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1.
Vet Res ; 52(1): 121, 2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1414142

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is causing a global crisis. It is still unresolved. Although many therapies and vaccines are being studied, they are still in their infancy. As this pandemic continues, rapid and accurate research for the development of therapies and vaccines is needed. Therefore, it is necessary to understand characteristics of diseases caused by SARS-CoV-2 through animal models. Syrian hamsters are known to be susceptible to SARS-CoV-2. They were intranasally inoculated with SARS-CoV-2. At 2, 4, 8, 12, and 16 days post-infection (dpi), these hamsters were euthanized, and tissues were collected for ultrastructural and microstructural examinations. Microscopic lesions were prominent in the upper and lower respiratory tracts from 2 and 4 dpi groups, respectively. The respiratory epithelium in the trachea, bronchiole, and alveolar showed pathological changes. Inflammatory cells including neutrophils, lymphocytes, macrophages, and eosinophils were infiltrated in/around tracheal lamina propria, pulmonary vessels, alveoli, and bronchiole. In pulmonary lesions, alveolar wall was thickened with infiltrated inflammatory cells, mainly neutrophils and macrophages. In the trachea, epithelial damages started from 2 dpi and recovered from 8 dpi, consistent with microscopic results, High levels of SARS-CoV-2 nucleoprotein were detected at 2 dpi and 4 dpi. In the lung, lesions were most severe at 8 dpi. Meanwhile, high levels of SARS-CoV-2 were detected at 4 dpi. Electron microscopic examinations revealed cellular changes in the trachea epithelium and alveolar epithelium such as vacuolation, sparse micro-organelle, and poor cellular margin. In the trachea epithelium, the number of cytoplasmic organelles was diminished, and small vesicles were prominent from 2 dpi. Some of these electron-lucent vesicles were filled with virion particles. From 8 dpi, the trachea epithelium started to recover. Because of shrunken nucleus and swollen cytoplasm, the N/C ratio of type 2 pneumocyte decreased at 8 and 12 dpi. From 8 dpi, lamellar bodies on type 2 pneumocyte cytoplasm were increasingly observed. Their number then decreased from 16 dpi. However, there was no significant change in type 1 pneumocyte. Viral vesicles were only observed in the cytoplasm of type 2 pneumocyte. In conclusion, ultra- and micro-structural changes presented in this study may provide useful information for SARS-CoV-2 studies in various fields.


Subject(s)
COVID-19/pathology , Respiratory System/pathology , SARS-CoV-2/pathogenicity , Animals , Cricetinae , Immunohistochemistry/veterinary , Male , Mesocricetus , Pilot Projects , RNA, Viral/chemistry , RNA, Viral/isolation & purification , Real-Time Polymerase Chain Reaction/veterinary , Respiratory System/chemistry , Respiratory System/ultrastructure , Respiratory System/virology , Time Factors , Trachea/pathology , Trachea/ultrastructure , Trachea/virology , Weight Loss
2.
Viruses ; 13(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1367929

ABSTRACT

The post-acute phase of SARS-CoV-2 infection was investigated in rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via the nose and throat, and viral RNA was occasionally detected in feces. This phase coincided with a transient change in systemic immune activation. Even after the alleged resolution of the infection, computed tomography (CT) and positron emission tomography (PET)-CT revealed pulmonary lesions and activated tracheobronchial lymph nodes in all animals. Post-mortem histological examination of the lung tissue revealed mostly marginal or resolving minimal lesions that were indicative of SARS-CoV-2 infection. Evidence for SARS-CoV-2-induced histopathology was also found in extrapulmonary tissue samples, such as conjunctiva, cervical, and mesenteric lymph nodes. However, 5-6 weeks after SARS-CoV-2 exposure, upon necropsy, viral RNA was still detectable in a wide range of tissue samples in 50% of the macaques and included amongst others the heart, the respiratory tract and surrounding lymph nodes, salivary gland, and conjunctiva. Subgenomic messenger RNA was detected in the lungs and tracheobronchial lymph nodes, indicative of ongoing virus replication during the post-acute phase. These results could be relevant for understanding the long-term consequences of COVID-19 in humans.


Subject(s)
COVID-19/pathology , COVID-19/virology , Lung/pathology , SARS-CoV-2/physiology , Animals , Antibodies, Viral/blood , COVID-19/immunology , Cytokines/blood , Disease Models, Animal , Humans , Lung/virology , Lymph Nodes/pathology , Lymph Nodes/physiopathology , Macaca fascicularis , Macaca mulatta , RNA, Messenger/analysis , RNA, Viral/analysis , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2/immunology , Virus Replication
3.
Viruses ; 13(8)2021 08 18.
Article in English | MEDLINE | ID: covidwho-1360824

ABSTRACT

The pre-clinical development of antiviral agents involves experimental trials in animals and ferrets as an animal model for the study of SARS-CoV-2. Here, we used mathematical models and experimental data to characterize the within-host infection dynamics of SARS-CoV-2 in ferrets. We also performed a global sensitivity analysis of model parameters impacting the characteristics of the viral infection. We provide estimates of the viral dynamic parameters in ferrets, such as the infection rate, the virus production rate, the infectious virus proportion, the infected cell death rate, the virus clearance rate, as well as other related characteristics, including the basic reproduction number, pre-peak infectious viral growth rate, post-peak infectious viral decay rate, pre-peak infectious viral doubling time, post-peak infectious virus half-life, and the target cell loss in the respiratory tract. These parameters and indices are not significantly different between animals infected with viral strains isolated from the environment and isolated from human hosts, indicating a potential for transmission from fomites. While the infection period in ferrets is relatively short, the similarity observed between our results and previous results in humans supports that ferrets can be an appropriate animal model for SARS-CoV-2 dynamics-related studies, and our estimates provide helpful information for such studies.


Subject(s)
COVID-19/virology , Disease Models, Animal , Ferrets , SARS-CoV-2/physiology , Animals , Basic Reproduction Number , COVID-19/immunology , COVID-19/pathology , COVID-19/transmission , Cell Death , Humans , Immunity, Innate , Models, Biological , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2/immunology , Sensitivity and Specificity , Viral Load , Virus Shedding
4.
Cell Rep ; 36(5): 109493, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1328703

ABSTRACT

Safe and effective vaccines are urgently needed to stop the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We construct a series of live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome and assess their safety and efficacy in Syrian hamsters. Animals were vaccinated with a single dose of the respective recoded virus and challenged 21 days later. Two of the tested viruses do not cause clinical symptoms but are highly immunogenic and induce strong protective immunity. Attenuated viruses replicate efficiently in the upper but not in the lower airways, causing only mild pulmonary histopathology. After challenge, hamsters develop no signs of disease and rapidly clear challenge virus: at no time could infectious virus be recovered from the lungs of infected animals. The ease with which attenuated virus candidates can be produced and administered favors their further development as vaccines to combat the ongoing pandemic.


Subject(s)
COVID-19 Vaccines , COVID-19/immunology , COVID-19/prevention & control , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Animals , Chlorocebus aethiops , Gene Editing , Genome, Viral , Humans , Immunity , Mesocricetus , Mutation , Pandemics/prevention & control , Vaccines, Attenuated , Vero Cells , Virus Replication
5.
PLoS Pathog ; 17(7): e1009705, 2021 07.
Article in English | MEDLINE | ID: covidwho-1311291

ABSTRACT

COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a disease affecting several organ systems. A model that captures all clinical symptoms of COVID-19 as well as long-haulers disease is needed. We investigated the host responses associated with infection in several major organ systems including the respiratory tract, the heart, and the kidneys after SARS-CoV-2 infection in Syrian hamsters. We found significant increases in inflammatory cytokines (IL-6, IL-1beta, and TNF) and type II interferons whereas type I interferons were inhibited. Examination of extrapulmonary tissue indicated inflammation in the kidney, liver, and heart which also lacked type I interferon upregulation. Histologically, the heart had evidence of myocarditis and microthrombi while the kidney had tubular inflammation. These results give insight into the multiorgan disease experienced by people with COVID-19 and possibly the prolonged disease in people with post-acute sequelae of SARS-CoV-2 (PASC).


Subject(s)
COVID-19/immunology , Down-Regulation/immunology , Interferon Type I/immunology , Kidney/immunology , Myocardium/immunology , Respiratory System/immunology , SARS-CoV-2/immunology , Animals , COVID-19/pathology , Cricetinae , Disease Models, Animal , Humans , Inflammation/immunology , Inflammation/pathology , Kidney/pathology , Kidney/virology , Male , Mesocricetus , Myocardium/pathology , Respiratory System/pathology , Respiratory System/virology
6.
EBioMedicine ; 68: 103403, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1245928

ABSTRACT

BACKGROUND: Within one year after its emergence, more than 108 million people acquired SARS-CoV-2 and almost 2·4 million succumbed to COVID-19. New SARS-CoV-2 variants of concern (VoC) are emerging all over the world, with the threat of being more readily transmitted, being more virulent, or escaping naturally acquired and vaccine-induced immunity. At least three major prototypic VoC have been identified, i.e. the United Kingdom, UK (B.1.1.7), South African (B.1.351) and Brazilian (B.1.1.28.1) variants. These are replacing formerly dominant strains and sparking new COVID-19 epidemics. METHODS: We studied the effect of infection with prototypic VoC from both B.1.1.7 and B.1.351 variants in female Syrian golden hamsters to assess their relative infectivity and virulence in direct comparison to two basal SARS-CoV-2 strains isolated in early 2020. FINDINGS: A very efficient infection of the lower respiratory tract of hamsters by these VoC is observed. In line with clinical evidence from patients infected with these VoC, no major differences in disease outcome were observed as compared to the original strains as was quantified by (i) histological scoring, (ii) micro-computed tomography, and (iii) analysis of the expression profiles of selected antiviral and pro-inflammatory cytokine genes. Noteworthy however, in hamsters infected with VoC B.1.1.7, a particularly strong elevation of proinflammatory cytokines was detected. INTERPRETATION: We established relevant preclinical infection models that will be pivotal to assess the efficacy of current and future vaccine(s) (candidates) as well as therapeutics (small molecules and antibodies) against two important SARS-CoV-2 VoC. FUNDING: Stated in the acknowledgment.


Subject(s)
COVID-19/pathology , Cytokines/genetics , Respiratory System/virology , SARS-CoV-2/pathogenicity , Animals , COVID-19/diagnostic imaging , COVID-19/genetics , Disease Models, Animal , Evolution, Molecular , Female , Gene Expression Profiling , Gene Expression Regulation , Mesocricetus , Respiratory System/diagnostic imaging , Respiratory System/pathology , SARS-CoV-2/classification , SARS-CoV-2/immunology , Virulence , X-Ray Microtomography
7.
J Pathol Clin Res ; 7(4): 326-337, 2021 07.
Article in English | MEDLINE | ID: covidwho-1173791

ABSTRACT

While coronavirus disease 2019 (COVID-19) primarily affects the respiratory tract, pathophysiological changes of the cardiovascular system remain to be elucidated. We performed a retrospective cardiopathological analysis of the heart and vasculature from 23 autopsies of COVID-19 patients, comparing the findings with control tissue. Myocardium from autopsies of COVID-19 patients was categorised into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive (n = 14) or negative (n = 9) based on the presence of viral RNA as determined by reverse transcriptase polymerase chain reaction (RT-PCR). Control tissue was selected from autopsies without COVID-19 (n = 10) with similar clinical sequelae. Histological characteristics were scored by ordinal and/or categorical grading. Five RT-PCR-positive cases underwent in situ hybridisation (ISH) for SARS-CoV-2. Patients with lethal COVID-19 infection were mostly male (78%) and had a high incidence of hypertension (91%), coronary artery disease (61%), and diabetes mellitus (48%). Patients with positive myocardial RT-PCR died earlier after hospital admission (5 versus 12 days, p < 0.001) than patients with negative RT-PCR. An increased severity of fibrin deposition, capillary dilatation, and microhaemorrhage was observed in RT-PCR-positive myocardium than in negatives and controls, with a positive correlation amongst these factors All cases with increased cardioinflammatory infiltrate, without myocyte necrosis (n = 4) or with myocarditis (n = 1), were RT-PCR negative. ISH revealed positivity of viral RNA in interstitial cells. Myocardial capillary dilatation, fibrin deposition, and microhaemorrhage may be the histomorphological correlate of COVID-19-associated coagulopathy. Increased cardioinflammation including one case of myocarditis was only detected in RT-PCR-negative hearts with significantly longer hospitalisation time. This may imply a secondary immunological response warranting further characterisation.


Subject(s)
COVID-19/pathology , COVID-19/virology , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2/pathogenicity , Adult , Autopsy/methods , COVID-19/complications , Female , Humans , Male , Middle Aged , Myocarditis/etiology , Myocarditis/pathology , Myocardium/pathology , RNA, Viral/genetics
8.
Front Cell Infect Microbiol ; 11: 643326, 2021.
Article in English | MEDLINE | ID: covidwho-1172964

ABSTRACT

Secondary bacterial infections enhance the disease burden of influenza infections substantially. Streptococcus pneumoniae (the pneumococcus) plays a major role in the synergism between bacterial and viral pathogens, which is based on complex interactions between the pathogen and the host immune response. Here, we discuss mechanisms that drive the pathogenesis of a secondary pneumococcal infection after an influenza infection with a focus on how pneumococci senses and adapts to the influenza-modified environment. We briefly summarize what is known regarding secondary bacterial infection in relation to COVID-19 and highlight the need to improve our current strategies to prevent and treat viral bacterial coinfections.


Subject(s)
COVID-19/complications , Influenza, Human , Pneumococcal Infections/pathology , Respiratory System/pathology , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/virology , Coinfection , Host-Pathogen Interactions/immunology , Humans , Influenza, Human/complications , Streptococcus pneumoniae
9.
Environ Health ; 20(1): 34, 2021 03 26.
Article in English | MEDLINE | ID: covidwho-1154012

ABSTRACT

BACKGROUND: An unusual feature of SARS-Cov-2 infection and the COVID-19 pandemic is that children are less severely affected than adults. This is especially paradoxical given the epidemiological links between poor air quality and increased COVID-19 severity in adults and that children are generally more vulnerable than adults to the adverse consequences of air pollution. OBJECTIVES: To identify gaps in knowledge about the factors that protect children from severe SARS-Cov-2 infection even in the face of air pollution, and to develop a transdisciplinary research strategy to address these gaps. METHODS: An international group of researchers interested in children's environmental health was invited to identify knowledge gaps and to develop research questions to close these gaps. DISCUSSION: Key research questions identified include: what are the effects of SAR-Cov-2 infection during pregnancy on the developing fetus and child; what is the impact of age at infection and genetic susceptibility on disease severity; why do some children with COVID-19 infection develop toxic shock and Kawasaki-like symptoms; what are the impacts of toxic environmental exposures including poor air quality, chemical and metal exposures on innate immunity, especially in the respiratory epithelium; what is the possible role of a "dirty" environment in conveying protection - an example of the "hygiene hypothesis"; and what are the long term health effects of SARS-Cov-2 infection in early life. CONCLUSION: A concerted research effort by a multidisciplinary team of scientists is needed to understand the links between environmental exposures, especially air pollution and COVID-19. We call for specific research funding to encourage basic and clinical research to understand if/why exposure to environmental factors is associated with more severe disease, why children appear to be protected, and how innate immune responses may be involved. Lessons learned about SARS-Cov-2 infection in our children will help us to understand and reduce disease severity in adults, the opposite of the usual scenario.


Subject(s)
COVID-19/epidemiology , Child Health , Environmental Exposure/adverse effects , Environmental Health , Adult , Age Factors , Air Pollution/adverse effects , Air Pollution/prevention & control , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , Child , Disease Susceptibility/epidemiology , Disease Susceptibility/immunology , Disease Susceptibility/pathology , Environmental Exposure/prevention & control , Fetal Development , Humans , Hygiene Hypothesis , Immunity, Innate , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2
10.
Eur J Clin Invest ; 50(7): e13259, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1084256

ABSTRACT

BACKGROUND: The clinical features of COVID-19 pneumonia range from a mild illness to patients with a very severe illness with acute hypoxemic respiratory failure requiring ventilation and Intensive Care Unit admission. AIMS: To provide a brief overview of the existing evidence for such differences in host response and outcome, and generate hypotheses for divergent patterns and avenues for future research, by highlighting similarities and differences in histopathological appearance between COVID-19 and influenza as well as previous coronavirus outbreaks, and by discussing predisposition through genetics and underlying disease. MATERIALS AND METHOD: We assessed the available early literature for histopathological patterns of COVID-19 pneumonia and underlying risk factors. RESULT: The histopathological spectrum of COVID-19 pneumonia includes variable patterns of epithelial damage, vascular complications, fibrosis and inflammation. Risk factors for a fatal disease include older age, respiratory disease, diabetes mellitus, obesity and hypertension. DISCUSSION: While some risk factors and their potential role in COVID-19 pneumonia are increasingly recognized, little is known about the mechanisms behind episodes of sudden deterioration or the infrequent idiosyncratic clinical demise in otherwise healthy and young subjects. CONCLUSION: The answer to many of the remaining questions regarding COVID-19 pneumonia pathogenesis may in time be provided by genotyping as well careful clinical, serological, radiological and histopathological phenotyping.


Subject(s)
Coronavirus Infections/pathology , Edema/pathology , Inflammation/pathology , Pneumonia, Viral/pathology , Respiratory Mucosa/pathology , Thrombosis/pathology , Age Factors , Angiotensin-Converting Enzyme 2 , Betacoronavirus , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Diabetes Mellitus/epidemiology , Fibrosis , Genetic Predisposition to Disease , HLA Antigens/genetics , Humans , Hypertension/epidemiology , Inflammation/immunology , Influenza, Human/pathology , Obesity/epidemiology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Polymorphism, Genetic , Respiratory Mucosa/immunology , Respiratory System/pathology , Risk Factors , SARS-CoV-2 , Serine Endopeptidases/genetics , Severe Acute Respiratory Syndrome/pathology
11.
PLoS One ; 15(12): e0243735, 2020.
Article in English | MEDLINE | ID: covidwho-1067396

ABSTRACT

INTRODUCTION: Wheezing is a major problem in children, and respiratory viruses are often believed to be the causative agent. While molecular detection tools enable identification of respiratory viruses in wheezing children, it remains unclear if and how these viruses are associated with wheezing. The objective of this systematic review is to clarify the prevalence of different respiratory viruses in children with wheezing. METHODS: We performed an electronic in Pubmed and Global Index Medicus on 01 July 2019 and manual search. We performed search of studies that have detected common respiratory viruses in children ≤18 years with wheezing. We included only studies using polymerase chain reaction (PCR) assays. Study data were extracted and the quality of articles assessed. We conducted sensitivity, subgroup, publication bias, and heterogeneity analyses using a random effects model. RESULTS: The systematic review included 33 studies. Rhinovirus, with a prevalence of 35.6% (95% CI 24.6-47.3, I2 98.4%), and respiratory syncytial virus, at 31.0% (95% CI 19.9-43.3, I2 96.4%), were the most common viruses detected. The prevalence of other respiratory viruses was as follows: human bocavirus 8.1% (95% CI 5.3-11.3, I2 84.6%), human adenovirus 7.7% (95% CI 2.6-15.0, I2 91.0%), influenza virus6.5% (95% CI 2.2-12.6, I2 92.4%), human metapneumovirus5.8% (95% CI 3.4-8.8, I2 89.0%), enterovirus 4.3% (95% CI 0.1-12.9, I2 96.2%), human parainfluenza virus 3.8% (95% CI 1.5-6.9, I2 79.1%), and human coronavirus 2.2% (95% CI 0.6-4.4, I2 79.4%). CONCLUSIONS: Our results suggest that rhinovirus and respiratory syncytial virus may contribute to the etiology of wheezing in children. While the clinical implications of molecular detection of respiratory viruses remains an interesting question, this study helps to illuminate the potential of role respiratory viruses in pediatric wheezing. REVIEW REGISTRATION: PROSPERO, CRD42018115128.


Subject(s)
Respiratory Sounds/etiology , Respiratory Sounds/genetics , Respiratory Tract Infections/diagnosis , Bocavirus/genetics , Bocavirus/isolation & purification , Bocavirus/pathogenicity , Child , Child, Preschool , Coronavirus/isolation & purification , Coronavirus/pathogenicity , Humans , Orthomyxoviridae/genetics , Orthomyxoviridae/isolation & purification , Orthomyxoviridae/pathogenicity , Parainfluenza Virus 1, Human/genetics , Parainfluenza Virus 1, Human/isolation & purification , Parainfluenza Virus 1, Human/pathogenicity , Polymerase Chain Reaction , Respiratory Sounds/physiopathology , Respiratory System/pathology , Respiratory System/virology , Respiratory Tract Infections/genetics , Respiratory Tract Infections/virology
12.
Emerg Microbes Infect ; 10(1): 291-304, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1062822

ABSTRACT

Effective treatments for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Dexamethasone has been shown to confer survival benefits to certain groups of hospitalized patients, but whether glucocorticoids such as dexamethasone and methylprednisolone should be used together with antivirals to prevent a boost of SARS-CoV-2 replication remains to be determined. Here, we show the beneficial effect of methylprednisolone alone and in combination with remdesivir in the hamster model of SARS-CoV-2 infection. Treatment with methylprednisolone boosted RNA replication of SARS-CoV-2 but suppressed viral induction of proinflammatory cytokines in human monocyte-derived macrophages. Although methylprednisolone monotherapy alleviated body weight loss as well as nasal and pulmonary inflammation, viral loads increased and antibody response against the receptor-binding domain of spike protein attenuated. In contrast, a combination of methylprednisolone with remdesivir not only prevented body weight loss and inflammation, but also dampened viral protein expression and viral loads. In addition, the suppressive effect of methylprednisolone on antibody response was alleviated in the presence of remdesivir. Thus, combinational anti-inflammatory and antiviral therapy might be an effective, safer and more versatile treatment option for COVID-19. These data support testing of the efficacy of a combination of methylprednisolone and remdesivir for the treatment of COVID-19 in randomized controlled clinical trials.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Methylprednisolone/therapeutic use , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Animals , Antibodies, Viral/blood , Antiviral Agents/pharmacology , COVID-19/pathology , COVID-19/virology , Cytokines/biosynthesis , Cytokines/immunology , Disease Models, Animal , Drug Therapy, Combination , Female , Humans , Macrophages/immunology , Macrophages/virology , Male , Mesocricetus , Methylprednisolone/pharmacology , RNA, Viral , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/immunology , Viral Load/drug effects , Virus Replication/drug effects
13.
Int J Infect Dis ; 102: 10-13, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1060139

ABSTRACT

OBJECTIVES: This study was performed during the early outbreak period of coronavirus disease 2019 (COVID-19) and the seasonal epidemics of other respiratory viral infections, in order to describe the extent of co-infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with other respiratory viruses. It also compared the diagnostic performances of upper respiratory tract (URT) and lower respiratory tract (LRT) samples for SARS-CoV-2 infection. METHODS: From 25 January to 29 March 2020, all URT and LRT samples collected from patients with suspected COVID-19 received in the virology laboratory of Pitié-Salpêtrière University Hospital (Paris, France) were simultaneously tested for SARS-CoV-2 and other respiratory viruses. RESULTS: A total of 1423 consecutive patients were tested: 677 (47.6%) males, 746 (52.4%) females, median age 50 (range, 1-103) years. Twenty-one (1.5%) patients were positive for both SARS-CoV-2 and other respiratory viruses. The detection rate of SARS-CoV-2 was significantly higher in LRT than in URT (53.6% vs. 13.4%; p<0.0001). The analysis of paired samples from 117 (8.2%) patients showed that SARS-CoV-2 load was lower in URT than in LRT samples in 65% of cases. CONCLUSION: The detection of other respiratory viruses in patients during this epidemic period could not rule out SARS-CoV-2 co-infection. Furthermore, LRT samples increased the accuracy of diagnosis of COVID-19.


Subject(s)
COVID-19/diagnosis , Respiratory System/virology , Virus Diseases/diagnosis , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19/pathology , COVID-19/virology , Child , Child, Preschool , Coinfection/epidemiology , Disease Outbreaks , Female , Hospitalization , Humans , Infant , Male , Middle Aged , Paris/epidemiology , Respiratory System/pathology , SARS-CoV-2/physiology , Virus Diseases/epidemiology , Virus Diseases/virology , Young Adult
14.
J Clin Invest ; 131(6)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1045635

ABSTRACT

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1-dependent (Arg-1-dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.


Subject(s)
COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , Adult , Aged , Aged, 80 and over , Arginase/blood , COVID-19/blood , COVID-19/pathology , Case-Control Studies , Cohort Studies , Female , Humans , Influenza, Human/blood , Influenza, Human/immunology , Influenza, Human/pathology , Interferon-gamma/blood , Interleukin-6/blood , Leukocyte Count , Male , Middle Aged , Myeloid-Derived Suppressor Cells/pathology , Pandemics , Respiratory System/immunology , Respiratory System/pathology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Young Adult
15.
Nat Biotechnol ; 38(8): 970-979, 2020 08.
Article in English | MEDLINE | ID: covidwho-1023942

ABSTRACT

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.


Subject(s)
Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Respiratory System/pathology , Single-Cell Analysis , Transcriptome , Adult , Aged , Angiotensin-Converting Enzyme 2 , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Cell Communication , Cell Differentiation , Coronavirus Infections/virology , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Humans , Immune System/pathology , Inflammation/immunology , Inflammation/pathology , Longitudinal Studies , Male , Middle Aged , Nasopharynx/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/virology , Respiratory System/immunology , Respiratory System/virology , Severity of Illness Index
16.
Cell Death Dis ; 12(1): 53, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1015001

ABSTRACT

Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.


Subject(s)
COVID-19/metabolism , Immunity, Innate/drug effects , Influenza, Human/metabolism , Interleukins/pharmacology , Pneumonia/prevention & control , Poly I-C/toxicity , Respiratory System/immunology , Animals , COVID-19/immunology , COVID-19/virology , Cytokines/metabolism , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Humans , Influenza A virus/isolation & purification , Influenza, Human/immunology , Influenza, Human/virology , Interleukin-1/blood , Interleukins/blood , Male , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Respiratory System/metabolism , Respiratory System/pathology , SARS-CoV-2/isolation & purification
18.
Nat Biotechnol ; 39(6): 705-716, 2021 06.
Article in English | MEDLINE | ID: covidwho-997913

ABSTRACT

In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies-angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial-immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.


Subject(s)
COVID-19/drug therapy , Chemokine CCL3/genetics , Chemokine CCL4/genetics , Hypertension/drug therapy , Receptors, CCR1/genetics , Adult , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Disease Progression , Female , Gene Expression Regulation/drug effects , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/pathology , Inflammation/complications , Inflammation/drug therapy , Inflammation/genetics , Inflammation/virology , Male , Middle Aged , RNA-Seq , Respiratory System/drug effects , Respiratory System/pathology , Respiratory System/virology , Risk Factors , SARS-CoV-2/pathogenicity , Single-Cell Analysis
19.
EBioMedicine ; 63: 103153, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-956065

ABSTRACT

BACKGROUND: The novel human coronavirus SARS-CoV-2 is a major ongoing global threat with huge economic burden. Like all respiratory viruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. METHODS: SARS-CoV-2 Victoria/01/2020 was passaged in Vero/hSLAM cells and virus titre determined by plaque assay. Challenge virus was delivered by intranasal instillation to female ferrets at 5.0 × 106 pfu/ml. Treatment groups received intranasal INNA-051, developed by Ena Respiratory. SARS-CoV-2 RNA was detected using the 2019-nCoV CDC RUO Kit and QuantStudio™ 7 Flex Real-Time PCR System. Histopathological analysis was performed using cut tissues stained with haematoxylin and eosin (H&E). FINDINGS: We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. After 5 days post-exposure to SARS-CoV-2, INNA-051 significantly reduced virus in throat swabs (p=<0.0001) by up to a 24 fold (96% reduction) and in nasal wash (p=0.0107) up to a 15 fold (93% reduction) in comparison to untreated animals. INTERPRETATION: The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT, to reduce SARS-CoV-2 transmission and provide protection against COVID-19. FUNDING: This work was funded by Ena Respiratory, Melbourne, Australia.


Subject(s)
Lipopeptides/administration & dosage , Respiratory System/virology , SARS-CoV-2/pathogenicity , Toll-Like Receptor 2/agonists , Toll-Like Receptor 6/agonists , Virus Shedding , Administration, Intranasal , Animals , COVID-19/drug therapy , COVID-19/pathology , Disease Models, Animal , Female , Ferrets , Immunity, Innate , Lipopeptides/chemistry , Lipopeptides/pharmacology , Nasal Cavity/pathology , Nasal Cavity/virology , Pharynx/pathology , Pharynx/virology , RNA, Viral/metabolism , Real-Time Polymerase Chain Reaction , Respiratory System/pathology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Viral Load/drug effects
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