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1.
Antiviral Res ; 200: 105270, 2022 04.
Article in English | MEDLINE | ID: covidwho-1763566

ABSTRACT

The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation elongation factor 1 alpha) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.


Subject(s)
COVID-19 , Depsipeptides , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chlorocebus aethiops , Depsipeptides/pharmacology , Peptides, Cyclic , SARS-CoV-2 , Vero Cells , Virus Replication
2.
Cell Rep Med ; 3(2): 100523, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1751231

ABSTRACT

To understand the determinants of long-term immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the concurrent impact of vaccination and emerging variants, we follow a prospective cohort of 332 patients with coronavirus disease 2019 (COVID-19) over more than a year after symptom onset. We evaluate plasma-neutralizing activity using HIV-based pseudoviruses expressing the spike of different SARS-CoV-2 variants and analyze them longitudinally using mixed-effects models. Long-term neutralizing activity is stable beyond 1 year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while the responses of non-hospitalized individuals are dominated by long-lived B cells. In both groups, vaccination boosts responses to natural infection. Long-term (>300 days from infection) responses in unvaccinated participants show a reduced efficacy against beta, but not alpha nor delta, variants. Multivariate analysis identifies the severity of primary infection as an independent determinant of higher magnitude and lower relative cross-neutralization activity of long-term neutralizing responses.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Adult , Aged , B-Lymphocytes/immunology , COVID-19/blood , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/therapeutic use , Female , Follow-Up Studies , Humans , Immunologic Memory , Kinetics , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , Treatment Outcome , Vaccination/methods , Young Adult
3.
Vet Pathol ; 59(4): 613-626, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1582698

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory disease, but it can also affect other organs including the central nervous system. Several animal models have been developed to address different key questions related to Coronavirus Disease 2019 (COVID-19). Wild-type mice are minimally susceptible to certain SARS-CoV-2 lineages (beta and gamma variants), whereas hACE2-transgenic mice succumb to SARS-CoV-2 and develop a fatal neurological disease. In this article, we aimed to chronologically characterize SARS-CoV-2 neuroinvasion and neuropathology. Necropsies were performed at different time points, and the brain and olfactory mucosa were processed for histopathological analysis. SARS-CoV-2 virological assays including immunohistochemistry were performed along with a panel of antibodies to assess neuroinflammation. At 6 to 7 days post inoculation (dpi), brain lesions were characterized by nonsuppurative meningoencephalitis and diffuse astrogliosis and microgliosis. Vasculitis and thrombosis were also present and associated with occasional microhemorrhages and spongiosis. Moreover, there was vacuolar degeneration of virus-infected neurons. At 2 dpi, SARS-CoV-2 immunolabeling was only found in the olfactory mucosa, but at 4 dpi intraneuronal virus immunolabeling had already reached most of the brain areas. Maximal distribution of the virus was observed throughout the brain at 6 to 7 dpi except for the cerebellum, which was mostly spared. Our results suggest an early entry of the virus through the olfactory mucosa and a rapid interneuronal spread of the virus leading to acute encephalitis and neuronal damage in this mouse model.


Subject(s)
COVID-19 , Nervous System Diseases , Rodent Diseases , Angiotensin-Converting Enzyme 2 , Animals , Brain/pathology , COVID-19/veterinary , Disease Models, Animal , Mice , Mice, Transgenic , Nervous System Diseases/pathology , Nervous System Diseases/veterinary , Peptidyl-Dipeptidase A/metabolism , Rodent Diseases/pathology , SARS-CoV-2
4.
Viruses ; 13(12)2021 12 16.
Article in English | MEDLINE | ID: covidwho-1580429

ABSTRACT

Several cases of naturally infected dogs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported despite the apparently low susceptibility of this species. Here, we document the first reported case of infection caused by the Delta (B.1.617.2) variant of concern (VOC) in a dog in Spain that lived with several household members suffering from Coronavirus Infectious Disease 2019 (COVID-19). The animal displayed mild digestive and respiratory clinical signs and had a low viral load in the oropharyngeal swab collected at the first sampling. Whole-genome sequencing indicated infection with the Delta variant, coinciding with the predominant variant during the fifth pandemic wave in Spain. The dog seroconverted, as detected 21 days after the first sampling, and developed neutralizing antibodies that cross-neutralized different SARS-CoV-2 variants. This study further emphasizes the importance of studying the susceptibility of animal species to different VOCs and their potential role as reservoirs in the context of COVID-19.


Subject(s)
COVID-19/veterinary , Dog Diseases/virology , SARS-CoV-2/isolation & purification , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19/transmission , COVID-19/virology , Dog Diseases/diagnosis , Dog Diseases/transmission , Dogs , Female , Genome, Viral/genetics , Pets/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Viral Zoonoses/diagnosis , Viral Zoonoses/transmission , Viral Zoonoses/virology
5.
J Infect Dis ; 225(4): 587-592, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1569705

ABSTRACT

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since 2019 has made mask-wearing, physical distancing, hygiene, and disinfection complementary measures to control virus transmission. Especially for health facilities, we evaluated the efficacy of an UV-C autonomous robot to inactivate SARS-CoV-2 desiccated on potentially contaminated surfaces. ASSUM (autonomous sanitary sterilization ultraviolet machine) robot was used in an experimental box simulating a hospital intensive care unit room. Desiccated SARS-CoV-2 samples were exposed to UV-C in 2 independent runs of 5, 12, and 20 minutes. Residual virus was eluted from surfaces and viral titration was carried out in Vero E6 cells. ASSUM inactivated SARS-CoV-2 by ≥ 99.91% to ≥ 99.99% titer reduction with 12 minutes or longer of UV-C exposure and onwards and a minimum distance of 100cm between the device and the SARS-CoV-2 desiccated samples. This study demonstrates that ASSUM UV-C device is able to inactivate SARS-CoV-2 within a few minutes.


Subject(s)
COVID-19 , Robotics , SARS-CoV-2/radiation effects , Sterilization/methods , Ultraviolet Rays , Virus Inactivation/radiation effects , COVID-19/prevention & control , Hospitals , Humans
6.
Emerg Microbes Infect ; 11(1): 91-94, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1541488

ABSTRACT

In order to assess the risk of SARS-CoV-2 infection, transmission and reservoir development in swine, we combined results of an experimental and two observational studies. First, intranasal and intratracheal challenge of eight pigs did not result in infection, based on clinical signs and PCR on swab and lung tissue samples. Two serum samples returned a low positive result in virus neutralization, in line with findings in other infection experiments in pigs. Next, a retrospective observational study was performed in the Netherlands in the spring of 2020. Serum samples (N =417) obtained at slaughter from 17 farms located in a region with a high human case incidence in the first wave of the pandemic. Samples were tested with protein micro array, plaque reduction neutralization test and receptor-binding-domain ELISA. None of the serum samples was positive in all three assays, although six samples from one farm returned a low positive result in PRNT (titers 40-80). Therefore we conclude that serological evidence for large scale transmission was not observed. Finally, an outbreak of respiratory disease in pigs on one farm, coinciding with recent exposure to SARS-CoV-2 infected animal caretakers, was investigated. Tonsil swabs and paired serum samples were tested. No evidence for infection with SARS-CoV-2 was found. In conclusion, Although in both the experimental and the observational study few samples returned low antibody titer results in PRNT infection with SARS-CoV-2 was not confirmed. It was concluded that sporadic infections in the field cannot be excluded, but large-scale SARS-CoV-2 transmission among pigs is unlikely.


Subject(s)
COVID-19/veterinary , SARS-CoV-2/physiology , Swine Diseases/epidemiology , Swine Diseases/transmission , Swine Diseases/virology , Animals , Environmental Exposure , Netherlands/epidemiology , Public Health Surveillance , Retrospective Studies , Swine
8.
Viruses ; 13(9)2021 08 25.
Article in English | MEDLINE | ID: covidwho-1374532

ABSTRACT

To date, no evidence supports the fact that animals play a role in the epidemiology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus infectious disease 2019 (COVID-19). However, several animal species are naturally susceptible to SARS-CoV-2 infection. Besides pets (cats, dogs, Syrian hamsters, and ferrets) and farm animals (minks), different zoo animal species have tested positive for SARS-CoV-2 (large felids and non-human primates). After the summer of 2020, a second wave of SARS-CoV-2 infection occurred in Barcelona (Spain), reaching a peak of positive cases in November. During that period, four lions (Panthera leo) at the Barcelona Zoo and three caretakers developed respiratory signs and tested positive for the SARS-CoV-2 antigen. Lion infection was monitored for several weeks and nasal, fecal, saliva, and blood samples were taken at different time-points. SARS-CoV-2 RNA was detected in nasal samples from all studied lions and the viral RNA was detected up to two weeks after the initial viral positive test in three out of four animals. The SARS-CoV-2 genome was also detected in the feces of animals at different times. Virus isolation was successful only from respiratory samples of two lions at an early time-point. The four animals developed neutralizing antibodies after the infection that were detectable four months after the initial diagnosis. The partial SARS-CoV-2 genome sequence from one animal caretaker was identical to the sequences obtained from lions. Chronology of the events, the viral dynamics, and the genomic data support human-to-lion transmission as the origin of infection.


Subject(s)
Animal Diseases/virology , COVID-19/veterinary , Lions , SARS-CoV-2 , Animal Diseases/diagnosis , Animal Diseases/immunology , Animal Diseases/transmission , Animals , Animals, Wild , Animals, Zoo , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Enzyme-Linked Immunosorbent Assay , Female , Genome, Viral , Genomics/methods , Host-Pathogen Interactions/immunology , Male , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spain
9.
Open Forum Infect Dis ; 8(7): ofab329, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1337280

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfections have been reported; however, most cases are milder than the primary infection. We report the first case of a life-threatening critical presentation of a SARS-CoV-2 reinfection. METHODS: A 62-year-old man from Palamós (Spain) suffered a first mild coronavirus disease 2019 (COVID-19) episode in March 2020, confirmed by 2 independent SARS-CoV-2 nasopharyngeal polymerase chain reaction (PCR) assays and a normal radiograph. He recovered completely and tested negative on 2 consecutive PCRs. In August 2020, the patient developed a second SARS-CoV-2 infection with life-threatening bilateral pneumonia and Acute respiratory distress syndrome criteria, requiring COVID-19-specific treatment (remdesivir + dexamethasone) plus high-flow oxygen therapy. Nasopharyngeal swabs from the second episode were obtained for virus quantification by real-time PCR, for virus outgrowth and sequencing. In addition, plasma and peripheral blood mononuclear cells during the hospitalization period were used to determine SARS-CoV-2-specific humoral and T-cell responses. RESULTS: Genomic analysis of SARS-CoV-2 showed that the virus had probably originated shortly before symptom onset. When the reinfection occurred, the subject showed a weak immune response, with marginal humoral and specific T-cell responses against SARS-CoV-2. All antibody isotypes tested as well as SARS-CoV-2 neutralizing antibodies increased sharply after day 8 postsymptoms. A slight increase of T-cell responses was observed at day 19 after symptom onset. CONCLUSIONS: The reinfection was firmly documented and occurred in the absence of robust preexisting humoral and cellular immunity. SARS-CoV-2 immunity in some subjects is unprotective and/or short-lived; therefore, SARS-CoV-2 vaccine schedules inducing long-term immunity will be required to bring the pandemic under control.

10.
Transbound Emerg Dis ; 68(4): 1721-1725, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1319349

ABSTRACT

Conventional piglets were inoculated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through different routes, including intranasal, intratracheal, intramuscular and intravenous ones. Although piglets were not susceptible to SARS-CoV-2 and lacked lesions or viral RNA in tissues/swabs, seroconversion was observed in pigs inoculated parenterally (intramuscularly or intravenously).


Subject(s)
COVID-19 , Swine Diseases , Animals , COVID-19/veterinary , Disease Models, Animal , Disease Susceptibility/veterinary , RNA, Viral , SARS-CoV-2 , Swine , Swine Diseases/virology
11.
Viruses ; 13(6)2021 06 12.
Article in English | MEDLINE | ID: covidwho-1270125

ABSTRACT

With the spread of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is a need to assess the protection conferred by both previous infections and current vaccination. Here we tested the neutralizing activity of infected and/or vaccinated individuals against pseudoviruses expressing the spike of the original SARS-CoV-2 isolate Wuhan-Hu-1 (WH1), the D614G mutant and the B.1.1.7 variant. Our data show that parameters of natural infection (time from infection and nature of the infecting variant) determined cross-neutralization. Uninfected vaccinees showed a small reduction in neutralization against the B.1.1.7 variant compared to both the WH1 strain and the D614G mutant. Interestingly, upon vaccination, previously infected individuals developed more robust neutralizing responses against B.1.1.7, suggesting that vaccines can boost the neutralization breadth conferred by natural infection.


Subject(s)
Antibodies, Neutralizing/blood , COVID-19 Vaccines/immunology , COVID-19/immunology , Neutralization Tests/statistics & numerical data , SARS-CoV-2/immunology , Vaccination/statistics & numerical data , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , COVID-19/blood , COVID-19 Serological Testing/statistics & numerical data , COVID-19 Vaccines/administration & dosage , Cross Reactions/immunology , Female , Humans , Immunity, Humoral , Male , Middle Aged , Prospective Studies , SARS-CoV-2/genetics
12.
PLoS Pathog ; 17(5): e1009229, 2021 05.
Article in English | MEDLINE | ID: covidwho-1239922

ABSTRACT

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.


Subject(s)
Camelids, New World , Coronavirus Infections/immunology , Interferon Type I/metabolism , Interferons/metabolism , Middle East Respiratory Syndrome Coronavirus/immunology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Camelids, New World/immunology , Camelids, New World/metabolism , Camelids, New World/virology , Chlorocebus aethiops , Coronavirus Infections/metabolism , Coronavirus Infections/prevention & control , Coronavirus Infections/veterinary , Disease Reservoirs/veterinary , Disease Resistance/drug effects , Disease Resistance/genetics , Disease Resistance/immunology , Gene Expression Regulation , Immunity, Innate/physiology , Inflammation/immunology , Inflammation/metabolism , Inflammation/veterinary , Inflammation/virology , Interferon Type I/genetics , Interferon Type I/pharmacology , Interferons/genetics , Interferons/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/physiology , Nasal Mucosa/drug effects , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Respiratory System/drug effects , Respiratory System/immunology , Respiratory System/metabolism , Respiratory System/virology , Vero Cells , Viral Load/drug effects , Virus Replication/drug effects
13.
Medicina Clínica (English Edition) ; 156(10):496-499, 2021.
Article in English | ScienceDirect | ID: covidwho-1230658

ABSTRACT

Aim To assess the changes induced by the COVID-19 lockdown on cardiac biometric variables recorded using an implantable cardiac monitor (ICM) in a patient population monitored for syncope work-up, as well to assess whether there has been an effect on arrhythmic events among the patients. Methods Longitudinal cohort study. We included 245 adult patients monitored with an ICM indicated for the investigation of syncope. The records from days 1 to 12 March 2020 (prior to the institution of lockdown by the state government) with days 16 to 28 March 2020 were compared. Results Daily physical exercise reduced markedly after the imposition of lockdown (132 [55–233] minutes vs. 78 [21–154] minutes). The mean daytime HR prior to lockdown was 77 [69–85] bpm, whereas during lockdown it was 74 [66–81] bpm. During the lockdown period, a drop in the variability in heart rate (114 [94–136] ms vs. 111 [92–133] ms) was observed. Although the incidence of AF was similar over both periods, the daily AF burden was significantly higher post-lockdown (405 [391–425] minutes vs. 423 [423–537] minutes). No differences in the number of other arrhythmias were found. Conclusions The establishment of mandatory lockdown has led to a marked drop in daily physical activity in this population which probably explains changes observed in other cardiac biometric variables. Although, in the short term, we have not documented an increased risk of arrhythmia, we cannot rule out an effect in the medium to long term or in other populations of at-risk patients. Resumen Objetivo Evaluar los cambios inducidos por el confinamiento durante la pandemia de COVID-19 en las variables biométricas cardiacas registradas, utilizando un monitor cardíaco implantable (ICM) en una población de pacientes monitorizada para el diagnóstico de síncope, así como evaluar si ha habido un efecto sobre los eventos arrítmicos. Métodos Estudio de cohorte prospectivo. Se incluyeron 245 pacientes adultos monitorizados con un ICM indicado para la investigación del síncope. Se compararon los registros de los días uno al 12 de marzo del 2020 (antes del establecimiento del confinamiento por parte del gobierno estatal) con los días 16 al 28 de marzo del 2020. Resultados El ejercicio físico diario se redujo notablemente después de la imposición del confinamiento (132 [55 a 233] vs. 78 [21 a 154] min). La frecuencia cardiaca diurna media antes del confinamiento fue de 77 (69 a 85) lpm, mientras que durante el mismo fue de 74 (66 a 81) lpm. Durante el período de confinamiento, se observó una disminución de la variabilidad de la frecuencia cardiaca (114 [94 a 136] vs. 111 [92 a 133] ms). Aunque la incidencia de fibrilación auricular (FA) fue similar en ambos períodos, la carga diaria de FA fue significativamente mayor después del bloqueo (405 [391 a 425] vs. 423 [423 a 537] min). No se encontraron diferencias en el número de otras arritmias. Conclusiones El establecimiento de un confinamiento obligatorio ha provocado un marcado descenso de la actividad física diaria en esta población, lo que probablemente explica los cambios observados en otras variables biométricas cardiacas. Si bien, a corto plazo, no se ha documentado un aumento del riesgo de arritmia, no podemos descartar un efecto a medio-largo plazo o en otras poblaciones de pacientes de riesgo.

14.
Front Pharmacol ; 12: 646676, 2021.
Article in English | MEDLINE | ID: covidwho-1178019

ABSTRACT

There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC50 below 25 µM or 102 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.

15.
Emerg Microbes Infect ; 10(1): 797-809, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1171753

ABSTRACT

Reinfections with SARS-CoV-2 have already been documented in humans, although its real incidence is currently unknown. Besides having a great impact on public health, this phenomenon raises the question of immunity generated by a single infection is sufficient to provide sterilizing/protective immunity to a subsequent SARS-CoV-2 re-exposure. The Golden Syrian hamster is a manageable animal model to explore immunological mechanisms able to counteract COVID-19, as it recapitulates pathological aspects of mild to moderately affected patients. Here, we report that SARS-CoV-2-inoculated hamsters resolve infection in the upper and lower respiratory tracts within seven days upon inoculation with the Cat01 (G614) SARS-CoV-2 isolate. Three weeks after the primary challenge, and despite high titres of neutralizing antibodies, half of the animals were susceptible to reinfection by both identical (Cat01, G614) and variant (WA/1, D614) SARS-CoV-2 isolates. However, upon re-inoculation, only nasal tissues were transiently infected with much lower viral replication than those observed after the first inoculation. These data indicate that a primary SARS-CoV-2 infection is not sufficient to elicit a sterilizing immunity in hamster models but protects against lung disease.


Subject(s)
COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions/immunology , Reinfection/virology , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/diagnosis , COVID-19/pathology , Cell Line , Cricetinae , Disease Models, Animal , Female , Humans , Immunity, Humoral , Immunohistochemistry , Male , Neutralization Tests , SARS-CoV-2/genetics , Viral Load , Virus Replication
16.
Med (N Y) ; 2(3): 313-320.e4, 2021 03 12.
Article in English | MEDLINE | ID: covidwho-1135490

ABSTRACT

BACKGROUND: Understanding mid-term kinetics of immunity to SARS-CoV-2 is the cornerstone for public health control of the pandemic and vaccine development. However, current evidence is rather based on limited measurements, losing sight of the temporal pattern of these changes. METHODS: We conducted a longitudinal analysis on a prospective cohort of COVID-19 patients followed up for >6 months. Neutralizing activity was evaluated using HIV reporter pseudoviruses expressing SARS-CoV-2 S protein. IgG antibody titer was evaluated by ELISA against the S2 subunit, the receptor binding domain (RBD), and the nucleoprotein (NP). Statistical analyses were carried out using mixed-effects models. FINDINGS: We found that individuals with mild or asymptomatic infection experienced an insignificant decay in neutralizing activity, which persisted 6 months after symptom onset or diagnosis. Hospitalized individuals showed higher neutralizing titers, which decreased following a 2-phase pattern, with an initial rapid decline that significantly slowed after day 80. Despite this initial decay, neutralizing activity at 6 months remained higher among hospitalized individuals compared to mild symptomatic. The slow decline in neutralizing activity at mid-term contrasted with the steep slope of anti-RBD, S2, or NP antibody titers, all of them showing a constant decline over the follow-up period. CONCLUSIONS: Our results reinforce the hypothesis that the quality of the neutralizing immune response against SARS-CoV-2 evolves over the post-convalescent stage.


Subject(s)
Antibodies, Neutralizing , COVID-19 , Antibodies, Viral , Humans , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
17.
Med Clin (Barc) ; 156(10): 496-499, 2021 05 21.
Article in English, Spanish | MEDLINE | ID: covidwho-1108521

ABSTRACT

AIM: To assess the changes induced by the COVID-19 lockdown on cardiac biometric variables recorded using an implantable cardiac monitor (ICM) in a patient population monitored for syncope work-up, as well to assess whether there has been an effect on arrhythmic events among the patients. METHODS: Longitudinal cohort study. We included 245 adult patients monitored with an ICM indicated for the investigation of syncope. The records from days 1 to 12 March 2020 (prior to the institution of lockdown by the state government) with days 16 to 28 March 2020 were compared. RESULTS: Daily physical exercise reduced markedly after the imposition of lockdown (132 [55-233] minutes vs. 78 [21-154] minutes). The mean daytime HR prior to lockdown was 77 [69-85] bpm, whereas during lockdown it was 74 [66-81] bpm. During the lockdown period, a drop in the variability in heart rate (114 [94-136] ms vs. 111 [92-133] ms) was observed. Although the incidence of AF was similar over both periods, the daily AF burden was significantly higher post-lockdown (405 [391-425] minutes vs. 423 [423-537] minutes). No differences in the number of other arrhythmias were found. CONCLUSIONS: The establishment of mandatory lockdown has led to a marked drop in daily physical activity in this population which probably explains changes observed in other cardiac biometric variables. Although, in the short term, we have not documented an increased risk of arrhythmia, we cannot rule out an effect in the medium to long term or in other populations of at-risk patients.


Subject(s)
COVID-19 , Pandemics , Adult , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/etiology , Communicable Disease Control , Humans , Longitudinal Studies , SARS-CoV-2 , Syncope/diagnosis , Syncope/epidemiology , Syncope/etiology
18.
Sci Rep ; 11(1): 2608, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1054053

ABSTRACT

The protective effect of neutralizing antibodies in SARS-CoV-2 infected individuals is not yet well defined. To address this issue, we have analyzed the kinetics of neutralizing antibody responses and their association with disease severity. Between March and May 2020, the prospective KING study enrolled 72 COVID-19+ participants grouped according to disease severity. SARS-CoV-2 infection was diagnosed by serological and virological tests. Plasma neutralizing responses were assessed against replicative virus and pseudoviral particles. Multiple regression and non-parametric tests were used to analyze dependence of parameters. The magnitude of neutralizing titers significantly increased with disease severity. Hospitalized individuals developed higher titers compared to mild-symptomatic and asymptomatic individuals, which together showed titers below the detection limit in 50% of cases. Longitudinal analysis confirmed the strong differences in neutralizing titers between non-hospitalized and hospitalized participants and showed rapid kinetics of appearance of neutralizing antibodies (50% and 80% of maximal activity reached after 11 and 17 days after symptoms onset, respectively) in hospitalized patients. No significant impact of age, gender or treatment on the neutralizing titers was observed in this limited cohort. These data identify a clear association of humoral immunity with disease severity and point to immune mechanisms other than antibodies as relevant players in COVID-19 protection.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adaptive Immunity/immunology , Adult , Antibodies, Neutralizing/blood , COVID-19/blood , Cohort Studies , Female , Humans , Immunity, Humoral/immunology , Immunoglobulin G/blood , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Spain/epidemiology
20.
Proc Natl Acad Sci U S A ; 117(40): 24790-24793, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-780139

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is considered a zoonotic pathogen mainly transmitted human to human. Few reports indicate that pets may be exposed to the virus. The present report describes a cat suffering from severe respiratory distress and thrombocytopenia living with a family with several members affected by COVID-19. Clinical signs of the cat prompted humanitarian euthanasia and a detailed postmortem investigation to assess whether a COVID-19-like disease was causing the condition. Necropsy results showed the animal suffered from feline hypertrophic cardiomyopathy and severe pulmonary edema and thrombosis. SARS-CoV-2 RNA was only detected in nasal swab, nasal turbinates, and mesenteric lymph node, but no evidence of histopathological lesions compatible with a viral infection were detected. The cat seroconverted against SARS-CoV-2, further evidencing a productive infection in this animal. We conclude that the animal had a subclinical SARS-CoV-2 infection concomitant to an unrelated cardiomyopathy that led to euthanasia.


Subject(s)
Betacoronavirus/isolation & purification , Cardiomyopathy, Hypertrophic/veterinary , Coronavirus Infections/veterinary , Pandemics/veterinary , Pneumonia, Viral/veterinary , Animals , COVID-19 , Cardiomyopathy, Hypertrophic/pathology , Cardiomyopathy, Hypertrophic/virology , Cats , Coronavirus Infections/complications , Coronavirus Infections/pathology , Fatal Outcome , Humans , Incidental Findings , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , SARS-CoV-2
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