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1.
Int J Environ Res Public Health ; 19(1)2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1613775

ABSTRACT

In pandemic times, the possibilities for conventional sports activities are severely limited; many sports facilities are closed or can only be used with restrictions. To counteract this lack of health activities and social exchange, people are increasingly adopting new digital sports solutions-a behavior change that had already started with the trend towards fitness apps and activity trackers. Existing research suggests that digital solutions increase the motivation to move and stay active. This work further investigates the potentials of digital sports incorporating the dimensions gender and preference for team sports versus individual sports. The study focuses on potential users, who were mostly younger professionals and academics. The results show that the SARS-CoV-19 pandemic had a significant negative impact on sports activity, particularly on persons preferring team sports. To compensate, most participants use more digital sports than before, and there is a positive correlation between the time spent physically active during the pandemic and the increase in motivation through digital sports. Nevertheless, there is still considerable skepticism regarding the potential of digital sports solutions to increase the motivation to do sports, increase performance, or raise a sense of team spirit when done in groups.


Subject(s)
COVID-19 , SARS Virus , Humans , Motivation , Pandemics , SARS-CoV-2
2.
Arch Microbiol ; 204(1): 77, 2021 Dec 25.
Article in English | MEDLINE | ID: covidwho-1588812

ABSTRACT

The aim of this scoping review was to identify knowledge gaps and to describe the current state of the research on the association between TMPRSS2 and the essential beta coronaviruses (Beta-CoVs) infection and the molecular mechanisms for this association. We searched MEDLINE (OVID), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). We included 13 studies. Evidence shows an essential role of TMPRSS2 in Spike protein activation, entry, and spread into host cells. Co-expression of TMPRSS2 with cell surface receptors (ACE2 or DPP4) increased virus entry. This serine protease is involved in the formation of large syncytia between infected cells. TMPRSS2 cleaved the Spike protein of SARS-CoV, SARS-CoV-2, and MERS-CoV, and increased virus propagation. Accumulating evidence suggests that TMPRSS2 is an essential protease for virus replication. We highlighted its critical molecular role in membrane fusion and the impact in viral mRNA replication, then promoting/driving pathogenesis and resistance.


Subject(s)
COVID-19 , Coronavirus Infections/genetics , Serine Endopeptidases , COVID-19/genetics , Cell Line , Humans , Middle East Respiratory Syndrome Coronavirus , SARS Virus , SARS-CoV-2 , Serine Endopeptidases/genetics , Spike Glycoprotein, Coronavirus , Virus Internalization
3.
Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124

ABSTRACT

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
4.
Methods Mol Biol ; 2410: 229-263, 2022.
Article in English | MEDLINE | ID: covidwho-1575944

ABSTRACT

Vaccines are one of mankind's greatest medical advances, and their use has drastically reduced and in some cases eliminated (e.g., smallpox) disease and death caused by infectious agents. Traditional vaccine modalities including live-attenuated pathogen vaccines, wholly inactivated pathogen vaccines, and protein-based pathogen subunit vaccines have successfully been used to create efficacious vaccines against measles, mumps, rubella, polio, and yellow fever. These traditional vaccine modalities, however, take many months to years to develop and have thus proven less effective for use in creating vaccines to emerging or reemerging infectious diseases (EIDs) including influenza, Human immunodeficiency virus (HIV), dengue virus (DENV), chikungunya virus (CHIKV), West Nile virus (WNV), Middle East respiratory syndrome (MERS), and the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV and SARS-CoV-2). As factors such as climate change and increased globalization continue to increase the pace of EID development, newer vaccine modalities are required to develop vaccines that can prevent or attenuate EID outbreaks throughout the world. One such modality, DNA vaccines, has been studied for over 30 years and has numerous qualities that make them ideal for meeting the challenge of EIDs including; (1) DNA vaccine candidates can be designed within hours of publishing of a pathogens genetic sequence; (2) they can be manufactured cheaply and rapidly in large quantities; (3) they are thermostable and have reduced requirement for a cold-chain during distribution, and (4) they have a remarkable safety record in the clinic. Optimizations made in plasmid design as well as in DNA vaccine delivery have greatly improved the immunogenicity of these vaccines. Here we describe the process of making a DNA vaccine to an EID pathogen and describe methods used for assessing the immunogenicity and protective efficacy of DNA vaccines in small animal models.


Subject(s)
Communicable Diseases, Emerging , Vaccines, DNA , Viral Vaccines , Animals , COVID-19 , Communicable Diseases, Emerging/prevention & control , Humans , Immunity , SARS Virus , SARS-CoV-2 , Vaccines, Attenuated/immunology , Vaccines, DNA/immunology , Vaccines, Inactivated/immunology , Vaccines, Synthetic/immunology , Viral Vaccines/genetics , Viral Vaccines/immunology
5.
J Chem Inf Model ; 62(1): 176-186, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1575860

ABSTRACT

The coronavirus disease 19 (COVID-19) pandemic is causing a global health crisis and has already caused a devastating societal and economic burden. The pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a high sequence and architecture identity with SARS-CoV, but far more people have been infected by SARS-CoV-2. Here, combining the structural data from cryo-electron microscopy and structure prediction, we constructed bottom-up Martini coarse-grained models of intact SARS-CoV and SARS-CoV-2 envelopes. Microsecond molecular dynamics simulations were performed, allowing us to explore their dynamics and supramolecular organization. Both SARS-CoV and SARS-CoV-2 envelopes present a spherical morphology, with structural proteins forming multiple string-like islands in the membrane and clusters between the heads of spike proteins. Critical differences between the SARS-CoV and SARS-CoV-2 envelopes are the interaction pattern between the spike proteins and the flexibility of the spike proteins. Our models provide structural and dynamic insights into the SARS virus envelopes and could be used for further investigation, such as drug design and membrane fusion and fission processes.


Subject(s)
COVID-19 , SARS Virus , Cryoelectron Microscopy , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Viral Envelope , Virion
6.
Emerg Infect Dis ; 27(11): 2973-2975, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1551460

ABSTRACT

A young man with smoldering multiple myeloma died of hypotensive shock 2.5 days after severe acute respiratory syndrome coronavirus 2 vaccination. Clinical findings suggested systemic capillary leak syndrome (SCLS); the patient had experienced a previous suspected flare episode. History of SCLS may indicate higher risk for SCLS after receiving this vaccine.


Subject(s)
COVID-19 , Capillary Leak Syndrome , Multiple Myeloma , SARS Virus , Capillary Leak Syndrome/chemically induced , Capillary Leak Syndrome/diagnosis , Humans , Male , Multiple Myeloma/complications , SARS-CoV-2
7.
Eur J Obstet Gynecol Reprod Biol ; 263: 171-175, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1544980

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infections, like most other viruses that affect the respiratory tract can cause severe maternal illness and adverse pregnancy outcomes. They are not only highly transmissible (acquired through droplets), but Host reservoirs such as dromedary camels for MERS-CoV and masked palm civet for SARS-CoV-1 are critical links in the onset of outbreaks. Clinically they present with flu-like symptoms and therefore a high index of suspicion is required to ensure timely diagnosis and tailored management. Although there are not many reported series on these infections in pregnancy they seem to be associated with an increased risk of preterm delivery and maternal mortality. Diagnosis is made by PCR from nasopharyngeal swabs. There are currently no effective anti-viral agents for these viruses but following infections various agents have been administered to patients. The most important aspect of management should be early identification of deterioration and intensive support and prevention of transmission. Our understanding of the evidence of the impact of both infections on pregnancies suggests the potential for future repeat outbreaks, hence the importance of maintaining vigilance across healthcare systems.


Subject(s)
Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , SARS Virus , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Disease Outbreaks , Female , Humans , Pregnancy , Pregnancy Outcome
8.
Int J Med Sci ; 18(3): 763-767, 2021.
Article in English | MEDLINE | ID: covidwho-1524479

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is an emerging disease. There has been a rapid increase in cases and deaths since it was identified in Wuhan, China, in early December 2019, with over 4,000,000 cases of COVID-19 including at least 250,000 deaths worldwide as of May 2020. However, limited data about the clinical characteristics of pregnant women with COVID-19 have been reported. Given the maternal physiologic and immune function changes during pregnancy, pregnant women may be at a higher risk of being infected with SARS-CoV-2 and developing more complicated clinical events. Information on severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) may provide insights into the effects of COVID-19's during pregnancy. Even though SARS and MERS have been associated with miscarriage, intrauterine death, fetal growth restriction and high case fatality rates, the clinical course of COVID-19 pneumonia in pregnant women has been reported to be similar to that in non-pregnant women. In addition, pregnant women do not appear to be at a higher risk of catching COVID-19 or suffering from more severe disease than other adults of similar age. Moreover, there is currently no evidence that the virus can be transmitted to the fetus during pregnancy or during childbirth. Babies and young children are also known to only experience mild forms of COVID-19. The aims of this systematic review were to summarize the possible symptoms, treatments, and pregnancy outcomes of women infected with COVID-19 during pregnancy.


Subject(s)
COVID-19/epidemiology , Infectious Disease Transmission, Vertical , Pregnancy Complications, Infectious/epidemiology , Pregnancy Outcome , SARS-CoV-2/immunology , Adult , COVID-19/immunology , COVID-19/therapy , COVID-19/transmission , Female , Humans , Infant, Newborn , Maternal Exposure , Middle East Respiratory Syndrome Coronavirus/immunology , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/therapy , Pregnancy Complications, Infectious/virology , SARS Virus/immunology , SARS-CoV-2/isolation & purification , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index
9.
Rev. latinoam. enferm. (Online) ; 29: e3494, 2021. graf
Article in English | LILACS (Americas) | ID: covidwho-1511859

ABSTRACT

Objective: to analyze, in the scientific literature, the knowledge available on the use of the prone position in pregnant women diagnosed with COVID-19 or other health conditions. Method: an integrative literature review developed through the following guiding question: What is the scientific knowledge available on the use of the prone position in pregnant women with COVID-19 or other health conditions? The search for studies was carried out in eight databases. Results: using the prone position in pregnant women with Acute Respiratory Distress syndrome allowed for improvements in lung compliance and oxygenation. It also allowed reducing uterine compression on the maternal large vessels, and a reduction in blood pressure was observed in pregnant women with pre-eclampsia. The prone position was also safe in the surgical management of pregnant patients. In addition, the following conditions stood out as disadvantages related to the prone position in pregnant women: possibility of aortocaval compression, causing severe hypotension, and inability to easily monitor fetal status or to perform emergency Cesarean sections. Conclusion: the prone position was considered safe, reliable and comfortable for its use in the clinical management of pregnant women, where specific care measures must be taken to avoid compression of gravid abdomen, as well as fetal monitoring is important to detect placental circulation impairment.


Objetivo: analizar, en la literatura científica, el conocimiento disponible sobre el uso de la posición prona en gestantes diagnosticadas con COVID-19 u otras condiciones de salud. Método: revisión integradora de la literatura desarrollada a través de la siguiente pregunta orientadora: ¿Qué conocimiento científico está disponible sobre la aplicación de la posición prona en gestantes con COVID-19 u otras condiciones de salud? La búsqueda de estudios se realizó en ocho bases de datos. Resultados: colocar a las gestantes con Síndrome de Dificultad Respiratoria Aguda en posición prona permitió mejorar la distensibilidad pulmonar y la oxigenación. También permitió una reducción de la compresión uterina de los grandes vasos maternos y se observó una reducción de la presión arterial en gestantes con preeclampsia. La posición prona también demostró ser segura en el manejo quirúrgico de pacientes embarazadas. Además, se destacaron desventajas relacionadas con la posición prona en la gestante: posibilidad de que ocurra una compresión aortocava, que provoque hipotensión severa, y la imposibilidad de monitorear fácilmente el estado fetal o realizar una cesárea de emergencia. Conclusión: la aplicación de la posición prona para el manejo clínico de la gestante se consideró segura, confiable y cómoda, se deben implementar cuidados específicos para evitar la compresión del vientre materno y monitorear al feto para detectar si la circulación placentaria está comprometida.


Objetivo: analisar, na literatura científica, o conhecimento disponível sobre a utilização da posição prona em gestantes diagnosticadas com COVID-19 ou outras condições de saúde. Método: revisão integrativa da literatura desenvolvida mediante a seguinte questão norteadora: Qual o conhecimento científico disponível sobre a aplicação da posição prona em gestantes com COVID-19 ou outras condições de saúde? A busca de estudos foi realizada em oito bases de dados. Resultados: a aplicação da posição prona em gestantes com Síndrome do Desconforto Respiratório Agudo permitiu a melhora na complacência pulmonar e na oxigenação. Também possibilitou redução da compressão uterina sobre grandes vasos maternos e foi observada redução da pressão arterial em gestantes com pré-eclâmpsia. A posição prona também se mostrou segura no manejo cirúrgico de pacientes grávidas. Ademais, destacaram-se como desvantagens relacionadas à posição prona em gestantes: a possibilidade de ocorrência de compressão aortocaval, causando hipotensão grave, e a incapacidade de monitorar facilmente o estado fetal ou realizar cesariana de emergência. Conclusão: a posição prona foi considerada segura, confiável e confortável para aplicação no manejo clínico de gestantes, na qual cuidados específicos devem ser tomados para evitar compressão do abdome gravídico, assim como é relevante a monitorização fetal para detectar comprometimento de circulação placentária.


Subject(s)
Humans , Female , Pregnancy , Placenta , Prone Position , SARS Virus , COVID-19
10.
Vox Sang ; 115(3): 146-151, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-1508355

ABSTRACT

BACKGROUND: Emerging viruses like severe acute respiratory syndrome coronavirus (SARS-CoV), Crimean-Congo haemorrhagic fever virus (CCHFV) and Nipah virus (NiV) have been identified to pose a potential threat to transfusion safety. In this study, the ability of the THERAFLEX UV-Platelets and THERAFLEX MB-Plasma pathogen inactivation systems to inactivate these viruses in platelet concentrates and plasma, respectively, was investigated. MATERIALS AND METHODS: Blood products were spiked with SARS-CoV, CCHFV or NiV, and then treated with increasing doses of UVC light (THERAFLEX UV-Platelets) or with methylene blue (MB) plus increasing doses of visible light (MB/light; THERAFLEX MB-Plasma). Samples were taken before and after treatment with each illumination dose and tested for residual infectivity. RESULTS: Treatment with half to three-fourths of the full UVC dose (0·2 J/cm2 ) reduced the infectivity of SARS-CoV (≥3·4 log), CCHFV (≥2·2 log) and NiV (≥4·3 log) to the limit of detection (LOD) in platelet concentrates, and treatment with MB and a fourth of the full light dose (120 J/cm2 ) decreased that of SARS-CoV (≥3·1 log), CCHFV (≥3·2 log) and NiV (≥2·7 log) to the LOD in plasma. CONCLUSION: Our study demonstrates that both THERAFLEX UV-Platelets (UVC) and THERAFLEX MB-Plasma (MB/light) effectively reduce the infectivity of SARS-CoV, CCHFV and NiV in platelet concentrates and plasma, respectively.


Subject(s)
Hemorrhagic Fever Virus, Crimean-Congo/radiation effects , Light , Methylene Blue/pharmacology , Nipah Virus/radiation effects , SARS Virus/radiation effects , Ultraviolet Rays , Virus Inactivation , Blood Platelets/virology , Blood Transfusion , Hemorrhagic Fever Virus, Crimean-Congo/drug effects , Humans , Nipah Virus/drug effects , Plasma/virology , SARS Virus/drug effects
11.
Sci Rep ; 11(1): 22042, 2021 11 11.
Article in English | MEDLINE | ID: covidwho-1510622

ABSTRACT

The mutation of SARS-CoV-2 influences viral function as residue replacements affect both physiochemical properties and folding conformations. Although a large amount of data on SARS-CoV-2 is available, the investigation of how viral functions change in response to mutations is hampered by a lack of effective structural analysis. Here, we exploit the advances of protein structure fingerprint technology to study the folding conformational changes induced by mutations. With integration of both protein sequences and folding conformations, the structures are aligned for SARS-CoV to SARS-CoV-2, including Alpha variant (lineage B.1.1.7) and Delta variant (lineage B.1.617.2). The results showed that the virus evolution with change in mutational positions and physicochemical properties increased the affinity between spike protein and ACE2, which plays a critical role in coronavirus entry into human cells. Additionally, these structural variations impact vaccine effectiveness and drug function over the course of SARS-CoV-2 evolution. The analysis of structural variations revealed how the coronavirus has gradually evolved in both structure and function and how the SARS-CoV-2 variants have contributed to more severe acute disease worldwide.


Subject(s)
COVID-19/virology , Evolution, Molecular , Mutation , SARS-CoV-2/genetics , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Humans , Models, Molecular , Protein Conformation , Protein Folding , Protein Interaction Maps , Protein Multimerization , SARS Virus/chemistry , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Sequence Alignment , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
12.
ScientificWorldJournal ; 2021: 9342748, 2021.
Article in English | MEDLINE | ID: covidwho-1495720

ABSTRACT

Background: Recently, an outbreak of a novel human coronavirus SARS-CoV-2 has become a world health concern leading to severe respiratory tract infections in humans. Virus transmission occurs through person-to-person contact, respiratory droplets, and contaminated hands or surfaces. Accordingly, we aim at reviewing the literature on all information available about the persistence of coronaviruses, including human and animal coronaviruses, on inanimate surfaces and inactivation strategies with biocides employed for chemical and physical disinfection. Method: A comprehensive search was systematically conducted in main databases from 1998 to 2020 to identify various viral disinfectants associated with HCoV and methods for control and prevention of this newly emerged virus. Results: The analysis of 62 studies shows that human coronaviruses such as severe acute respiratory syndrome (SARS) coronavirus, Middle East respiratory syndrome (MERS) coronavirus or endemic human coronaviruses (HCoV), canine coronavirus (CCV), transmissible gastroenteritis virus (TGEV), and mouse hepatitis virus (MHV) can be efficiently inactivated by physical and chemical disinfectants at different concentrations (70, 80, 85, and 95%) of 2-propanol (70 and 80%) in less than or equal to 60 s and 0.5% hydrogen peroxide or 0.1% sodium hypochlorite within 1 minute. Additionally, glutaraldehyde (0.5-2%), formaldehyde (0.7-1%), and povidone-iodine (0.1-0.75%) could readily inactivate coronaviruses. Moreover, dry heat at 56°C, ultraviolet light dose of 0.2 to 140 J/cm2, and gamma irradiation could effectively inactivate coronavirus. The WHO recommends the use of 0.1% sodium hypochlorite solution or an ethanol-based disinfectant with an ethanol concentration between 62% and 71%. Conclusion: The results of the present study can help researchers, policymakers, health decision makers, and people perceive and take the correct measures to control and prevent further transmission of COVID-19. Prevention and decontamination will be the main ways to stop the ongoing outbreak of COVID-19.


Subject(s)
COVID-19/prevention & control , Disinfectants/pharmacology , Disinfection/instrumentation , SARS-CoV-2 , Virus Inactivation/drug effects , 2-Propanol/pharmacology , Animals , COVID-19/virology , Coronavirus, Canine/drug effects , Disinfection/methods , Ethanol/pharmacology , Formaldehyde/pharmacology , Gamma Rays , Glutaral/pharmacology , Hot Temperature , Humans , Hydrogen Peroxide/pharmacology , Mice , Middle East Respiratory Syndrome Coronavirus/drug effects , Murine hepatitis virus/drug effects , Povidone-Iodine/pharmacology , SARS Virus/drug effects , Sodium Hypochlorite/pharmacology , Transmissible gastroenteritis virus/drug effects , Ultraviolet Rays
13.
mBio ; 12(5): e0234221, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1494971

ABSTRACT

The recent emergence and spread of zoonotic viruses highlights that animal-sourced viruses are the biggest threat to global public health. Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an HKU2-related bat coronavirus that was spilled over from Rhinolophus bats to swine, causing large-scale outbreaks of severe diarrhea disease in piglets in China. Unlike other porcine coronaviruses, SADS-CoV possesses broad species tissue tropism, including primary human cells, implying a significant risk of cross-species spillover. To explore host dependency factors for SADS-CoV as therapeutic targets, we employed genome-wide CRISPR knockout library screening in HeLa cells. Consistent with two independent screens, we identified the zinc finger DHHC-type palmitoyltransferase 17 (ZDHHC17 or ZD17) as an important host factor for SADS-CoV infection. Through truncation mutagenesis, we demonstrated that the DHHC domain of ZD17 that is involved in palmitoylation is important for SADS-CoV infection. Mechanistic studies revealed that ZD17 is required for SADS-CoV genomic RNA replication. Treatment of infected cells with the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly suppressed SADS-CoV infection. Our findings provide insight on SADS-CoV-host interactions and a potential therapeutic application. IMPORTANCE The recent emergence of deadly zoonotic viral diseases, including Ebola virus and SARS-CoV-2, emphasizes the importance of pandemic preparedness for the animal-sourced viruses with potential risk of animal-to-human spillover. Over the last 2 decades, three significant coronaviruses of bat origin, SARS-CoV, MERS-CoV, and SARS-CoV-2, have caused millions of deaths with significant economy and public health impacts. Lack of effective therapeutics against these coronaviruses was one of the contributing factors to such losses. Although SADS-CoV, another coronavirus of bat origin, was only known to cause fatal diarrhea disease in piglets, the ability to infect cells derived from multiple species, including human, highlights the potential risk of animal-to-human spillover. As part of our effort in pandemic preparedness, we explore SADS-CoV host dependency factors as targets for host-directed therapeutic development and found zinc finger DHHC-type palmitoyltransferase 17 is a promising drug target against SADS-CoV replication. We also demonstrated that a palmitoylation inhibitor, 2-bromopalmitate (2-BP), can be used as an inhibitor for SADS-CoV treatment.


Subject(s)
Acyltransferases/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Alphacoronavirus/pathogenicity , Nerve Tissue Proteins/metabolism , Acyltransferases/genetics , Adaptor Proteins, Signal Transducing/genetics , Alphacoronavirus/drug effects , Animals , COVID-19/metabolism , HeLa Cells , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Nerve Tissue Proteins/genetics , Palmitates/pharmacology , SARS Virus/drug effects , SARS Virus/pathogenicity , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Swine
14.
Anaesthesia ; 77(1): 22-27, 2022 01.
Article in English | MEDLINE | ID: covidwho-1483808

ABSTRACT

Manual facemask ventilation, a core component of elective and emergency airway management, is classified as an aerosol-generating procedure. This designation is based on one epidemiological study suggesting an association between facemask ventilation and transmission during the SARS-CoV-1 outbreak in 2003. There is no direct evidence to indicate whether facemask ventilation is a high-risk procedure for aerosol generation. We conducted aerosol monitoring during routine facemask ventilation and facemask ventilation with an intentionally generated leak in anaesthetised patients. Recordings were made in ultraclean operating theatres and compared against the aerosol generated by tidal breathing and cough manoeuvres. Respiratory aerosol from tidal breathing in 11 patients was reliably detected above the very low background particle concentrations with median [IQR (range)] particle counts of 191 (77-486 [4-1313]) and 2 (1-5 [0-13]) particles.l-1 , respectively, p = 0.002. The median (IQR [range]) aerosol concentration detected during facemask ventilation without a leak (3 (0-9 [0-43]) particles.l-1 ) and with an intentional leak (11 (7-26 [1-62]) particles.l-1 ) was 64-fold (p = 0.001) and 17-fold (p = 0.002) lower than that of tidal breathing, respectively. Median (IQR [range]) peak particle concentration during facemask ventilation both without a leak (60 (0-60 [0-120]) particles.l-1 ) and with a leak (120 (60-180 [60-480]) particles.l-1 ) were 20-fold (p = 0.002) and 10-fold (0.001) lower than a cough (1260 (800-3242 [100-3682]) particles.l-1 ), respectively. This study demonstrates that facemask ventilation, even when performed with an intentional leak, does not generate high levels of bioaerosol. On the basis of this evidence, we argue facemask ventilation should not be considered an aerosol-generating procedure.


Subject(s)
Masks , /chemistry , Adult , Aged , Cough/etiology , Female , Humans , Male , Middle Aged , SARS Virus/isolation & purification , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology
15.
Eur J Endocrinol ; 185(1): 137-144, 2021 May 28.
Article in English | MEDLINE | ID: covidwho-1477604

ABSTRACT

Objective: Hyponatremia is the most common electrolyte disorder in hospitalized patients and occurs in about 30% of patients with pneumonia. Hyponatremia has been associated with a worse outcome in several pathologic conditions The main objective of this study was to determine whether serum sodium alterations may be independent predictors of the outcome of hospitalized COVID-19 patients. Design and methods: In this observational study, data from 441 laboratory-confirmed COVID-19 patients admitted to a University Hospital were collected. After excluding 61 patients (no serum sodium at admission available, saline solution infusion before sodium assessment, transfer from another hospital), data from 380 patients were analyzed. Results: 274 (72.1%) patients had normonatremia at admission, 87 (22.9%) patients had hyponatremia and 19 (5%) patients had hypernatremia. We found an inverse correlation between serum sodium and IL-6, whereas a direct correlation between serum sodium and PaO2/FiO2 ratio was observed. Patients with hyponatremia had a higher prevalence of non-invasive ventilation and ICU transfer than those with normonatremia or hypernatremia. Hyponatremia was an independent predictor of in-hospital mortality (2.7-fold increase vs normonatremia) and each mEq/L of serum sodium reduction was associated with a 14.4% increased risk of death. Conclusions: These results suggest that serum sodium at admission may be considered as an early prognostic marker of disease severity in hospitalized COVID-19 patients.


Subject(s)
COVID-19/blood , SARS-CoV-2 , Severity of Illness Index , Sodium/blood , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/mortality , Comorbidity , Critical Care/statistics & numerical data , Female , Fluorocarbons/blood , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Hydrocarbons, Brominated/blood , Hypernatremia/epidemiology , Hyponatremia/epidemiology , Interleukin-6/blood , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS Virus
16.
Nat Commun ; 12(1): 6055, 2021 10 18.
Article in English | MEDLINE | ID: covidwho-1475294

ABSTRACT

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/administration & dosage , Indoles/administration & dosage , Leucine/administration & dosage , Pyrrolidinones/administration & dosage , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacokinetics , Alanine/administration & dosage , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/pharmacokinetics , Animals , COVID-19/virology , Chlorocebus aethiops , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/enzymology , Coronavirus Protease Inhibitors/adverse effects , Coronavirus Protease Inhibitors/pharmacokinetics , Disease Models, Animal , Drug Design , Drug Synergism , Drug Therapy, Combination , HeLa Cells , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Infusions, Intravenous , Leucine/adverse effects , Leucine/pharmacokinetics , Mice , Pyrrolidinones/adverse effects , Pyrrolidinones/pharmacokinetics , SARS Virus/drug effects , SARS Virus/enzymology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Vero Cells
17.
Signal Transduct Target Ther ; 6(1): 367, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475287

ABSTRACT

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.


Subject(s)
Cytokine Release Syndrome , Signal Transduction/immunology , Acute Disease , Autoimmune Diseases/complications , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Graft vs Host Disease/complications , Graft vs Host Disease/immunology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive/adverse effects , Influenza, Human/complications , Influenza, Human/immunology , Neoplasms/complications , Neoplasms/immunology , Neoplasms/therapy , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/therapy
18.
Viruses ; 13(10)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470996

ABSTRACT

Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1ß. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1ß release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.


Subject(s)
Immunity, Innate/immunology , Inflammasomes/immunology , Macrophages/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Viral Envelope Proteins/immunology , Viral Fusion Proteins/immunology , Cell Line, Tumor , Cytomegalovirus/immunology , Hepacivirus/immunology , Humans , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Pyroptosis/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , THP-1 Cells
19.
J Exp Med ; 218(12)2021 12 06.
Article in English | MEDLINE | ID: covidwho-1462245

ABSTRACT

Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.


Subject(s)
Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Polysaccharides/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Motifs , Animals , COVID-19/genetics , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Female , Humans , Male , Mice , Mice, Inbred BALB C , Polysaccharides/genetics , Protein Domains , SARS Virus/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
20.
J Med Case Rep ; 15(1): 505, 2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1463266

ABSTRACT

BACKGROUND: The clinical presentation of severe acute respiratory syndrome coronavirus-2 infection is highly variable from asymptomatic infection to fulminant disease. The reasons for the variation are only starting to unravel, with risk factors including age and certain comorbidities as well as genetic defects causing immunological perturbations in the interferon pathways. CASE PRESENTATION: We report the case of an otherwise healthy Caucasian man, who at ages 60 and 64 years suffered from severe H1N1 influenza virus infection and severe acute respiratory syndrome coronavirus-2 infections, respectively. In both cases, there were acute kidney impairment and the need for intensive care unit admission as well as mechanical ventilation. Fortunately, after both infections there was full clinical recovery. The severity of the infections indicates an underlying impairment in the ability to control these kinds of infections. Challenge of patient peripheral blood mononuclear cells showed impaired type I and III antiviral interferon responses and reduced interferon-stimulated gene expression. However, despite investigation of patient samples by whole exome sequencing and enzyme-linked immunosorbent assay, no known disease-causing genetic variants related to interferon pathways were found, nor were interferon autoantibodies demonstrated. Thus, any underlying immunological cause of this unusual susceptibility to severe viral infections remains unresolved. CONCLUSION: The patient experienced very similar severe clinical pictures triggered by H1N1 and severe acute respiratory syndrome coronavirus-2 infections, indicating an underlying inability to contain these infections. We were unable to show that the patient had any of the currently known types of immune incompetence but identified genetic changes possibly contributing to the severe course of both infections. Further analyses to delineate contribution factors are needed.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , SARS Virus , Humans , Leukocytes, Mononuclear , Male , Middle Aged , SARS-CoV-2
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