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1.
PLoS One ; 17(11): e0277201, 2022.
Article in English | MEDLINE | ID: covidwho-2197029

ABSTRACT

OBJECTIVES: Respiratory tract infection (RTI) incidence varies between people, but little is known about why. The aim of this study is therefore to identify risk factors for acquiring RTIs. METHODS: We conducted a secondary analysis of 16,908 participants in the PRIMIT study, a pre-pandemic randomised trial showing handwashing reduced incidence of RTIs in the community. Data was analysed using multivariable logistic regression analyses of self-reported RTI acquisition. RESULTS: After controlling for handwashing, RTI in the previous year (1 to 2 RTIs: adjusted OR 1.96, 95% CI 1.79 to 2.13, p<0.001; 3 to 5 RTIs: aOR 3.89, 95% CI 3.49 to 4.33, p<0.001; ≥6 RTIs: OR 5.52, 95% CI 4.37 to 6.97, p<0.001); skin conditions that prevent handwashing (aOR 1.39, 95% CI 1.24 to 1.55, p<0.001); children under 16 years in the household (aOR 1.27, 95% CI 1.12, 1.43, p<0.001); chronic lung condition (aOR 1.16, 95% CI 1.02 to 1.32, p = 0.026); female sex (aOR 1.10, 95% CI 1.03 to 1.18, p = 0.005), and post-secondary education (aOR 1.09, 95% CI 1.02 to 1.17, p = 0.01) increased the likelihood of RTI. Those over the age of 65 years were less likely to develop an infection (aOR 0.89, 95% CI 0.82 to 0.97, p = 0.009). Household crowding and influenza vaccination do not influence RTI acquisition. A post-hoc exploratory analysis found no evidence these subgroups differentially benefited from handwashing. CONCLUSIONS: Previous RTIs, chronic lung conditions, skin conditions that prevent handwashing, and the presence of household children predispose to RTI acquisition. Further research is needed to understand how host and microbial factors explain the relationship between previous and future RTIs.


Subject(s)
Community-Acquired Infections , Respiratory Tract Infections , Aged , Child , Female , Humans , Community-Acquired Infections/epidemiology , Community-Acquired Infections/prevention & control , Crowding , Family Characteristics , Respiratory System , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/prevention & control , Risk Factors
2.
Respir Care ; 67(12): 1609-1632, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2144287

ABSTRACT

Delphi survey techniques are a common consensus method used to collect feedback from an expert panel to inform practices, establish guidelines, and identify research priorities. Collecting respiratory therapists' (RT) expertise and experiences as part of consensus-building methodologies is one way to ensure that they align with RT practices and to better influence respiratory care practice. This narrative review aimed to report the RT representation in expert panels of Delphi studies focused on respiratory therapy practices and research priorities. The research question that guided this review is: to what extent are RTs included as expert participants among published Delphi studies relate to respiratory therapy and research topics? We conducted a structured search of the literature and identified 23 papers that reported Delphi studies related to respiratory care practices and 15 that reported on respiratory-related research priorities. Delphi studies that focused on reporting consensus on respiratory care practices included the following: (1) mechanical ventilation, (2) high-flow nasal cannula therapy, (3) COVID-19 respiratory management, (4) home oxygen therapy, (5) cardiopulmonary monitoring, and (6) disease-specific guidelines. Delphi studies that focused on establishing respiratory research priorities included the following: (1) theory and practice-orientated knowledge gaps, and (2) priority research topics for empirical investigation. The results of this review suggest that RTs were rarely included as expert participants and, when involved, were minimally represented (5% to 33%). Given RTs' diverse and relevant experience in respiratory care, incorporating their perspectives to inform future education, respiratory care practices, and research priorities would allow evidence to better align with knowledge gaps deemed important for the respiratory therapy profession.


Subject(s)
COVID-19 , Humans , Delphi Technique , Respiratory System , Research , Allied Health Personnel
3.
Elife ; 112022 11 08.
Article in English | MEDLINE | ID: covidwho-2124072

ABSTRACT

Co-infected hosts, individuals that carry more than one infectious agent at any one time, have been suggested to facilitate pathogen transmission, including the emergence of supershedding events. However, how the host immune response mediates the interactions between co-infecting pathogens and how these affect the dynamics of shedding remains largely unclear. We used laboratory experiments and a modeling approach to examine temporal changes in the shedding of the respiratory bacterium Bordetella bronchiseptica in rabbits with one or two gastrointestinal helminth species. Experimental data showed that rabbits co-infected with one or both helminths shed significantly more B. bronchiseptica, by direct contact with an agar petri dish, than rabbits with bacteria alone. Co-infected hosts generated supershedding events of higher intensity and more frequently than hosts with no helminths. To explain this variation in shedding an infection-immune model was developed and fitted to rabbits of each group. Simulations suggested that differences in the magnitude and duration of shedding could be explained by the effect of the two helminths on the relative contribution of neutrophils and specific IgA and IgG to B. bronchiseptica neutralization in the respiratory tract. However, the interactions between infection and immune response at the scale of analysis that we used could not capture the rapid variation in the intensity of shedding of every rabbit. We suggest that fast and local changes at the level of respiratory tissue probably played a more important role. This study indicates that co-infected hosts are important source of variation in shedding, and provides a quantitative explanation into the role of helminths to the dynamics of respiratory bacterial infections.


Subject(s)
Bordetella Infections , Bordetella bronchiseptica , Helminths , Respiratory Tract Infections , Animals , Rabbits , Bordetella Infections/microbiology , Respiratory Tract Infections/microbiology , Respiratory System
4.
Viruses ; 14(11)2022 Nov 14.
Article in English | MEDLINE | ID: covidwho-2110280

ABSTRACT

Viral respiratory infections contribute to significant morbidity and mortality in children. Currently, there are limited reports on the composition and abundance of the normal commensal respiratory virome in comparison to those in severe acute respiratory infections (SARIs) state. This study characterised the respiratory RNA virome in children ≤ 5 years with (n = 149) and without (n = 139) SARI during the summer and winter of 2020/2021 seasons in South Africa. Nasopharyngeal swabs were, collected, pooled, enriched for viral RNA detection, sequenced using Illumina MiSeq, and analysed using the Genome Detective bioinformatic tool. Overall, Picornaviridae, Paramoxyviridae, Pneumoviridae, Picobirnaviridae, Totiviridae, and Retroviridae families were the most abundant viral population in both groups across both seasons. Human rhinovirus and endogenous retrovirus K113 were detected in most pools, with exclusive detection of Pneumoviridae in SARI pools. Generally, higher viral diversity/abundance was seen in children with SARI and in the summer pools. Several plant/animal viruses, eukaryotic viruses with unclear pathogenicity including a distinct rhinovirus A type, were detected. This study provides remarkable data on the respiratory RNA virome in children with and without SARI with a degree of heterogeneity of known viruses colonizing their respiratory tract. The implication of the detected viruses in the dynamics/progression of SARI requires further investigations.


Subject(s)
COVID-19 , Pneumonia , Respiratory Tract Infections , Viruses , Child , Animals , Humans , Virome , South Africa/epidemiology , Seasons , RNA , Pandemics , Viruses/genetics , Respiratory System
5.
Sci Immunol ; 7(76): eadd4853, 2022 10 28.
Article in English | MEDLINE | ID: covidwho-2088390

ABSTRACT

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Immunity, Mucosal , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Viral Vaccines/genetics , Antibodies, Viral , RNA, Messenger , COVID-19/prevention & control , COVID-19 Vaccines , Vaccination , Respiratory System , Antibodies, Neutralizing
8.
Recent Adv Antiinfect Drug Discov ; 17(1): 2-12, 2022.
Article in English | MEDLINE | ID: covidwho-2065268

ABSTRACT

BACKGROUND: COVID-19 is still soaring, and the new delta COVID-19 variant is on the rise and spreading around the world. OBJECTIVE: We conducted a patent analysis to better understand the therapeutic strategy developed for antivirals available for the disorders of the respiratory system. MATERIALS AND METHODS: European granted patents filed from January 2002 to June 2021 were analyzed. We used a combination of International patent classification (IPC) "A61p31/12" and "A61p11/00" to search the relevant documents. RESULTS: Our study showed R&D of antiviral drugs for disorders of the respiratory system to be decreasing over the past 20 years. Chemical drugs showed various chemical structures. The development of chemical drugs or herbal medicines appeared to commence earlier than the biological products. Also, the results indicated that large global companies play a leading role in developing kinase inhibitors as chemical drugs. CONCLUSION: There are three strategies for developing antiviral drugs for the disorders of the respiratory system, including chemical drugs, herbal medicines or natural products, and biological products. Herbal medicines may provide a new insight and approach to developing antiviral drugs for disorders of the respiratory system. A combination of chemical drugs and natural products may be a promising therapeutic method for treating patients with COVID- 19.


Subject(s)
Biological Products , COVID-19 , Plants, Medicinal , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Respiratory System , SARS-CoV-2
9.
Vet Res ; 53(1): 70, 2022 Sep 06.
Article in English | MEDLINE | ID: covidwho-2064844

ABSTRACT

Bovine respiratory disease (BRD) is one of the most important diseases impacting the global cattle industry, resulting in significant economic loss. Commonly referred to as shipping fever, BRD is especially concerning for young calves during transport when they are most susceptible to developing disease. Despite years of extensive study, managing BRD remains challenging as its aetiology involves complex interactions between pathogens, environmental and host factors. While at the beginning of the twentieth century, scientists believed that BRD was only caused by bacterial infections ("bovine pasteurellosis"), we now know that viruses play a key role in BRD induction. Mixtures of pathogenic bacteria and viruses are frequently isolated from respiratory secretions of animals with respiratory illness. The increased diagnostic screening data has changed our understanding of pathogens contributing to BRD development. In this review, we aim to comprehensively examine experimental evidence from all existing studies performed to understand coinfections between respiratory pathogens in cattle. Despite the fact that pneumonia has not always been successfully reproduced by in vivo calf modelling, several studies attempted to investigate the clinical significance of interactions between different pathogens. The most studied model of pneumonia induction has been reproduced by a primary viral infection followed by a secondary bacterial superinfection, with strong evidence suggesting this could potentially be one of the most common scenarios during BRD onset. Different in vitro studies indicated that viral priming may increase bacterial adherence and colonization of the respiratory tract, suggesting a possible mechanism underpinning bronchopneumonia onset in cattle. In addition, a few in vivo studies on viral coinfections and bacterial coinfections demonstrated that a primary viral infection could also increase the pathogenicity of a secondary viral infection and, similarly, dual infections with two bacterial pathogens could increase the severity of BRD lesions. Therefore, different scenarios of pathogen dynamics could be hypothesized for BRD onset which are not limited to a primary viral infection followed by a secondary bacterial superinfection.


Subject(s)
Bovine Respiratory Disease Complex , Cattle Diseases , Coinfection , Pasteurella Infections , Respiratory Tract Diseases , Superinfection , Virus Diseases , Animals , Bacteria , Cattle , Cattle Diseases/microbiology , Coinfection/veterinary , Pasteurella Infections/veterinary , Respiratory System , Respiratory Tract Diseases/veterinary , Superinfection/veterinary , Virus Diseases/veterinary
10.
Microbiome ; 10(1): 165, 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-2053973

ABSTRACT

SARS-CoV-2 infection causes COVID-19 disease, which can result in consequences ranging from undetectable to fatal, focusing attention on the modulators of outcomes. The respiratory tract microbiome is thought to modulate the outcomes of infections such as influenza as well as acute lung injury, raising the question to what degree does the airway microbiome influence COVID-19? Here, we review the results of 56 studies examining COVID-19 and the respiratory tract microbiome, summarize the main generalizations, and point to useful avenues for further research. Although the results vary among studies, a few consistent findings stand out. The diversity of bacterial communities in the oropharynx typically declined with increasing disease severity. The relative abundance of Haemophilus and Neisseria also declined with severity. Multiple microbiome measures tracked with measures of systemic immune responses and COVID outcomes. For many of the conclusions drawn in these studies, the direction of causality is unknown-did an alteration in the microbiome result in increased COVID severity, did COVID severity alter the microbiome, or was some third factor the primary driver, such as medication use. Follow-up mechanistic studies can help answer these questions. Video Abstract.


Subject(s)
COVID-19 , Influenza, Human , Microbiota , Humans , Respiratory System , SARS-CoV-2
11.
PLoS One ; 17(7): e0270770, 2022.
Article in English | MEDLINE | ID: covidwho-2039352

ABSTRACT

BACKGROUND: The risk and characteristics of upper respiratory tract (URT) bacterial infections (URT-BI) among HIV (+) patients is understudied. We analyzed factors associated with its occurrence and the spectrum of culturable pathogens among patients routinely followed at the HIV Out-Patient Clinic in Warsaw. METHODS: All HIV (+) patients with available URT swab culture were included into analyses. Patients were followed from the day of registration in the clinic until first positive URT swab culture or last clinical visit from January 1, 2007 to July 31, 2016. Cox proportional hazard models were used to identify factors associated with positive URT swabs culture (those with p<0.1 in univariate included into multivariable). RESULTS: In total 474 patients were included into the analyses, 166 with culturable URT swab. In general, 416 (87.8%) patients were male, 342 (72.1%) were infected through MSM contact, 253 (53.4%) were on antiretroviral therapy. Median follow-up time was 3.4 (1.3-5.7) years, age 35.2 (30.6-42.6) years and CD4+ count 528 (400-685) cells/µl. The most common cultured bacteria were S. aureus (40.4%) and S. pyogenes (13.9%) (Table 1). Patients with culturable URT-BI were more likely to be MSM (68.5% vs 78.9%; p<0.016), have detectable viral load (20.9% vs 12.0%; p<0.0001) and CD4+ cell count <500 cells/µl (55.2% vs 39.0%; p = 0.003) (Table 2). In multivariate survival analyses detectable viral load (HR3.13; 95%Cl: 2.34-4.19) and MSM (1.63;1.09-2.42) were increasing, but older age (0.63;0.58-0.69, per 5 years older) and higher CD4+ count (0.90;0.85-0.95, per 100 cells/µl) decreasing the risk of culturable URT-BI (Table 2). CONCLUSIONS: Culturable URT-BI are common among HIV-positive patients with high CD4+ count. Similarly to general population most common cultured bacteria were S. aureus and S. pyogenes. Risk factors identified in multivariate survival analysis indicate that younger MSM patients with detectable HIV viral load are at highest risk. In clinical practice this group of patients requires special attention.


Subject(s)
Bacterial Infections , HIV Infections , Respiratory Tract Infections , Sexual and Gender Minorities , Adult , Antiretroviral Therapy, Highly Active , Bacteria , Bacterial Infections/complications , Bacterial Infections/drug therapy , Bacterial Infections/epidemiology , CD4 Lymphocyte Count , Female , HIV Infections/drug therapy , Homosexuality, Male , Humans , Male , Reinfection , Respiratory System , Respiratory Tract Infections/complications , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/epidemiology , Risk Factors , Staphylococcus aureus , Viral Load
12.
Cells ; 11(14)2022 07 19.
Article in English | MEDLINE | ID: covidwho-2032862

ABSTRACT

A multitude of evidence has suggested the differential incidence, prevalence and severity of asthma between males and females. A compilation of recent literature recognized sex differences as a significant non-modifiable risk factor in asthma pathogenesis. Understanding the cellular and mechanistic basis of sex differences remains complex and the pivotal point of this ever elusive quest, which remains to be clarified in the current scenario. Sex steroids are an integral part of human development and evolution while also playing a critical role in the conditioning of the immune system and thereby influencing the function of peripheral organs. Classical perspectives suggest a pre-defined effect of sex steroids, generalizing estrogens popularly under the "estrogen paradox" due to conflicting reports associating estrogen with a pro- and anti-inflammatory role. On the other hand, androgens are classified as "anti-inflammatory," serving a protective role in mitigating inflammation. Although considered mainstream and simplistic, this observation remains valid for numerous reasons, as elaborated in the current review. Women appear immune-favored with stronger and more responsive immune elements than men. However, the remarkable female predominance of diverse autoimmune and allergic diseases contradicts this observation suggesting that hormonal differences between the sexes might modulate the normal and dysfunctional regulation of the immune system. This review illustrates the potential relationship between key elements of the immune cell system and their interplay with sex steroids, relevant to structural cells in the pathophysiology of asthma and many other lung diseases. Here, we discuss established and emerging paradigms in the clarification of observed sex differences in asthma in the context of the immune system, which will deepen our understanding of asthma etiopathology.


Subject(s)
Asthma , Asthma/pathology , Estrogens , Female , Gonadal Steroid Hormones , Humans , Male , Respiratory System/pathology , Steroids
14.
Sci Rep ; 12(1): 11125, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-2028698

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a biosafety level (BSL)-3 pathogen; therefore, its research environment is limited. Pseudotyped viruses that mimic the infection of SARS-CoV-2 have been widely used for in vitro evaluation because they are available in BSL-2 containment laboratories. However, in vivo application is inadequate. Therefore, animal models instigated with animal BSL-2 will provide opportunities for in vivo evaluation. Hamsters (6-10-week-old males) were intratracheally inoculated with luciferase-expressing vesicular stomatitis virus (VSV)-based SARS-CoV-2 pseudotyped virus. The lungs were harvested 24-72 h after inoculation and luminescence was measured using an in vivo imaging system. Lung luminescence after inoculation with the SARS-CoV-2 pseudotyped virus increased in a dose-dependent manner and peaked at 48 h. The VSV-G (envelope G) pseudotyped virus also induced luminescence; however, a 100-fold concentration was required to reach a level similar to that of the SARS-CoV-2 pseudotyped virus. The SARS-CoV-2 pseudotyped virus is applicable to SARS-CoV-2 respiratory infections in a hamster model. Because of the single-round infectious virus, the model can be used to study the steps from viral binding to entry, which will be useful for future research on SARS-CoV-2 entry without using live SARS-CoV-2 or transgenic animals.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Cricetinae , Male , Respiratory Rate , Respiratory System , Viral Pseudotyping
15.
J Occup Environ Med ; 64(11): e792, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2018293
16.
Nat Immunol ; 23(9): 1324-1329, 2022 09.
Article in English | MEDLINE | ID: covidwho-2016769

ABSTRACT

T cells can contribute to clearance of respiratory viruses that cause acute-resolving infections such as SARS-CoV-2, helping to provide long-lived protection against disease. Recent studies have suggested an additional role for T cells in resisting overt infection: pre-existing cross-reactive responses were preferentially enriched in healthcare workers who had abortive infections1, and in household contacts protected from infection2. We hypothesize that such early viral control would require pre-existing cross-reactive memory T cells already resident at the site of infection; such airway-resident responses have been shown to be critical for mediating protection after intranasal vaccination in a murine model of SARS-CoV3. Bronchoalveolar lavage samples from the lower respiratory tract of healthy donors obtained before the COVID-19 pandemic revealed airway-resident, SARS-CoV-2-cross-reactive T cells, which correlated with the strength of human seasonal coronavirus immunity. We therefore demonstrate the potential to harness functional airway-resident SARS-CoV-2-reactive T cells in next-generation mucosal vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Viral , Cross Reactions , Humans , Mice , Pandemics , Respiratory System
17.
Microbiome ; 10(1): 65, 2022 04 22.
Article in English | MEDLINE | ID: covidwho-2002234

ABSTRACT

BACKGROUND: Critically ill 2019 coronavirus disease (COVID-19) patients under invasive mechanical ventilation (IMV) are 10 to 40 times more likely to die than the general population. Although progression from mild to severe COVID-19 has been associated with hypoxia, uncontrolled inflammation, and coagulopathy, the mechanisms involved in the progression to severity are poorly understood. METHODS: The virome of tracheal aspirates (TA) from 25 COVID-19 patients under IMV was assessed through unbiased RNA sequencing (RNA-seq), and correlation analyses were conducted using available clinical data. Unbiased sequences from nasopharyngeal swabs (NS) from mild cases and TA from non-COVID patients were included in our study for further comparisons. RESULTS: We found higher levels and differential expression of human endogenous retrovirus K (HERV-K) genes in TA from critically ill and deceased patients when comparing nasopharyngeal swabs from mild cases to TA from non-COVID patients. In critically ill patients, higher HERV-K levels were associated with early mortality (within 14 days of diagnosis) in the intensive care unit. Increased HERV-K expression in deceased patients was associated with IL-17-related inflammation, monocyte activation, and an increased consumption of clotting/fibrinolysis factors. Moreover, increased HERV-K expression was detected in human primary monocytes from healthy donors after experimental SARS-CoV-2 infection in vitro. CONCLUSION: Our data implicate the levels of HERV-K transcripts in the physiopathology of COVID-19 in the respiratory tract of patients under invasive mechanical ventilation. Video abstract.


Subject(s)
COVID-19 , Endogenous Retroviruses , Critical Illness , Endogenous Retroviruses/genetics , Humans , Inflammation , Respiratory System , SARS-CoV-2
18.
EBioMedicine ; 81: 104132, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1996118

ABSTRACT

BACKGROUND: Human seasonal coronaviruses usually cause mild upper-respiratory tract infection, but severe complications can occur in specific populations. Research into seasonal coronaviruses is limited and robust experimental models are largely lacking. This study aims to establish human airway organoids (hAOs)-based systems for seasonal coronavirus infection and to demonstrate their applications in studying virus-host interactions and therapeutic development. METHODS: The infections of seasonal coronaviruses 229E, OC43 and NL63 in 3D cultured hAOs with undifferentiated or differentiated phenotypes were tested. The kinetics of virus replication and production was profiled at 33 °C and 37 °C. Genome-wide transcriptome analysis by RNA sequencing was performed in hAOs under various conditions. The antiviral activity of molnupiravir and remdesivir, two approved medications for treating COVID19, was tested. FINDINGS: HAOs efficiently support the replication and infectious virus production of seasonal coronaviruses 229E, OC43 and NL63. Interestingly, seasonal coronaviruses replicate much more efficiently at 33 °C compared to 37 °C, resulting in over 10-fold higher levels of viral replication. Genome-wide transcriptomic analyses revealed distinct patterns of infection-triggered host responses at 33 °C compared to 37 °C temperature. Treatment of molnupiravir and remdesivir dose-dependently inhibited the replication of 229E, OC43 and NL63 in hAOs. INTERPRETATION: HAOs are capable of modeling 229E, OC43 and NL63 infections. The intriguing finding that lower temperature resembling that in the upper respiratory tract favors viral replication may help to better understand the pathogenesis and transmissibility of seasonal coronaviruses. HAOs-based innovative models shall facilitate the research and therapeutic development against seasonal coronavirus infections. FUNDING: This research is supported by funding of a VIDI grant (No. 91719300) from the Netherlands Organization for Scientific Research and the Dutch Cancer Society Young Investigator Grant (10140) to Q.P., and the ZonMw COVID project (114025011) from the Netherlands Organization for Health Research and Development to R.R.


Subject(s)
COVID-19 , Coronavirus 229E, Human , Respiratory Tract Infections , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus 229E, Human/genetics , Humans , Organoids/pathology , Respiratory System/pathology , Respiratory Tract Infections/pathology , Seasons
19.
Nat Commun ; 13(1): 4484, 2022 08 15.
Article in English | MEDLINE | ID: covidwho-1991585

ABSTRACT

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.


Subject(s)
COVID-19 , DNA-Binding Proteins , Transcription Factors , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , DNA-Binding Proteins/genetics , Epithelial Cells/metabolism , Humans , Peptidyl-Dipeptidase A/metabolism , Respiratory System , SARS-CoV-2 , Transcription Factors/genetics
20.
Br Dent J ; 230(5): 305, 2021 03.
Article in English | MEDLINE | ID: covidwho-1383093
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