scholarly journals SARS-CoV-2 Omicron variant replication in human respiratory tract ex vivo

2021 ◽  
Author(s):  
Michael C. W. Chan ◽  
Kenrie PY Hui ◽  
John Ho ◽  
Man-chun Cheung ◽  
Ka-chun Ng ◽  
...  
Keyword(s):  
Human Lung ◽  
Ex Vivo ◽  
Natural Infection ◽  
Severe Disease ◽  
Lung Parenchyma ◽  
Global Public Health ◽  
Wild Type ◽  
Human Respiratory Tract ◽  
Human Bronchus ◽  
Cellular Tropism

Abstract Emergence of SARS-CoV-2 variants of concern (VOC) with progressively increased transmissibility between humans is a threat to global public health. Omicron variant also evades immunity from natural infection or vaccines1. It is unclear whether its exceptional transmissibility is due to immune evasion or inherent virological properties.We compared the replication competence and cellular tropism of the wild type (WT) virus, D614G, Alpha, Beta, Delta and Omicron variants in ex vivo explant cultures of human bronchus and lung. Dependence on TMPRSS2 for infection was also evaluated. We show that Omicron replicated faster than all other SARS-CoV-2 in the bronchus but less efficiently in the lung parenchyma. All VOCs had similar cellular tropism as the WT. Delta was more dependent on serine protease than other VOCs tested.Our findings demonstrate that Omicron is inherently able to replicate faster than other variants known to date and this likely contributes to its inherently higher transmissibility, irrespective of its ability to evade antibody immunity. The lower replication competence of Omicron in human lung may be compatible with reduced severity but the determinants of severe disease are multifactorial. These findings provide important biological clues to the transmissibility and pathogenesis of SARS-CoV-2 VOCs.

scholarly journals Herd immunity induced by COVID-19 vaccination programs to suppress epidemics caused by SARS-CoV-2 wild type and variants in China

2021 ◽  
Author(s):  
Hengcong Liu ◽  
Juanjuan Zhang ◽  
Jun Cai ◽  
Xiaowei Deng ◽  
Cheng Peng ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Disease Burden ◽  
Natural Infection ◽  
Severe Disease ◽  
Herd Immunity ◽  
Data Driven ◽  
Vaccination Program ◽  
Wild Type ◽  
Vaccination Programs ◽  
And Control

To allow a return to a pre-COVID-19 lifestyle, virtually every country has initiated a vaccination program to mitigate severe disease burden and control transmission; over 3.6 billion vaccine doses have been administered as of July 2021. However, it remains to be seen whether herd immunity will be within reach of these programs, especially as more transmissible SARS-CoV-2 variants continue to emerge. To address this question, we developed a data-driven model of SARS-CoV-2 transmission for Shanghai, China, a population with low prior immunity from natural infection. We found that extending the vaccination program to individuals aged 3-17 years plays a key role to reach herd immunity for the original SARS-CoV-2 lineages. With a vaccine efficacy 74% against infection, vaccine-induced herd immunity would require coverages of 93% or higher. Herd immunity for new variants, such as Alpha or Delta, can only be achieved with more efficacious vaccines and coverages above 80-90%. A continuation of the current pace of vaccination in China would reach 72% coverage by September 2021; although this program would fail to reach herd immunity it would reduce deaths by 95-100% in case of an outbreak. Efforts should be taken to increase population's confidence and willingness to be vaccinated and to guarantee highly efficacious vaccines against more transmissible variants of concern.

scholarly journals Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

Viruses ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 29
Author(s):  
Isabelle Bernard ◽  
Daniel Limonta ◽  
Lara K. Mahal ◽  
Tom C. Hobman
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Human Lung ◽  
Neurological Diseases ◽  
Severe Disease ◽  
Respiratory Illness ◽  
Global Public Health ◽  
Angiotensin Converting Enzyme 2 ◽  
The Relationship ◽  
Cardiac Microvascular Endothelial Cells

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) poses a persistent threat to global public health. Although primarily a respiratory illness, extrapulmonary manifestations of COVID-19 include gastrointestinal, cardiovascular, renal and neurological diseases. Recent studies suggest that dysfunction of the endothelium during COVID-19 may exacerbate these deleterious events by inciting inflammatory and microvascular thrombotic processes. Although controversial, there is evidence that SARS-CoV-2 may infect endothelial cells by binding to the angiotensin-converting enzyme 2 (ACE2) cellular receptor using the viral Spike protein. In this review, we explore current insights into the relationship between SARS-CoV-2 infection, endothelial dysfunction due to ACE2 downregulation, and deleterious pulmonary and extra-pulmonary immunothrombotic complications in severe COVID-19. We also discuss preclinical and clinical development of therapeutic agents targeting SARS-CoV-2-mediated endothelial dysfunction. Finally, we present evidence of SARS-CoV-2 replication in primary human lung and cardiac microvascular endothelial cells. Accordingly, in striving to understand the parameters that lead to severe disease in COVID-19 patients, it is important to consider how direct infection of endothelial cells by SARS-CoV-2 may contribute to this process.

scholarly journals A52 MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity

2019 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
D K W Chu ◽  
K P Y Hui ◽  
R A P M Perera ◽  
E Miguel ◽  
J O Oladipo ◽  
...  
Keyword(s):  
Arabian Peninsula ◽  
Ex Vivo ◽  
Molecular Dating ◽  
Health Concern ◽  
Phenotypic Characterization ◽  
Global Public Health ◽  
Accessory Gene ◽  
African Countries ◽  
Human Bronchus ◽  
Clade C

Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) causes a zoonotic respiratory disease of global public health concern, and dromedary camels are the only proven source of this zoonotic infection. Although MERS-CoV infection is ubiquitous in dromedaries across Africa and the Arabian Peninsula, the continuous appearance of zoonotic MERS cases in humans is confined to the Arabian Peninsula. MERS-CoV from Africa has hitherto been poorly studied. Here, we report the genetic and phenotypic characterization of MERS-CoV from dromedaries in African countries. Phylogenetically, viruses from dromedaries in Africa formed a monophyletic clade, which we have provisionally designated as virus clade C. Molecular dating analyses of MERS-CoV, including clade C viruses, suggests that the ancestral MERS-CoV in dromedaries could have spread to the two continents within a short timeframe. Camel MERS-CoVs from west and north African countries form a subclade (C1) that shares genetic signatures of a major deletion in the accessory gene ORF4b. Compared with human and camel MERS-CoV from Saudi Arabia, virus isolates from Burkina Faso (BF785) and Nigeria (Nig1657) had lower virus replication competence in Calu-3 cells and in ex vivo cultures of human bronchus and lung, and BF785 replicated to lower titer in lungs of human DPP4-transduced mice. However, it is still inconclusive whether ORF4b deletions may lead to the reduced replication competence of BF785 and Nig1657. Genetic and phenotypic differences in West African viruses may be relevant to the zoonotic potential of MERS-CoV.

scholarly journals Tropism of influenza B viruses in human respiratory tract explants and airway organoids

2019 ◽  
Vol 54 (2) ◽  
pp. 1900008 ◽  
Author(s):  
Christine H.T. Bui ◽  
Renee W.Y. Chan ◽  
Mandy M.T. Ng ◽  
M-C. Cheung ◽  
Ka-chun Ng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Respiratory Tract ◽  
Influenza A ◽  
Ex Vivo ◽  
Alveolar Epithelial Cells ◽  
Influenza B ◽  
Type I ◽  
Human Respiratory Tract ◽  
Human Bronchus ◽  
Human Airway

Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevantex vivoexplant cultures of human bronchus and lung, human airway organoids, andin vitrocultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited.

scholarly journals Human ex vivo lung perfusion: a novel model to study human lung diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nayra Cárdenes ◽  
John Sembrat ◽  
Kentaro Noda ◽  
Tyler Lovelace ◽  
Diana Álvarez ◽  
...  
Keyword(s):  
Lung Diseases ◽  
Human Lung ◽  
Ex Vivo ◽  
Lung Parenchyma ◽  
Lung Perfusion ◽  
Lung Mechanics ◽  
Preclinical Model ◽  
Pulmonary Hemodynamics ◽  
Ex Vivo Lung Perfusion ◽  
Chronic Lung Diseases

AbstractExperimental animal models to predict physiological responses to injury and stress in humans have inherent limitations. Therefore, the development of preclinical human models is of paramount importance. Ex vivo lung perfusion (EVLP) has typically been used to recondition donor lungs before transplantation. However, this technique has recently advanced into a model to emulate lung mechanics and physiology during injury. In the present study, we propose that the EVLP of diseased human lungs is a well-suited preclinical model for translational research on chronic lung diseases. Throughout this paper, we demonstrate this technique's feasibility in pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), emphysema, and non-disease donor lungs not suitable for transplantation. In this study, we aimed to perfuse the lungs for 6 h with the EVLP system. This facilitated a robust and continuous assessment of airway mechanics, pulmonary hemodynamics, gas exchange, and biochemical parameters. We then collected at different time points tissue biopsies of lung parenchyma to isolate RNA and DNA to identify each disease's unique gene expression. Thus, demonstrating that EVLP could successfully serve as a clinically relevant experimental model to derive essential insights into pulmonary pathophysiology and various human lung diseases.

scholarly journals MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity

2018 ◽  
Vol 115 (12) ◽  
pp. 3144-3149 ◽  
Author(s):  
Daniel K. W. Chu ◽  
Kenrie P. Y. Hui ◽  
Ranawaka A. P. M. Perera ◽  
Eve Miguel ◽  
Daniela Niemeyer ◽  
...  
Keyword(s):  
Burkina Faso ◽  
Reverse Genetics ◽  
Arabian Peninsula ◽  
Ex Vivo ◽  
Health Concern ◽  
Type I ◽  
Global Public Health ◽  
Accessory Gene ◽  
Human Bronchus ◽  
Emc Virus

Middle East respiratory syndrome coronavirus (MERS-CoV) causes a zoonotic respiratory disease of global public health concern, and dromedary camels are the only proven source of zoonotic infection. Although MERS-CoV infection is ubiquitous in dromedaries across Africa as well as in the Arabian Peninsula, zoonotic disease appears confined to the Arabian Peninsula. MERS-CoVs from Africa have hitherto been poorly studied. We genetically and phenotypically characterized MERS-CoV from dromedaries sampled in Morocco, Burkina Faso, Nigeria, and Ethiopia. Viruses from Africa (clade C) are phylogenetically distinct from contemporary viruses from the Arabian Peninsula (clades A and B) but remain antigenically similar in microneutralization tests. Viruses from West (Nigeria, Burkina Faso) and North (Morocco) Africa form a subclade, C1, that shares clade-defining genetic signatures including deletions in the accessory gene ORF4b. Compared with human and camel MERS-CoV from Saudi Arabia, virus isolates from Burkina Faso (BF785) and Nigeria (Nig1657) had lower virus replication competence in Calu-3 cells and in ex vivo cultures of human bronchus and lung. BF785 replicated to lower titer in lungs of human DPP4-transduced mice. A reverse genetics-derived recombinant MERS-CoV (EMC) lacking ORF4b elicited higher type I and III IFN responses than the isogenic EMC virus in Calu-3 cells. However, ORF4b deletions may not be the major determinant of the reduced replication competence of BF785 and Nig1657. Genetic and phenotypic differences in West African viruses may be relevant to zoonotic potential. There is an urgent need for studies of MERS-CoV at the animal–human interface.

scholarly journals Phenotypic and genetic characterization of MERS coronaviruses from Africa to understand their zoonotic potential

2021 ◽  
Vol 118 (25) ◽  
pp. e2103984118
Author(s):  
Ziqi Zhou ◽  
Kenrie P. Y. Hui ◽  
Ray T. Y. So ◽  
Huibin Lv ◽  
Ranawaka A. P. M. Perera ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Arabian Peninsula ◽  
Ex Vivo ◽  
Prototype Strain ◽  
Health Concern ◽  
Epithelial Cell Line ◽  
Global Public Health ◽  
Human Bronchus

Coronaviruses are pathogens of pandemic potential. Middle East respiratory syndrome coronavirus (MERS-CoV) causes a zoonotic respiratory disease of global public health concern, and dromedary camels are the only proven source of zoonotic infection. More than 70% of MERS-CoV–infected dromedaries are found in East, North, and West Africa, but zoonotic MERS disease is only reported from the Arabian Peninsula. We compared viral replication competence of clade A and B viruses from the Arabian Peninsula with genetically diverse clade C viruses found in East (Egypt, Kenya, and Ethiopia), North (Morocco), and West (Nigeria and Burkina Faso) Africa. Viruses from Africa had lower replication competence in ex vivo cultures of the human lung and in lungs of experimentally infected human-DPP4 (hDPP4) knockin mice. We used lentivirus pseudotypes expressing MERS-CoV spike from Saudi Arabian clade A prototype strain (EMC) or African clade C1.1 viruses and demonstrated that clade C1.1 spike was associated with reduced virus entry into the respiratory epithelial cell line Calu-3. Isogenic EMC viruses with spike protein from EMC or clade C1.1 generated by reverse genetics showed that the clade C1.1 spike was associated with reduced virus replication competence in Calu-3 cells in vitro, in ex vivo human bronchus, and in lungs of hDPP4 knockin mice in vivo. These findings may explain why zoonotic MERS disease has not been reported from Africa so far, despite exposure to and infection with MERS-CoV.

scholarly journals Tropism and innate host responses of influenza A/H5N6 virus: an analysis ofex vivoandin vitrocultures of the human respiratory tract

2017 ◽  
Vol 49 (3) ◽  
pp. 1601710 ◽  
Author(s):  
Kenrie P. Y. Hui ◽  
Louisa L. Y. Chan ◽  
Denise I. T. Kuok ◽  
Chris K. P. Mok ◽  
Zi-feng Yang ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Influenza A ◽  
H5n1 Virus ◽  
Ex Vivo ◽  
Alveolar Epithelial Cells ◽  
Human Respiratory Tract ◽  
Human Bronchus ◽  
Cytokines And Chemokines ◽  
Hpai H5n1

Since their first isolation in 2013, influenza A/H5N6 viruses have spread amongst poultry across multiple provinces in China and to Laos, Vietnam and Myanmar. So far, there have been 14 human H5N6 infections with 10 fatalities.We investigated the tropism, replication competence and cytokine induction of one human and two avian H5N6 isolates inex vivoandin vitrocultures derived from the human respiratory tract. Virus tropism and replication were studied inex vivocultures of human nasopharynx, bronchus and lung. Induction of cytokines and chemokines was measuredin vitroin virus-infected primary human alveolar epithelial cells.Human H5N6 virus replicated more efficiently than highly pathogenic avian influenza (HPAI) H5N1 virus and as efficiently as H1N1pdm inex vivohuman bronchus and lung and was also able to replicate inex vivocultures of human nasopharynx. Avian H5N6 viruses replicated less efficiently than H1N1pdm in human bronchial tissues and to similar titres as HPAI H5N1 in the lung. While the human H5N6 virus had affinity for avian-like receptors, the two avian isolates had binding affinity for both avian- and human-like receptors. All three H5N6 viruses were less potent inducers of pro-inflammatory cytokines compared with H5N1 virus.Human H5N6 virus appears better adapted to infect the human airways than H5N1 virus and may pose a significant public health threat.

scholarly journals Protective efficacy of a SARS-CoV-2 DNA vaccine in wild-type and immunosuppressed Syrian hamsters

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Rebecca L. Brocato ◽  
Steven A. Kwilas ◽  
Robert K. Kim ◽  
Xiankun Zeng ◽  
Lucia M. Principe ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Severe Disease ◽  
Disease Model ◽  
Wild Type ◽  
Jet Injection ◽  
Syrian Hamsters ◽  
Dna Targeting

AbstractA worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.

Sign in / Sign up

Export Citation Format

Share Document