SARS-CoV-2 transmission via apical syncytia release from primary bronchial epithelia and infectivity restriction in children epithelia

The beta-coronavirus SARS-CoV-2 is at the origin of a persistent worldwide pandemic. SARS-CoV-2 infections initiate in the bronchi of the upper respiratory tract and are able to disseminate to the lower respiratory tract eventually causing acute severe respiratory syndrome with a high degree of mortality in the elderly. Here we use reconstituted primary bronchial epithelia from adult and children donors to follow the infection dynamic following infection with SARS-CoV-2. We show that in bronchial epithelia derived from adult donors, infections initiate in multi-ciliated cells. Then, infection rapidly spread within 24-48h throughout the whole epithelia. Within 3-4 days, large apical syncytia form between multi-ciliated cells and basal cells, which dissipate into the apical lumen. We show that these syncytia are a significant source of the released infectious dose. In stark contrast to these findings, bronchial epithelia reconstituted from children donors are intrinsically more resistant to virus infection and show active restriction of virus spread. This restriction is paired with accelerated release of IFN compared to adult donors. Taken together our findings reveal apical syncytia formation as an underappreciated source of infectious virus for either local dissemination or release into the environment. Furthermore, we provide direct evidence that children bronchial epithelia are more resistant to infection with SARS-CoV-2 providing experimental support for epidemiological observations that SARS-CoV-2 cases fatality is linked to age.

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Age-related susceptibility of ferrets to SARS-CoV-2 infection

Journal of Virology ◽

10.1128/jvi.01455-21 ◽

2021 ◽

Author(s):

Mathias Martins ◽

Maureen H.V. Fernandes ◽

Lok R. Joshi ◽

Diego G. Diel

Keyword(s):

Respiratory Tract ◽

Viral Replication ◽

Viral Entry ◽

Upper Respiratory Tract ◽

Infectious Dose ◽

Virus Shedding ◽

Age Related ◽

Infection Dynamics ◽

Upper Respiratory ◽

Effect Of Age

Susceptibility to SARS-CoV-2 and the outcome of COVID-19 have been linked to underlying health conditions and the age of affected individuals. Here we assessed the effect of age on SARS-CoV-2 infection using a ferret model. For this, young (6-month-old) and aged (18-to-39-month-old) ferrets were inoculated intranasally with various doses of SARS-CoV-2. By using infectious virus shedding in respiratory secretions and seroconversion, we estimated that the infectious dose of SARS-CoV-2 in aged animals is ∼32 plaque forming units (PFU) per animal while in young animals it was estimated to be ∼100 PFU. We showed that viral replication in the upper respiratory tract and shedding in respiratory secretions is enhanced in aged ferrets when compared to young animals. Similar to observations in humans, this was associated with higher transcription levels of two key viral entry factors - ACE2 and TMPRSS2 - in the upper respiratory tract of aged ferrets. Importance In humans, ACE2 and TMPRSS2 are expressed in various cells and tissues, and a differential expression have been described in young and old people, with a higher level of expressing cells being detected in the nasal brushing of older people when compared to young individuals. We described the same pattern occurring in ferrets and we demonstrated that age affects susceptibility of ferrets to SARS-CoV-2. Aged animals were more likely to get infected when exposed to lower infectious dose of the virus when compared to young animals and the viral replication in the URT and shedding is enhanced in aged ferrets. Together these results suggest that the higher infectivity and enhanced ability of SARS-CoV-2 to replicate in aged individuals is associated – at least in part – with transcription levels of ACE2 and TMPRSS2 at the sites of virus entry. The young and aged ferret model developed here may represent a great platform to assess age-related differences in SARS-CoV-2 infection dynamics and replication.

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Uptake of Sialic Acid by NontypeableHaemophilus influenzaeIncreases Complement Resistance through Decreasing IgM-Dependent Complement Activation

Infection and Immunity ◽

10.1128/iai.00077-19 ◽

2019 ◽

Vol 87 (6) ◽

Cited By ~ 3

Author(s):

Marjolein M. P. Oerlemans ◽

Sam J. Moons ◽

Jurriaan J. A. Heming ◽

Thomas J. Boltje ◽

Marien I. de Jonge ◽

...

Keyword(s):

Respiratory Tract ◽

Complement Activation ◽

Respiratory Tract Infections ◽

The Elderly ◽

Antibiotic Use ◽

Sialic Acids ◽

Classical Pathway ◽

Upper Respiratory Tract ◽

Content Type ◽

Tract Infections

ABSTRACTAlthough nontypeableHaemophilus influenzae(NTHi) is a human-specific nasopharyngeal commensal bacterium, it also causes upper respiratory tract infections in children and lower respiratory tract infections in the elderly, resulting in frequent antibiotic use. The transition from symbiotic colonizing bacterium to opportunistic pathogen is not completely understood. Incorporation of sialic acids into lipooligosaccharides is thought to play an important role in bacterial virulence. It has been known for more than 25 years that sialic acids increase resistance to complement-mediated killing; however, the mechanism of action has not been elucidated thus far. Here, we provide evidence that growth of NTHi in the presence of sialic acids Neu5Ac and Neu5Gc decreases complement-mediated killing through abrogating the classical pathway of complement activation by preventing mainly IgM antibody binding to the bacterial surface. Therefore, strategies that interfere with uptake or incorporation of sialic acids into the lipooligosaccharide, such as novel antibiotics and vaccines, might be worth exploring to prevent or treat NTHi infections.

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Common upper respiratory tract problems in the elderly—A guide to clinical diagnosis and prudent prescription

South African Family Practice ◽

10.1080/20786204.2006.10873390 ◽

2006 ◽

Vol 48 (5) ◽

pp. 20-23 ◽

Cited By ~ 1

Author(s):

L Geffen

Keyword(s):

Respiratory Tract ◽

Clinical Diagnosis ◽

The Elderly ◽

Upper Respiratory Tract ◽

Upper Respiratory

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Acute upper respiratory tract viral illness and influenza immunization in homes for the elderly

Epidemiology and Infection ◽

10.1017/s0950268800048251 ◽

1990 ◽

Vol 105 (3) ◽

pp. 609-618 ◽

Cited By ~ 42

Author(s):

K. G. Nicholson ◽

D. J. Baker ◽

A. Farquhar ◽

D. Hurd ◽

J. Kent ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Respiratory Tract ◽

The Elderly ◽

Upper Respiratory Tract ◽

Medical Conditions ◽

Influenza Immunization ◽

Immunization Rates ◽

Homes For The Elderly ◽

Upper Respiratory ◽

Syncytial Virus

SUMMARYOccupants of 482 long-stay and 33 short-stay beds in 11 Leicester City Council homes for the elderly were studied during a 30-week period from September 1988 to March 1989 to determine the incidence, aetiology, morbidity, and mortality of acute upper respiratory tract viral infections and the use of influenza vaccine.Influenza immunization rates by home ranged from 15·4 to 90% (mean 45%). There were no differences in the distribution of medical conditions by home. The highest immunization rates were seen in people with chest disease (77%), heart disease (60%), diabetes (56%), and those with three medical conditions (75%). There was an average of 0·7 upper respiratory episodes per bed per annum with a mortality of 3·4% (6/179). Half of all episodes were seen by a general medical practitioner and 81 of 90 (90%) referrals were prescribed antibiotics costing approximately £7.50 per patient. Lower respiratory tract complications developed during 45 (25%) of 179 episodes including 3 of 12 coronavirus infections, 3 of 9 respiratory syncytial virus infections, 2 of 4 adenovirus infections, 1 of 11 rhinovirus infections, but none of 5 influenza infections. Respiratory infections were caused mostly by pathogens other than influenza virus during the influenza period documented nationally. This highlights the role of coronaviruses, respiratory syncytial virus, and unidentified agents in the elderly, and questions the assumptions made in American estimates on the impact of influenza and the value of influenza vaccines.

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Age-related susceptibility of ferrets to SARS-CoV-2 infection

10.1101/2021.08.16.456510 ◽

2021 ◽

Author(s):

Mathias Martins ◽

Maureen H.V. Fernandes ◽

Lok R Joshi ◽

Diego Diel

Keyword(s):

Respiratory Tract ◽

Viral Entry ◽

Infectious Virus ◽

Health Conditions ◽

Upper Respiratory Tract ◽

Infectious Dose ◽

Virus Shedding ◽

Age Related ◽

Upper Respiratory ◽

Effect Of Age

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Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics

Journal of Experimental Medicine ◽

10.1084/jem.20210583 ◽

2021 ◽

Vol 218 (8) ◽

Author(s):

Nagarjuna R. Cheemarla ◽

Timothy A. Watkins ◽

Valia T. Mihaylova ◽

Bao Wang ◽

Dejian Zhao ◽

...

Keyword(s):

Respiratory Tract ◽

Viral Replication ◽

Innate Immune ◽

Airway Epithelial ◽

Upper Respiratory Tract ◽

Infectious Dose ◽

Interferon Stimulated Genes ◽

Upper Respiratory ◽

Early Replication

Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.

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The nasopharyngeal microbiome

Emerging Topics in Life Sciences ◽

10.1042/etls20170041 ◽

2017 ◽

Vol 1 (4) ◽

pp. 297-312 ◽

Cited By ~ 4

Author(s):

David W. Cleary ◽

Stuart C. Clarke

Keyword(s):

Respiratory Tract ◽

The Elderly ◽

Airway Disease ◽

Invasive Disease ◽

Microbial Consortia ◽

Environmental Drivers ◽

Respiratory Morbidity ◽

Future Research ◽

Upper Respiratory Tract ◽

Chronic Airway Disease

Human microbiomes have received increasing attention over the last 10 years, leading to a pervasiveness of hypotheses relating dysbiosis to health and disease. The respiratory tract has received much less attention in this respect than that of, for example, the human gut. Nevertheless, progress has been made in elucidating the immunological, ecological and environmental drivers that govern these microbial consortia and the potential consequences of aberrant microbiomes. In this review, we consider the microbiome of the nasopharynx, a specific niche of the upper respiratory tract. The nasopharynx is an important site, anatomically with respect to its gateway position between upper and lower airways, and for pathogenic bacterial colonisation. The dynamics of the latter are important for long-term respiratory morbidity, acute infections of both invasive and non-invasive disease and associations with chronic airway disease exacerbations. Here, we review the development of the nasopharyngeal (NP) microbiome over the life course, examining it from the early establishment of resilient profiles in neonates through to perturbations associated with pneumonia risk in the elderly. We focus specifically on the commensal, opportunistically pathogenic members of the NP microbiome that includes Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis. In addition, we consider the role of relatively harmless genera such as Dolosigranulum and Corynebacterium. Understanding that the NP microbiome plays such a key, beneficial role in maintaining equilibrium of commensal species, prevention of pathogen outgrowth and host immunity enables future research to be directed appropriately.

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THE QUANTITATIVE AND QUALITATIVE PARAMETERS OF RHYNTHYTOCOGRAMS IN METHANOL AND FORMALDEHYDE IMPACT IN PRODUCTION ENVIRONMENT

Russian Clinical Laboratory Diagnostics ◽

10.18821/0869-2084-2019-64-2-78-82 ◽

2019 ◽

Vol 64 (2) ◽

pp. 78-82

Author(s):

L. A. Bankovskaya ◽

A. P. Shchekotova ◽

N. N. Malyutina

Keyword(s):

Respiratory Tract ◽

Chronic Inflammation ◽

Work Experience ◽

Degenerative Changes ◽

Ciliated Epithelium ◽

Upper Respiratory Tract ◽

Production Environment ◽

Chemical Production ◽

Upper Respiratory ◽

High Degree

This study is devoted to assessing the state of the mucous membrane of the upper respiratory tract of the workers of chemical production of methanol and formaldehyde. A total of 450 workers were examined by rhinocytogram (RCH) evaluation. As a result of the study, studies have found that people with work experience of up to 10 years in the production of methanol and formaldehyde in the RCH the siggns of chronic inflammation is more likely to be detected. More experienced patients (more than 10 years of work experience) studies have found the establishment of morphological signs of protective and degenerative changes in ciliated epithelium, and there is a high degree of connection between the development of protective changes and the exposure to chemicals (RR = 2.71, etiological share, EF = 56.4%) and the development of degenerative changes (RR = 3.28, EF = 65.4%). These results are considered by the authors as the biomarkers of the development of a professionally conditioned lesion of the upper respiratory tract.

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Streptococcus pneumoniae Colonization Disrupts the Microbial Community within the Upper Respiratory Tract of Aging Mice

Infection and Immunity ◽

10.1128/iai.01275-15 ◽

2016 ◽

Vol 84 (4) ◽

pp. 906-916 ◽

Cited By ~ 19

Author(s):

Netusha Thevaranjan ◽

Fiona J. Whelan ◽

Alicja Puchta ◽

Eta Ashu ◽

Laura Rossi ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Respiratory Tract ◽

Bacterial Colonization ◽

The Elderly ◽

Rrna Gene ◽

Host Immune System ◽

Upper Respiratory Tract ◽

Content Type ◽

Increased Risk ◽

Upper Respiratory

Nasopharyngeal colonization by the Gram-positive bacteriumStreptococcus pneumoniaeis a prerequisite for pneumonia and invasive pneumococcal diseases. Colonization is asymptomatic, involving dynamic and complex interplay between commensals, the host immune system, and environmental factors. The elderly are at an increased risk of developing pneumonia, which might be due to changes in the respiratory microbiota that would impact bacterial colonization and persistence within this niche. We hypothesized that the composition of the upper respiratory tract (URT) microbiota changes with age and subsequently can contribute to sustained colonization and inefficient clearance ofS. pneumoniae. To test this, we used a mouse model of pneumococcal colonization to compare the composition of the URT microbiota in young, middle-aged, and old mice in the naive state and during the course of colonization using nasal pharyngeal washes. Sequencing of variable region 3 (V3) of the 16S rRNA gene was used to identify changes occurring with age and throughout the course ofS. pneumoniaecolonization. We discovered that age affects the composition of the URT microbiota and that colonization withS. pneumoniaeis more disruptive of preexisting communities in older mice. We have further shown that host-pathogen interactions followingS. pneumoniaecolonization can impact the populations of resident microbes, includingStaphylococcusandHaemophilus. Together, our findings indicate alterations to the URT microbiota could be detrimental to the elderly, resulting in increased colonization ofS. pneumoniaeand decreased efficiency in its clearance.

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