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1.
Frontiers in molecular biosciences ; 9, 2022.
Article in English | EuropePMC | ID: covidwho-1863974

ABSTRACT

The ongoing pandemic coronavirus disease (COVID-19) caused by a novel corona virus, namely, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had a major impact on global public health. COVID-19 cases continue to increase across the globe with high mortality rates in immunocompromised patients. There is still a pressing demand for drug discovery and vaccine development against this highly contagious disease. To design and develop antiviral drugs against COVID-19, the main protease (Mpro) has emerged as one of the important drug targets. In this context, the present work explored Jadwar (Delphinium denudatum)–derived natural alkaloids as potential inhibitors against Mpro of SARS-CoV-2 by employing a combination of molecular docking and molecular dynamic simulation–based methods. Molecular docking and interaction profile analysis revealed strong binding on the Mpro functional domain with four natural alkaloids viz. panicutine (−7.4 kcal/mol), vilmorrianone (−7.0 kcal/mol), denudatine (−6.0 kcal/mol), and condelphine (−5.9 kcal/mol). The molecular docking results evaluated by using the MD simulations on 200 nanoseconds confirmed highly stable interactions of these compounds with the Mpro. Additionally, mechanics/generalized Born/Poisson–Boltzmann surface area (MM/G/P/BSA) free energy calculations also affirmed the docking results. Natural alkaloids explored in the present study possess the essential drug-likeness properties, namely, absorption, distribution, metabolism, and excretion (ADME), and are in accordance with Lipinski’s rule of five. The results of this study suggest that these four bioactive molecules, namely, condelphine, denudatine, panicutine, and vilmorrianone, might be effective candidates against COVID-19 and can be further investigated using a number of experimental methods.

2.
Front Public Health ; 10: 846115, 2022.
Article in English | MEDLINE | ID: covidwho-1753422

ABSTRACT

In December 2019, a novel coronavirus emerged in Wuhan, China, rapidly spreading into a global pandemic. Italy was the first European country to experience SARS-CoV-2 epidemic, and one of the most severely affected during the first wave of diffusion. In contrast to the general restriction of people movements in Europe, the number of migrants arriving at Italian borders via the Mediterranean Sea route in the summer of 2020 had increased dramatically, representing a possible, uncontrolled source for the introduction of novel SARS-CoV-2 variants. Importantly, most of the migrants came from African countries showing limited SARS-CoV-2 epidemiological surveillance. In this study, we characterized the SARS-CoV-2 genome isolated from an asymptomatic migrant arrived in Sardinia via the Mediterranean route in September 2020, in comparison with SARS-CoV-2 isolates arrived in Sicily through the Libyan migration route; with SARS-CoV-2 isolates circulating in Sardinia during 2020; and with viral genomes reported in African countries during the same summer. Results showed that our sequence is not phylogenetically related to isolates from migrants arriving in Sicily, nor to isolates circulating in Sardinia territory, having greater similarity to SARS-CoV-2 genomes reported in countries known for being sites of migrant embarkation to Italy. This is in line with the hypothesis that most SARS-CoV-2 infections among migrants have been acquired prior to embarking to Italy, possibly during the travel to or the stay in crowded Libyan immigrant camps. Overall, these observations underline the importance of dedicated SARS-CoV-2 surveillance of migrants arriving in Italy and in Europe through the Mediterranean routes.


Subject(s)
COVID-19 , Transients and Migrants , COVID-19/epidemiology , Genomics , Humans , Mediterranean Sea , SARS-CoV-2/genetics
4.
J Intern Med ; 291(2): 232-240, 2022 02.
Article in English | MEDLINE | ID: covidwho-1455598

ABSTRACT

BACKGROUND: Anti-SARS-CoV-2 S antibodies prevent viral replication. Critically ill COVID-19 patients show viral material in plasma, associated with a dysregulated host response. If these antibodies influence survival and viral dissemination in ICU-COVID patients is unknown. PATIENTS/METHODS: We studied the impact of anti-SARS-CoV-2 S antibodies levels on survival, viral RNA-load in plasma, and N-antigenaemia in 92 COVID-19 patients over ICU admission. RESULTS: Frequency of N-antigenaemia was >2.5-fold higher in absence of antibodies. Antibodies correlated inversely with viral RNA-load in plasma, representing a protective factor against mortality (adjusted HR [CI 95%], p): (S IgM [AUC ≥ 60]: 0.44 [0.22; 0.88], 0.020); (S IgG [AUC ≥ 237]: 0.31 [0.16; 0.61], <0.001). Viral RNA-load in plasma and N-antigenaemia predicted increased mortality: (N1-viral load [≥2.156 copies/ml]: 2.25 [1.16; 4.36], 0.016); (N-antigenaemia: 2.45 [1.27; 4.69], 0.007). CONCLUSIONS: Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. Our findings support that these antibodies contribute to prevent systemic dissemination of SARS-CoV-2.


Subject(s)
Antibodies, Viral/blood , Antigens, Viral/blood , COVID-19 , COVID-19/immunology , COVID-19/mortality , Critical Illness , Humans , RNA, Viral/blood , SARS-CoV-2
6.
EClinicalMedicine ; 37: 100975, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1284051

ABSTRACT

BACKGROUND: The SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2) has led to more than 165 million COVID-19 cases and >3.4 million deaths worldwide. Epidemiological analysis has revealed that the risk of developing severe COVID-19 increases with age. Despite a disproportionate number of older individuals and long-term care facilities being affected by SARS-CoV-2 and COVID-19, very little is understood about the immune responses and development of humoral immunity in the extremely old person after SARS-CoV-2 infection. Here we conducted a serological study to investigate the development of humoral immunity in centenarians following a SARS-CoV-2 outbreak in a long-term care facility. METHODS: Extreme aged individuals and centenarians who were residents in a long-term care facility and infected with or exposed to SARS-CoV-2 were investigated between April and June 2020 for the development of antibodies to SARS-CoV-2. Blood samples were collected from positive and bystander individuals 30 and 60 days after original diagnosis of SARS-CoV-2 infection. Plasma was used to quantify IgG, IgA, and IgM isotypes and subsequent subclasses of antibodies specific for SARS-CoV-2 spike protein. The function of anti-spike was then assessed by virus neutralization assays against the native SARS-CoV-2 virus. FINDINGS: Fifteen long-term care residents were investigated for SARS-CoV-2 infection. All individuals had a Clinical Frailty scale score ≥5 and were of extreme older age or were centenarians. Six women with a median age of 98.8 years tested positive for SARS-CoV-2. Anti-spike IgG antibody titers were the highest titers observed in our cohort with all IgG positive individuals having virus neutralization ability. Additionally, 5 out of the 6 positive participants had a robust IgA anti-SARS-CoV-2 response. In all 5, antibodies were detected after 60 days from initial diagnosis.

8.
Eur J Clin Invest ; 51(6): e13501, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1054522

ABSTRACT

BACKGROUND: The presence of SARS-CoV-2 RNA in plasma has been linked to disease severity and mortality. We compared RT-qPCR to droplet digital PCR (ddPCR) to detect SARS-CoV-2 RNA in plasma from COVID-19 patients (mild, moderate, and critical disease). METHODS: The presence/concentration of SARS-CoV-2 RNA in plasma was compared in three groups of COVID-19 patients (30 outpatients, 30 ward patients and 30 ICU patients) using both RT-qPCR and ddPCR. Plasma was obtained in the first 24h following admission, and RNA was extracted using eMAG. ddPCR was performed using Bio-Rad SARS-CoV-2 detection kit, and RT-qPCR was performed using GeneFinder™ COVID-19 Plus RealAmp Kit. Statistical analysis was performed using Statistical Package for the Social Science. RESULTS: SARS-CoV-2 RNA was detected, using ddPCR and RT-qPCR, in 91% and 87% of ICU patients, 27% and 23% of ward patients and 3% and 3% of outpatients. The concordance of the results obtained by both methods was excellent (Cohen's kappa index = 0.953). RT-qPCR was able to detect 34/36 (94.4%) patients positive for viral RNA in plasma by ddPCR. Viral RNA load was higher in ICU patients compared with the other groups (P < .001), by both ddPCR and RT-qPCR. AUC analysis revealed Ct values (RT-qPCR) and viral RNA load values (ddPCR) can similarly differentiate between patients admitted to wards and to the ICU (AUC of 0.90 and 0.89, respectively). CONCLUSION: Both methods yielded similar prevalence of RNAemia between groups, with ICU patients showing the highest (>85%). RT-qPCR was as useful as ddPCR to detect and quantify SARS-CoV-2 RNAemia in plasma.


Subject(s)
COVID-19/blood , RNA, Viral/blood , Real-Time Polymerase Chain Reaction/methods , Aged , Ambulatory Care , Female , Humans , Intensive Care Units , Male , Middle Aged , Patients' Rooms , Polymerase Chain Reaction/methods , SARS-CoV-2/genetics , Severity of Illness Index
9.
J Infect Dev Ctries ; 14(1): 1-2, 2020 01 31.
Article in English | MEDLINE | ID: covidwho-826993
10.
J Infect Dev Ctries ; 14(5): 428-432, 2020 05 31.
Article in English | MEDLINE | ID: covidwho-596261

ABSTRACT

Older adults have been disproportionately affected by the COVID-19 pandemic, with many outbreaks occurring in Long Term Care Facilities (LTCFs). We discuss this vulnerability among LTCF residents using an ecological framework, on levels spanning from the individual to families and caregivers, institutions, health services and systems, communities, and contextual government policies. Challenges abound for fully understanding the burden of COVID-19 in LTCF, including differences in nomenclature, data collection systems, cultural differences, varied social welfare models, and (often) under-resourcing of the LTC sector. Registration of cases and deaths may be limited by testing capacity and policy, record-keeping and reporting procedures. Hospitalization and death rates may be inaccurate depending on atypical presentations and whether or not residents' goals of care include escalation of care and transfer to hospital. Given the important contribution of frailty, use of the Clinical Frailty Scale (CFS) is discussed as a readily implementable measure, as are lessons learned from the study of frailty in relation to influenza. Biomarkers hold emerging promise in helping to predict disease severity and address the puzzle of why some frail LTCF residents are resilient to COVID-19, either remaining test-negative despite exposure or having asymptomatic infection, while others experience the full range of illness severity including critical illness and death. Strong and coordinated surveillance and research focused on LTCFs and their frail residents is required. These efforts should include widespread assessment of frailty using feasible and readily implementable tools such as the CFS, and rigorous reporting of morbidity and mortality in LTCFs.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Frailty , Long-Term Care , Pneumonia, Viral/epidemiology , COVID-19 , Health Policy , Humans , Pandemics , Resilience, Psychological , SARS-CoV-2 , Severity of Illness Index
11.
Cell ; 182(2): 429-446.e14, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-381993

ABSTRACT

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiratory System/virology , Reverse Genetics/methods , Aged , Angiotensin-Converting Enzyme 2 , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Cell Line , Cells, Cultured , Chlorocebus aethiops , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Cystic Fibrosis/pathology , DNA, Recombinant , Female , Furin/metabolism , Humans , Immunization, Passive , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Nasal Mucosa/metabolism , Nasal Mucosa/pathology , Nasal Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/immunology , Respiratory System/pathology , SARS-CoV-2 , Serine Endopeptidases/metabolism , Vero Cells , Virulence , Virus Replication
14.
J Infect Dev Ctries ; 14(1): 3-17, 2020 01 31.
Article in English | MEDLINE | ID: covidwho-1512

ABSTRACT

On 31 December 2019 the Wuhan Health Commission reported a cluster of atypical pneumonia cases that was linked to a wet market in the city of Wuhan, China. The first patients began experiencing symptoms of illness in mid-December 2019. Clinical isolates were found to contain a novel coronavirus with similarity to bat coronaviruses. As of 28 January 2020, there are in excess of 4,500 laboratory-confirmed cases, with > 100 known deaths. As with the SARS-CoV, infections in children appear to be rare. Travel-related cases have been confirmed in multiple countries and regions outside mainland China including Germany, France, Thailand, Japan, South Korea, Vietnam, Canada, and the United States, as well as Hong Kong and Taiwan. Domestically in China, the virus has also been noted in several cities and provinces with cases in all but one provinence. While zoonotic transmission appears to be the original source of infections, the most alarming development is that human-to-human transmission is now prevelant. Of particular concern is that many healthcare workers have been infected in the current epidemic. There are several critical clinical questions that need to be resolved, including how efficient is human-to-human transmission? What is the animal reservoir? Is there an intermediate animal reservoir? Do the vaccines generated to the SARS-CoV or MERS-CoV or their proteins offer protection against 2019-nCoV? We offer a research perspective on the next steps for the generation of vaccines. We also present data on the use of in silico docking in gaining insight into 2019-nCoV Spike-receptor binding to aid in therapeutic development. Diagnostic PCR protocols can be found at https://www.who.int/health-topics/coronavirus/laboratory-diagnostics-for-novel-coronavirus.


Subject(s)
Betacoronavirus , Coronavirus Infections/transmission , Disease Reservoirs/veterinary , Disease Transmission, Infectious , Pneumonia, Viral/transmission , Animals , Betacoronavirus/genetics , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Disease Reservoirs/virology , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Sequence Analysis, Protein , Travel , Vaccination , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Vaccines , Zoonoses
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