in China, traditional Chinese medicine (TCM) has been used to treat COVID-19 with a high clinical cure rate. The treatment economics of TCM is good. The immune-regulating and antiviral TCM can enhance human immunity and exert an antiviral effect. They have been widely used in the anti-COVID-19 treatment. We consulted the database of CNKI, Wanfang, VIP and PubMed for screening the immune-regulating and antiviral TCMs (Glycyrrhizae Radix et Rhizoma, Pogostemonis Herba, Lonicerae Japonicae Flos, Scutellariae Radix, Forsythiae Fructus, Magnoliae Officinalis Cortex, Bupleuri Radix, Isatidis Radix, Rhei Radix et Rhizoma, Astragali Radix, and Houttuyniae Herba). This article summarizes the physicochemical and pharmacokinetic characteristics, and the clinical application of the effective components of immune-regulating and antiviral TCM in the prescriptions and Chinese patent medicines, in order to provide a better reference for the clinical application of TCM.

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