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1.
Physiol Rep ; 9(20): e15075, 2021 10.
Article in English | MEDLINE | ID: covidwho-1485552

ABSTRACT

Exercise has substantial health benefits, but the effects of exercise on immune status and susceptibility to respiratory infections are less clear. Furthermore, there is limited research examining the effects of prolonged exercise on local respiratory immunity and antiviral activity. To assess the upper respiratory tract in response to exercise, we collected nasal lavage fluid (NALF) from human subjects (1) at rest, (2) after 45 min of moderate-intensity exercise, and (3) after 180 min of moderate-intensity exercise. To assess immune responses of the lower respiratory tract, we utilized a murine model to examine the effect of exercise duration on bronchoalveolar lavage (BAL) fluid immune cell content and lung gene expression. NALF cell counts did not change after 45 min of exercise, whereas 180 min significantly increased total cells and leukocytes in NALF. Importantly, fold change in NALF leukocytes correlated with the post-exercise fatigue rating in the 180-min exercise condition. The acellular portion of NALF contained strong antiviral activity against Influenza A in both resting and exercise paradigms. In mice undergoing moderate-intensity exercise, BAL total cells and neutrophils decreased in response to 45 or 90 min of exercise. In lung lobes, increased expression of heat shock proteins suggested that cellular stress occurred in response to exercise. However, a broad upregulation of inflammatory genes was not observed, even at 180 min of exercise. This work demonstrates that exercise duration differentially alters the cellularity of respiratory tract fluids, antiviral activity, and gene expression. These changes in local mucosal immunity may influence resistance to respiratory viruses, including influenza or possibly other pathogens in which nasal mucosa plays a protective role, such as rhinovirus or SARS-CoV-2.


Subject(s)
Exercise/physiology , Influenza A virus/immunology , Leukocytes/immunology , Lung/immunology , Nasal Lavage Fluid/immunology , Neutrophils/immunology , Adolescent , Adult , Animals , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Female , Gene Expression , Humans , Leukocytes/metabolism , Lung/cytology , Lung/metabolism , Male , Mice , Mice, Inbred BALB C , Nasal Lavage/methods , Nasal Lavage Fluid/cytology , Nasal Mucosa/cytology , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Neutrophils/metabolism , Time Factors , Young Adult
2.
Nat Commun ; 12(1): 5621, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1437680

ABSTRACT

Although serological studies have shown that antibodies against SARS-CoV-2 play an important role in protection against (re)infection, the dynamics of mucosal antibodies during primary infection and their potential impact on viral load and the resolution of disease symptoms remain unclear. During the first pandemic wave, we assessed the longitudinal nasal antibody response in index cases with mild COVID-19 and their household contacts. Nasal and serum antibody responses were analysed for up to nine months. Higher nasal receptor binding domain and spike protein-specific antibody levels at study inclusion were associated with lower viral load. Older age was correlated with more frequent COVID-19 related symptoms. Receptor binding domain and spike protein-specific mucosal antibodies were associated with the resolution of systemic, but not respiratory symptoms. Finally, receptor binding domain and spike protein-specific mucosal antibodies remained elevated up to nine months after symptom onset.


Subject(s)
Antibodies, Neutralizing/analysis , Antibodies, Viral/analysis , COVID-19/diagnosis , Nasal Mucosa/metabolism , SARS-CoV-2/immunology , Adolescent , Adult , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/immunology , Antibodies, Viral/metabolism , COVID-19/blood , COVID-19/immunology , COVID-19/virology , COVID-19 Serological Testing/statistics & numerical data , Child , Humans , Immunity, Mucosal , Longitudinal Studies , Male , Middle Aged , Nasal Mucosa/immunology , Nasal Mucosa/virology , Severity of Illness Index , Viral Load , Young Adult
3.
Viruses ; 12(10)2020 10 16.
Article in English | MEDLINE | ID: covidwho-1389518

ABSTRACT

To address the expression pattern of the SARS-CoV-2 receptor ACE2 and the viral priming protease TMPRSS2 in the respiratory tract, this study investigated RNA sequencing transcriptome profiling of samples of airway and oral mucosa. As shown, ACE2 has medium levels of expression in both small airway epithelium and masticatory mucosa, and high levels of expression in nasal epithelium. The expression of ACE2 is low in mucosal-associated invariant T (MAIT) cells and cannot be detected in alveolar macrophages. TMPRSS2 is highly expressed in small airway epithelium and nasal epithelium and has lower expression in masticatory mucosa. Our results provide the molecular basis that the nasal mucosa is the most susceptible locus in the respiratory tract for SARS-CoV-2 infection and consequently for subsequent droplet transmission and should be the focus for protection against SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/genetics , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/genetics , Serine Endopeptidases/biosynthesis , Virus Internalization , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Epithelium/metabolism , Epithelium/virology , Gene Expression , Gene Expression Profiling , Humans , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Respiratory System/metabolism , Respiratory System/virology , SARS-CoV-2 , Serine Endopeptidases/genetics
5.
Sci Rep ; 11(1): 15927, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1345584

ABSTRACT

Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.


Subject(s)
COVID-19/immunology , Nasal Mucosa/immunology , SARS-CoV-2/immunology , Adolescent , Adult , COVID-19/genetics , Child , Child, Preschool , Female , Humans , Immunity, Cellular , Immunity, Innate , Infant , Male , Middle Aged , Nasal Mucosa/cytology , Nasal Mucosa/metabolism , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transcriptome , Young Adult
6.
Virology ; 561: 65-68, 2021 09.
Article in English | MEDLINE | ID: covidwho-1279712

ABSTRACT

The global COVID-19 pandemic caused by SARS-CoV-2 predominantly affects the elderly. Differential expression of SARS-CoV-2 entry genes may underlie the variable susceptibility in different patient groups. Here, we examined the gene expression of key SARS-CoV-2 entry factors in mucosal biopsies to delineate the roles of age and existing chronic airway disease. A significant inverse correlation between ACE2 and age and a downregulation of NRP1 in patients with airway disease were noted. These results indicate that the interplay between various factors may influence susceptibility and the disease course.


Subject(s)
COVID-19/genetics , COVID-19/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Nasal Mucosa/metabolism , Nasal Mucosa/virology , SARS-CoV-2/physiology , Adolescent , Adult , Age Factors , Aged , Biomarkers , Child , Child, Preschool , Comorbidity , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Virus Internalization , Young Adult
7.
Aging (Albany NY) ; 13(11): 14552-14556, 2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1267005

ABSTRACT

SARS-CoV-2 more readily affects the elderly, especially as they present co-morbidities. In the COVID-19 pathogeny, ACE2 appears to be the key cell receptor for SARS-CoV-2 to infect humans. The level of ACE2 gene expression influences the susceptibility of contracting SARS-CoV-2. In circumstances in which the ACE2 level is low, the incidence of Covid-19 seems to be fewer. Two clinical patterns illustrate this observation, i. e., in infants and in Alzheimer's disease (AD). Very young children and AD patients get little COVID-19, in part probably due to decreased expression of ACE2. The determination of the nasal level of ACE2 gene expression could provide a useful scale to predict the susceptibility to contract the SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/etiology , SARS-CoV-2/metabolism , Alzheimer Disease/complications , Alzheimer Disease/metabolism , COVID-19/metabolism , Cerebrum/metabolism , Disease Susceptibility , Gene Expression , Humans , Infant , Nasal Mucosa/metabolism
8.
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
9.
J Laryngol Otol ; 135(9): 773-778, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1233677

ABSTRACT

OBJECTIVE: Severe acute respiratory syndrome coronavirus-2 uses angiotensin-converting enzyme-2 as a primary receptor for invasion. This study investigated angiotensin-converting enzyme-2 expression in the sinonasal mucosa of patients with chronic rhinosinusitis, as this could be linked to a susceptibility to severe acute respiratory syndrome coronavirus-2 infection. METHODS: Ethmoid sinus specimens were obtained from 27 patients with eosinophilic chronic rhinosinusitis, 18 with non-eosinophilic chronic rhinosinusitis and 18 controls. The angiotensin-converting enzyme-2 and other inflammatory cytokine and chemokine messenger RNA levels were assessed by quantitative reverse transcription polymerase chain reaction. Angiotensin-converting enzyme-2 positive cells were examined immunohistologically. RESULTS: The eosinophilic chronic rhinosinusitis patients showed a significant decrease in angiotensin-converting enzyme-2 messenger RNA expression. In the chronic rhinosinusitis patients, angiotensin-converting enzyme-2 messenger RNA levels were positively correlated with tumour necrosis factor-α and interleukin-1ß (r = 0.4971 and r = 0.3082, respectively), and negatively correlated with eotaxin-3 (r = -0.2938). Angiotensin-converting enzyme-2 immunoreactivity was mainly localised in the ciliated epithelial cells. CONCLUSION: Eosinophilic chronic rhinosinusitis patients with type 2 inflammation showed decreased angiotensin-converting enzyme-2 expression in their sinus mucosa. Angiotensin-converting enzyme-2 regulation was positively related to pro-inflammatory cytokines, especially tumour necrosis factor-α production, in chronic rhinosinusitis patients.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Nasal Mucosa/enzymology , Rhinitis/enzymology , Sinusitis/enzymology , Adult , COVID-19/etiology , Chronic Disease , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Reverse Transcriptase Polymerase Chain Reaction , Rhinitis/complications , Rhinitis/metabolism , SARS-CoV-2/metabolism , Sinusitis/complications , Sinusitis/metabolism
10.
Anat Rec (Hoboken) ; 304(6): 1185-1193, 2021 06.
Article in English | MEDLINE | ID: covidwho-1184569

ABSTRACT

Estrogen is an important hormone for health in both genders. It is indispensable to glucose homeostasis, immune robustness, bone health, cardiovascular health, and neural functions. The main way that estrogen acts in the cells is through estrogen receptors (ERs). The presence of specific estrogen receptors is required for estrogen to have its characteristic ubiquitous action in almost all tissues. Estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) are the major isoforms of estrogen that are highly specific in humans and enable selective hormonal actions in different tissues. This article reviews some of the observed estrogen actions and effects in different tissues and cells through these specific receptors. This ubiquitous, almost ordinary hormone may reveal itself as a significant factor that helped us to better understand the complexity of the human immune system response against respiratory infections, including the COVID-19, and especially in the current state of this painful pandemic.


Subject(s)
COVID-19/immunology , Estrogen Receptor alpha/immunology , Estrogen Receptor beta/immunology , Immune System/immunology , Respiratory System/immunology , SARS-CoV-2/immunology , Animals , COVID-19/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Humans , Immune System/metabolism , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Respiratory System/metabolism , SARS-CoV-2/metabolism
11.
Sci Rep ; 11(1): 7107, 2021 03 29.
Article in English | MEDLINE | ID: covidwho-1157915

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity.1,2 The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean = 12.71%) and 3 sites greater DNAm (mean = 1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference = 3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference = 1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference = 7.86%) and females (mean absolute difference = 8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences. Findings need to be confirmed among adults and patients with risk factors for COVID-19 severity.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , DNA Methylation , Nasal Mucosa/metabolism , Adolescent , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19/virology , Child , Female , Humans , Male , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index
12.
Front Immunol ; 12: 595343, 2021.
Article in English | MEDLINE | ID: covidwho-1133908

ABSTRACT

Likely as in other viral respiratory diseases, SARS-CoV-2 elicit a local immune response, which includes production and releasing of both cytokines and secretory immunoglobulin (SIgA). Therefore, in this study, we investigated the levels of specific-SIgA for SARS-CoV-2 and cytokines in the airways mucosa 37 patients who were suspected of COVID-19. According to the RT-PCR results, the patients were separated into three groups: negative for COVID-19 and other viruses (NEGS, n = 5); negative for COVID-19 but positive for the presence of other viruses (OTHERS, n = 5); and the positive for COVID-19 (COVID-19, n = 27). Higher specific-SIgA for SARS-CoV-2, IFN-ß, and IFN-γ were found in the COVID-19 group than in the other groups. Increased IL-12p70 levels were observed in OTHERS group as compared to COVID-19 group. When the COVID-19 group was sub stratified according to the illness severity, significant differences and correlations were found for the same parameters described above comparing severe COVID-19 to the mild COVID-19 group and other non-COVID-19 groups. For the first time, significant differences are shown in the airway's mucosa immune responses in different groups of patients with or without respiratory SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/metabolism , COVID-19/immunology , Immunoglobulin A/metabolism , Interferons/metabolism , Lung/pathology , Nasal Mucosa/metabolism , SARS-CoV-2/physiology , Adolescent , Adult , Aged , Brazil , Child , Disease Progression , Female , Humans , Male , Middle Aged , Nasal Mucosa/immunology , Young Adult
14.
PLoS Pathog ; 16(12): e1009130, 2020 12.
Article in English | MEDLINE | ID: covidwho-962381

ABSTRACT

The novel coronavirus SARS-CoV-2 is the causative agent of Coronavirus Disease 2019 (COVID-19), a global healthcare and economic catastrophe. Understanding of the host immune response to SARS-CoV-2 is still in its infancy. A 382-nt deletion strain lacking ORF8 (Δ382 herein) was isolated in Singapore in March 2020. Infection with Δ382 was associated with less severe disease in patients, compared to infection with wild-type SARS-CoV-2. Here, we established Nasal Epithelial cells (NECs) differentiated from healthy nasal-tissue derived stem cells as a suitable model for the ex-vivo study of SARS-CoV-2 mediated pathogenesis. Infection of NECs with either SARS-CoV-2 or Δ382 resulted in virus particles released exclusively from the apical side, with similar replication kinetics. Screening of a panel of 49 cytokines for basolateral secretion from infected NECs identified CXCL10 as the only cytokine significantly induced upon infection, at comparable levels in both wild-type and Δ382 infected cells. Transcriptome analysis revealed the temporal up-regulation of distinct gene subsets during infection, with anti-viral signaling pathways only detected at late time-points (72 hours post-infection, hpi). This immune response to SARS-CoV-2 was significantly attenuated when compared to infection with an influenza strain, H3N2, which elicited an inflammatory response within 8 hpi, and a greater magnitude of anti-viral gene up-regulation at late time-points. Remarkably, Δ382 induced a host transcriptional response nearly identical to that of wild-type SARS-CoV-2 at every post-infection time-point examined. In accordance with previous results, Δ382 infected cells showed an absence of transcripts mapping to ORF8, and conserved expression of other SARS-CoV-2 genes. Our findings shed light on the airway epithelial response to SARS-CoV-2 infection, and demonstrate a non-essential role for ORF8 in modulating host gene expression and cytokine production from infected cells.


Subject(s)
COVID-19/virology , Nasal Mucosa/virology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Viral Proteins/genetics , Chemokine CXCL10/immunology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Host-Pathogen Interactions/physiology , Humans , Kinetics , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Transcriptome , Viral Proteins/immunology , Virus Replication/physiology
15.
FEBS J ; 287(17): 3672-3676, 2020 09.
Article in English | MEDLINE | ID: covidwho-960854

ABSTRACT

The novel coronavirus SARS-CoV-2 is the causative agent of the global coronavirus disease 2019 (COVID-19) outbreak. In addition to pneumonia, other COVID-19-associated symptoms have been reported, including loss of smell (anosmia). However, the connection between infection with coronavirus and anosmia remains enigmatic. It has been reported that defects in olfactory cilia lead to anosmia. In this Viewpoint, we summarize transmission electron microscopic studies of cilia in virus-infected cells. In the human nasal epithelium, coronavirus infects the ciliated cells and causes deciliation. Research has shown that viruses such as influenza and Sendai attach to the ciliary membrane. The Sendai virus enters cilia by fusing its viral membrane with the ciliary membrane. A recent study on SARS-CoV-2-human protein-protein interactions revealed that the viral nonstructural protein Nsp13 interacts with the centrosome components, providing a potential molecular link. The mucociliary escalator removes inhaled pathogenic particles and functions as the first line of protection mechanism against viral infection in the human airway. Thus, future investigation into the virus-cilium interface will help further the battle against COVID-19.


Subject(s)
Anosmia/metabolism , COVID-19/metabolism , Centrosome/virology , Cilia/virology , Nasal Mucosa/virology , SARS-CoV-2/pathogenicity , Viral Nonstructural Proteins/metabolism , Anosmia/complications , Anosmia/physiopathology , Anosmia/virology , COVID-19/complications , COVID-19/physiopathology , COVID-19/virology , Centrosome/metabolism , Centrosome/ultrastructure , Cilia/metabolism , Cilia/ultrastructure , Host-Pathogen Interactions/genetics , Humans , Methyltransferases/genetics , Methyltransferases/metabolism , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Nasal Mucosa/metabolism , Nasal Mucosa/ultrastructure , Orthomyxoviridae/metabolism , Orthomyxoviridae/pathogenicity , Protein Binding , RNA Helicases/genetics , RNA Helicases/metabolism , SARS-CoV-2/metabolism , Sendai virus/metabolism , Sendai virus/pathogenicity , Severity of Illness Index , Smell/physiology , Viral Nonstructural Proteins/genetics
17.
Aust J Gen Pract ; 49(11): 728-732, 2020 11.
Article in English | MEDLINE | ID: covidwho-895901

ABSTRACT

BACKGROUND: General practitioners (GPs) have some of the highest rates of mortality from COVID-19 among healthcare workers. SARS-CoV-2 has unique properties that place GPs at particular risk. OBJECTIVE: The aim of this article is to discuss the nose-related features of SARS-CoV-2 that place GPs at risk, and to make recommendations pertinent to the safety and protection of primary healthcare physicians. DISCUSSION: The highest viral load of SARS-CoV-2 is in the nose and nasopharynx. It is often highest early in the illness, before the development of symptoms. Further, SARS-CoV-2 replicates and continues to shed in the nasopharynx long after the virus is no longer detectable in the lower respiratory tract. This places any physician performing examinations on, or procedures involving, the upper respiratory tract at risk for contracting COVID-19. New-onset hyposmia and dysgeusia are indicators for COVID-19 and should be included in screening protocols.


Subject(s)
Betacoronavirus , Coronavirus Infections , General Practitioners/statistics & numerical data , Infection Control , Nasal Cavity/virology , Nasopharynx/virology , Olfaction Disorders/virology , Pandemics , Pneumonia, Viral , Australia , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/mortality , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Coronavirus Infections/virology , Disease Transmission, Infectious/prevention & control , Humans , Infection Control/instrumentation , Infection Control/methods , Infection Control/standards , Nasal Mucosa/metabolism , Occupational Exposure/prevention & control , Occupational Exposure/statistics & numerical data , Pandemics/prevention & control , Personal Protective Equipment/supply & distribution , Pneumonia, Viral/mortality , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Practice Guidelines as Topic , Primary Health Care/standards , Risk Management , SARS-CoV-2 , Viral Load
18.
Nat Commun ; 11(1): 5139, 2020 10 12.
Article in English | MEDLINE | ID: covidwho-851270

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Interferons/metabolism , Interleukin-13/metabolism , Nasal Mucosa/pathology , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/virology , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2 , COVID-19 , Child , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Epithelial Cells/metabolism , Gene Expression Profiling , Gene Expression Regulation , Genetic Variation , Host-Pathogen Interactions , Humans , Inflammation , Middle Aged , Nasal Mucosa/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , SARS-CoV-2 , Serine Endopeptidases/metabolism , Virus Internalization
19.
J Biol Chem ; 295(45): 15174-15182, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-759661

ABSTRACT

Sphingosine has been shown to prevent and eliminate bacterial infections of the respiratory tract, but it is unknown whether sphingosine can be also employed to prevent viral infections. To test this hypothesis, we analyzed whether sphingosine regulates the infection of cultured and freshly isolated ex vivo human epithelial cells with pseudoviral particles expressing SARS-CoV-2 spike (pp-VSV-SARS-CoV-2 spike) that served as a bona fide system mimicking SARS-CoV-2 infection. We demonstrate that exogenously applied sphingosine suspended in 0.9% NaCl prevents cellular infection with pp-SARS-CoV-2 spike. Pretreatment of cultured Vero epithelial cells or freshly isolated human nasal epithelial cells with low concentrations of sphingosine prevented adhesion of and infection with pp-VSV-SARS-CoV-2 spike. Mechanistically, we demonstrate that sphingosine binds to ACE2, the cellular receptor of SARS-CoV-2, and prevents the interaction of the receptor-binding domain of the viral spike protein with ACE2. These data indicate that sphingosine prevents at least some viral infections by interfering with the interaction of the virus with its receptor. Our data also suggest that further preclinical and finally clinical examination of sphingosine is warranted for potential use as a prophylactic or early treatment for coronavirus disease-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Sphingosine/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Cells, Cultured , Chlorocebus aethiops , HEK293 Cells , Humans , Nasal Mucosa/metabolism , Nasal Mucosa/virology , Protein Binding , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects
20.
Cell Rep ; 32(12): 108175, 2020 09 22.
Article in English | MEDLINE | ID: covidwho-747293

ABSTRACT

To predict the tropism of human coronaviruses, we profile 28 SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) using single-cell transcriptomics across various healthy human tissues. SCARFs include cellular factors both facilitating and restricting viral entry. Intestinal goblet cells, enterocytes, and kidney proximal tubule cells appear highly permissive to SARS-CoV-2, consistent with clinical data. Our analysis also predicts non-canonical entry paths for lung and brain infections. Spermatogonial cells and prostate endocrine cells also appear to be permissive to SARS-CoV-2 infection, suggesting male-specific vulnerabilities. Both pro- and anti-viral factors are highly expressed within the nasal epithelium, with potential age-dependent variation, predicting an important battleground for coronavirus infection. Our analysis also suggests that early embryonic and placental development are at moderate risk of infection. Lastly, SCARF expression appears broadly conserved across a subset of primate organs examined. Our study establishes a resource for investigations of coronavirus biology and pathology.


Subject(s)
Coronavirus Infections/pathology , Nasal Mucosa/metabolism , Pneumonia, Viral/pathology , Receptors, Virus/genetics , Viral Tropism/genetics , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/growth & development , COVID-19 , Cell Line , Chlorocebus aethiops , Enterocytes/metabolism , Gene Expression Profiling , Goblet Cells/metabolism , HEK293 Cells , Humans , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/metabolism , Nasal Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Single-Cell Analysis , Vero Cells
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