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mBio ; 14(2): e0007823, 2023 04 25.
Article in English | MEDLINE | ID: covidwho-2301899


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has evolved into multiple variants. Animal models are important to understand variant pathogenesis, particularly for variants with mutations that have significant phenotypic or epidemiological effects. Here, cohorts of naive or previously infected Syrian hamsters (Mesocricetus auratus) were infected with variants to investigate viral pathogenesis and disease protection. Naive hamsters infected with SARS-CoV-2 variants had consistent clinical outcomes, tissue viral titers, and pathology, while hamsters that recovered from initial infection and were reinfected demonstrated less severe clinical disease and lung pathology than their naive counterparts. Males had more frequent clinical signs than females in most variant groups, but few sex variations in tissue viral titers and lung pathology were observed. These findings support the use of Syrian hamsters as a SARS-CoV-2 model and highlight the importance of considering sex differences when using this species. IMPORTANCE With the continued circulation and emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, understanding differences in the effects between the initial infection and a subsequent reinfection on disease pathogenesis is critical and highly relevant. This study characterizes Syrian hamsters as an animal model to study reinfection with SARS-CoV-2. Previous infection reduced the disease severity of reinfection with different SARS-CoV-2 variants.

COVID-19 , SARS-CoV-2 , Cricetinae , Animals , Female , Humans , Male , Mesocricetus , SARS-CoV-2/genetics , COVID-19/pathology , Lung/pathology , Reinfection/pathology , Disease Models, Animal
J Virol ; 96(1): e0096421, 2022 01 12.
Article in English | MEDLINE | ID: covidwho-1631789


A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2 × 103 and 2 × 104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2 × 101 and 2 × 102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in postmortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human postmortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. IMPORTANCE The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases, caused nearly 5 million deaths worldwide as of October 2021, and has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of antiviral drugs and therapeutics.

COVID-19/pathology , Disease Models, Animal , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Humans , Immune Sera/immunology , Keratin-18/genetics , Mice , Mice, Transgenic , Promoter Regions, Genetic , Reinfection/immunology , Reinfection/mortality , Reinfection/pathology , Reinfection/virology , SARS-CoV-2/immunology , Viral Proteins/genetics , Viral Proteins/metabolism
Future Oncol ; 18(5): 533-541, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1538323


Introduction: The objective of this study was to evaluate the clinical and laboratory outcomes of solid cancer patients who were reinfected with COVID-19. Methods: Patients who were tested negative on the COVID-19 PCR test and those with improved clinical conditions after infection with COVID-19 were enrolled in this study. Patients who received a positive COVID-19 PCR test 28 days after the initial positive PCR test were considered as reinfected. Results: A total of 1024 patients with the diagnosis of solid malignancy and COVID-19 PCR positivity were examined. The reinfection rate was 3.1%. Mortality rate of reinfection was 34.3%. The serum ferritin and creatinine values in reinfection were found to be significantly higher than the first infection (respectively; p = 0.015, p = 0.014). Conclusion: This study has demonstrated one of the first preliminary clinical results of COVID-19 reinfection in solid cancer patients.

Plain language summary Solid cancer patients are at a higher risk than general population in terms of COVID-19 infectivity and COVID-19-associated death and disease. It is also known that COVID-19 infection has a more severe course in immunocompromised patients. Solid cancer patients may be a vulnerable subgroup of patients to reinfection with COVID-19. The rate of reinfection was 3.1% (n = 32) in our study population of 1024 solid cancer patients who were tested positive on a COVID-19 PCR test. The death rate of the patients with solid cancer was 34.3% (n = 11). In addition, we demonstrated that intensive care follow-up is significantly longer during the reinfection period. It was demonstrated that the time between the last dose of chemotherapy for the patients and the reinfection COVID PCR positivity did not affect the death rate. The COVID-19 pandemic has affected people's daily lives and treatments in many aspects. Owing to the high death rate of reinfection, even if cancer patients have reinfection, our approach is to continue cancer treatment as soon as the patient is cured. Finally, we support the priority vaccination of cancer patients.

COVID-19 Nucleic Acid Testing/methods , COVID-19/complications , Neoplasms/pathology , Reinfection/pathology , SARS-CoV-2/pathogenicity , Adult , Aged , Aged, 80 and over , COVID-19/pathology , COVID-19/virology , Female , Humans , Male , Middle Aged , Neoplasms/therapy , Neoplasms/virology , Prognosis , Reinfection/virology , SARS-CoV-2/isolation & purification , Survival Rate
Genomics ; 113(4): 1628-1638, 2021 07.
Article in English | MEDLINE | ID: covidwho-1386752


Sequencing the SARS-CoV-2 genome from clinical samples can be challenging, especially in specimens with low viral titer. Here we report Accurate SARS-CoV-2 genome Reconstruction (ACoRE), an amplicon-based viral genome sequencing workflow for the complete and accurate reconstruction of SARS-CoV-2 sequences from clinical samples, including suboptimal ones that would usually be excluded even if unique and irreplaceable. The protocol was optimized to improve flexibility and the combination of technical replicates was established as the central strategy to achieve accurate analysis of low-titer/suboptimal samples. We demonstrated the utility of the approach by achieving complete genome reconstruction and the identification of false-positive variants in >170 clinical samples, thus avoiding the generation of inaccurate and/or incomplete sequences. Most importantly, ACoRE was crucial to identify the correct viral strain responsible of a relapse case, that would be otherwise mis-classified as a re-infection due to missing or incorrect variant identification by a standard workflow.

COVID-19/genetics , Genome, Viral/genetics , Reinfection/genetics , SARS-CoV-2/genetics , COVID-19/pathology , COVID-19/virology , Genetic Variation/genetics , Humans , Reinfection/pathology , Reinfection/virology , SARS-CoV-2/pathogenicity , Whole Genome Sequencing
EBioMedicine ; 71: 103561, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1372964


BACKGROUND: Assessment of the kinetics of SARS-CoV-2 antibodies is essential in predicting risk of reinfection and durability of vaccine protection. METHODS: This is a prospective, monocentric, longitudinal, cohort clinical study. Healthcare workers (HCW) from Strasbourg University Hospital were enrolled between April 6th and May 7th, 2020 and followed up to 422 days. Serial serum samples were tested for antibodies against the Receptor Binding Domain (RBD) of the spike protein and nucleocapsid protein (N) to characterize the kinetics of SARS-CoV-2 antibodies and the incidence of reinfection. Live-neutralization assays were performed for a subset of samples before and after vaccination to analyze sensitivity to SARS-CoV-2 variants. FINDINGS: A total of 4290 samples from 393 convalescent COVID-19 and 916 COVID-19 negative individuals were analyzed. In convalescent individuals, SARS-CoV-2 antibodies followed a triphasic kinetic model with half-lives at month (M) 11-13 of 283 days (95% CI 231-349) for anti-N and 725 days (95% CI 623-921) for anti-RBD IgG, which stabilized at a median of 1.54 log BAU/mL (95% CI 1.42-1.67). The incidence of SARS-CoV-2 infections was 12.22 and 0.40 per 100 person-years in COVID-19-negative and COVID-19-positive HCW, respectively, indicating a relative reduction in the incidence of SARS-CoV-2 reinfection of 96.7%. Live-virus neutralization assay revealed that after one year, variants D614G and B.1.1.7, but less so B.1.351, were sensitive to anti-RBD antibodies at 1.4 log BAU/mL, while IgG ≥ 2.0 log BAU/mL strongly neutralized all three variants. These latter anti-RBD IgG titers were reached by all vaccinated HCW regardless of pre-vaccination IgG levels and type of vaccine. INTERPRETATION: Our study demonstrates a long-term persistence of anti-RBD antibodies that may reduce risk of reinfection. By significantly increasing cross-neutralizing antibody titers, a single-dose vaccination strengthens protection against variants. FUN1DING: None.

COVID-19/pathology , Immunity, Humoral , Reinfection/pathology , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Kinetics , Longitudinal Studies , Male , Middle Aged , Phosphoproteins/immunology , Prospective Studies , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/immunology , Time Factors
Front Immunol ; 12: 701295, 2021.
Article in English | MEDLINE | ID: covidwho-1359190


The current pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already become a global threat to the human population. Infection with SARS-CoV-2 leads to a wide spectrum of clinical manifestations. Ocular abnormalities have been reported in association with COVID-19, but the nature of the impairments was not specified. Here, we report a case of a female patient diagnosed with glaucoma on re-hospitalization for ocular complications two months after being discharged from the hospital upon recovery from COVID-19. Meanwhile, the patient was found re-positive for SARS-CoV-2 in the upper respiratory tract. The infection was also diagnosed in the aqueous humor through immunostaining with antibodies against the N protein and S protein of SARS-CoV-2. Considering the eye is an immune-privileged site, we speculate that SARS-CoV-2 survived in the eye and resulted in the patient testing re-positive for SARS-CoV-2.

Aqueous Humor/virology , COVID-19/pathology , Glaucoma/pathology , Reinfection/pathology , Aged , COVID-19/complications , Eye/pathology , Eye/virology , Female , Glaucoma/complications , Humans , SARS-CoV-2/isolation & purification