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Article ; Online: Impact of changes in human airway epithelial cellular composition and differentiation on SARS-CoV-2 infection biology

Melissa Thaler / Ying Wang / Anne M. van der Does / Alen Faiz / Dennis K. Ninaber / Natacha S. Ogando / Hendrik Beckert / Christian Taube / Clarisse Salgado-Benvindo / Eric J. Snijder / Peter J. Bredenbeek / Pieter S. Hiemstra / Martijn J. van Hemert

Journal of Innate Immunity (2023)

2023

Abstract: The consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can range from asymptomatic to fatal disease. Variations in epithelial susceptibility to SARS-CoV-2 infection depend on the anatomical location from the ... ...

Abstract	The consequences of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can range from asymptomatic to fatal disease. Variations in epithelial susceptibility to SARS-CoV-2 infection depend on the anatomical location from the proximal to distal respiratory tract. However, the cellular biology underlying these variations is not completely understood. Thus, air-liquid interface (ALI) cultures of well-differentiated primary human tracheal and bronchial epithelial cells were employed to study the impact of epithelial cellular composition and differentiation on SARS-CoV-2 infection by transcriptional (RNA sequencing) and immunofluorescent analyses. Changes of cellular composition were investigated by varying time of differentiation or by using specific compounds. We found that SARS-CoV-2 primarily infected ciliated cells but also goblet cells and transient secretory cells. Viral replication was impacted by differences in cellular composition, which depended on culturing time and anatomical origin. A higher percentage of ciliated cells correlated with a higher viral load. However, DAPT-treatment, which increased number of ciliated cells and reduced goblet cells, decreased viral load, indicating the contribution of goblet cells to infection. Cell-entry factors, especially cathepsin L and transmembrane protease serine 2, were also affected by differentiation time. In conclusion, our study demonstrates that viral replication is affected by changes in cellular composition, especially in cells related to the mucociliary system. This could explain in part the variable susceptibility to SARS-CoV-2 infection between individuals and between anatomical locations in the respiratory tract.
Keywords	Medicine ; R ; Internal medicine ; RC31-1245
Subject code	570
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	Karger Publishers
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Yellow Fever 17D Virus Replicon-Based Vaccine Platform for Emerging Coronaviruses

Nadia Oreshkova / Sebenzile K. Myeni / Niraj Mishra / Irina C. Albulescu / Tim J. Dalebout / Eric J. Snijder / Peter J. Bredenbeek / Kai Dallmeier / Marjolein Kikkert

Vaccines, Vol 9, Iss 1492, p

2021 Volume 1492

Abstract: The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live- ... ...

Abstract	The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live-attenuated virus vaccine with an impressive efficacy record in humans, and therefore, it is a very attractive platform for the development of novel chimeric vaccines against various pathogens. In the present study, we generated a YF17D-based replicon vaccine platform by replacing the prM and E surface proteins of YF17D with antigenic subdomains from the spike (S) proteins of three different betacoronaviruses: MERS-CoV, SARS-CoV and MHV. The prM and E proteins were provided in trans for the packaging of these RNA replicons into single-round infectious particles capable of expressing coronavirus antigens in infected cells. YF17D replicon particles expressing the S1 regions of the MERS-CoV and SARS-CoV spike proteins were immunogenic in mice and elicited (neutralizing) antibody responses against both the YF17D vector and the coronavirus inserts. Thus, YF17D replicon-based vaccines, and their potential DNA- or mRNA-based derivatives, may constitute a promising and particularly safe vaccine platform for current and future emerging coronaviruses.
Keywords	coronavirus ; vaccine platform ; YFV-17D ; YF17D ; MERS-CoV ; SARS-CoV ; Medicine ; R
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs

Andrea MacFadden / Zoe O’Donoghue / Patricia A. G. C. Silva / Erich G. Chapman / René C. Olsthoorn / Mark G. Sterken / Gorben P. Pijlman / Peter J. Bredenbeek / Jeffrey S. Kieft

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 11

Abstract: Subgenomic flavivirus RNAs are generated by a host exoribonuclease and play an important role in virus replication and pathogenesis. Here, the authors show the mechanism by which subgenomic flavivirus RNAs are generated and identify two structurally ... ...

Abstract	Subgenomic flavivirus RNAs are generated by a host exoribonuclease and play an important role in virus replication and pathogenesis. Here, the authors show the mechanism by which subgenomic flavivirus RNAs are generated and identify two structurally distinct sfRNA classes in flaviviruses.
Keywords	Science ; Q
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Quasispecies composition and evolution of a typical Zika virus clinical isolate from Suriname

Sander van Boheemen / Ali Tas / S. Yahya Anvar / Rebecca van Grootveld / Irina C. Albulescu / Martijn P. Bauer / Mariet C. Feltkamp / Peter J. Bredenbeek / Martijn J. van Hemert

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 7

Abstract: Abstract The arthropod-borne Zika virus (ZIKV) is currently causing a major international public health threat in the Americas. This study describes the isolation of ZIKV from the plasma of a 29-year-old female traveler that developed typical symptoms, ... ...

Abstract	Abstract The arthropod-borne Zika virus (ZIKV) is currently causing a major international public health threat in the Americas. This study describes the isolation of ZIKV from the plasma of a 29-year-old female traveler that developed typical symptoms, like rash, fever and headache upon return from Suriname. The complete genome sequence including the 5′ and 3′ untranslated regions was determined and phylogenetic analysis showed the isolate clustering within the Asian lineage, close to other viruses that have recently been isolated in the Americas. In addition, the viral quasispecies composition was analyzed by single molecule real time sequencing, which suggested a mutation frequency of 1.4 × 10−4 for this ZIKV isolate. Continued passaging of the virus in cell culture led to the selection of variants with mutations in NS1 and the E protein. The latter might influence virus binding to cell surface heparan sulfate.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses.

Huib H Rabouw / Martijn A Langereis / Robert C M Knaap / Tim J Dalebout / Javier Canton / Isabel Sola / Luis Enjuanes / Peter J Bredenbeek / Marjolein Kikkert / Raoul J de Groot / Frank J M van Kuppeveld

PLoS Pathogens, Vol 12, Iss 10, p e

2016 Volume 1005982

Abstract: Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infections that can be life-threatening. To establish an infection and spread, MERS-CoV, like most other viruses, must navigate through an intricate network of antiviral ... ...

Abstract	Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infections that can be life-threatening. To establish an infection and spread, MERS-CoV, like most other viruses, must navigate through an intricate network of antiviral host responses. Besides the well-known type I interferon (IFN-α/β) response, the protein kinase R (PKR)-mediated stress response is being recognized as an important innate response pathway. Upon detecting viral dsRNA, PKR phosphorylates eIF2α, leading to the inhibition of cellular and viral translation and the formation of stress granules (SGs), which are increasingly recognized as platforms for antiviral signaling pathways. It is unknown whether cellular infection by MERS-CoV activates the stress response pathway or whether the virus has evolved strategies to suppress this infection-limiting pathway. Here, we show that cellular infection with MERS-CoV does not lead to the formation of SGs. By transiently expressing the MERS-CoV accessory proteins individually, we identified a role of protein 4a (p4a) in preventing activation of the stress response pathway. Expression of MERS-CoV p4a impeded dsRNA-mediated PKR activation, thereby rescuing translation inhibition and preventing SG formation. In contrast, p4a failed to suppress stress response pathway activation that is independent of PKR and dsRNA. MERS-CoV p4a is a dsRNA binding protein. Mutation of the dsRNA binding motif in p4a disrupted its PKR antagonistic activity. By inserting p4a in a picornavirus lacking its natural PKR antagonist, we showed that p4a exerts PKR antagonistic activity also under infection conditions. However, a recombinant MERS-CoV deficient in p4a expression still suppressed SG formation, indicating the expression of at least one other stress response antagonist. This virus also suppressed the dsRNA-independent stress response pathway. Thus, MERS-CoV interferes with antiviral stress responses using at least two different mechanisms, with p4a suppressing the PKR-dependent stress response ...
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2016-10-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Intradermally administered yellow fever vaccine at reduced dose induces a protective immune response

Anna H Roukens / Ann C Vossen / Peter J Bredenbeek / Jaap T van Dissel / Leo G Visser

PLoS ONE, Vol 3, Iss 4, p e

a randomized controlled non-inferiority trial.

2008 Volume 1993

Abstract: Implementation of yellow fever vaccination is currently hampered by limited supply of vaccine. An alternative route of administration with reduced amounts of vaccine but without loss of vaccine efficacy would boost vaccination programmes.A randomized, ... ...

Abstract	Implementation of yellow fever vaccination is currently hampered by limited supply of vaccine. An alternative route of administration with reduced amounts of vaccine but without loss of vaccine efficacy would boost vaccination programmes.A randomized, controlled, non-inferiority trial was conducted in a Dutch university center between August 2005 and February 2007. A total of 155 primary vaccinated and 20 previously vaccinated volunteers participated. Participants were randomly assigned in a 1ratio1 ratio to receive intradermal (i.d.) vaccination with live attenuated yellow fever 17D vaccine at a reduced dose (1/5(th); 0.1 mL) or the conventional subcutaneous (s.c.) vaccination (0.5 mL). Antibody neutralization titers were determined at 2, 4 and 8 weeks and 1 year after vaccination by counting the reduction in virus-induced plaques in the presence of serial serum dilutions. Adverse events were documented in a 3-week dairy. Viraemia was measured 5 days after vaccination. From 2 weeks up to one year after vaccination, the maximum serum-dilution at which 80% of the virus plaques were neutralized, which indicates protection against yellow fever, did not differ between those given a reduced i.d. dose or standard s.c. dose of vaccine. In all cases the WHO standard of seroprotection (i.e. 80% virus neutralization) was reached (in 77/77 and 78/78, respectively). Similar results were found in the previously vaccinated individuals. Viraemia was detected in half of the primary vaccinated participants, which was not predictive of serological response. In revaccinees no viraemia was detected.Intradermal administration of one fifth of the amount of yellow fever vaccine administered subcutaneously results in protective seroimmunity in all volunteers. Albeit this vaccination route should enable vaccination of five-times as many individuals at risk for disease, these results should now be confirmed in field studies in areas with potential yellow fever virus transmission to change vaccination policy.Nederlands Trial Register ...
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2008-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Elderly subjects have a delayed antibody response and prolonged viraemia following yellow fever vaccination

Anna H Roukens / Darius Soonawala / Simone A Joosten / Adriëtte W de Visser / Xiaohong Jiang / Kees Dirksen / Marjolein de Gruijter / Jaap T van Dissel / Peter J Bredenbeek / Leo G Visser

PLoS ONE, Vol 6, Iss 12, p e

a prospective controlled cohort study.

2011 Volume 27753

Abstract: BACKGROUND: Yellow fever vaccination (YF-17D) can cause serious adverse events (SAEs). The mechanism of these SAEs is poorly understood. Older age has been identified as a risk factor. We tested the hypothesis that the humoral immune response to yellow ... ...

Abstract	BACKGROUND: Yellow fever vaccination (YF-17D) can cause serious adverse events (SAEs). The mechanism of these SAEs is poorly understood. Older age has been identified as a risk factor. We tested the hypothesis that the humoral immune response to yellow fever vaccine develops more slowly in elderly than in younger subjects. METHOD: We vaccinated young volunteers (18-28 yrs, N = 30) and elderly travelers (60-81 yrs, N = 28) with YF-17D and measured their neutralizing antibody titers and plasma YF-17D RNA copy numbers before vaccination and 3, 5, 10, 14 and 28 days after vaccination. RESULTS: Ten days after vaccination seroprotection was attained by 77% (23/30) of the young participants and by 50% (14/28) of the elderly participants (p = 0.03). Accordingly, the Geometric Mean Titer of younger participants was higher than the GMT of the elderly participants. At day 10 the difference was +2.9 IU/ml (95% CI 1.8-4.7, p = 0.00004) and at day 14 +1.8 IU/ml (95% CI 1.1-2.9, p = 0.02, using a mixed linear model. Viraemia was more common in the elderly (86%, 24/28) than in the younger participants (60%, 14/30) (p = 0.03) with higher YF-17D RNA copy numbers in the elderly participants. CONCLUSIONS: We found that elderly subjects had a delayed antibody response and higher viraemia levels after yellow fever primovaccination. We postulate that with older age, a weaker immune response to yellow fever vaccine allows the attenuated virus to cause higher viraemia levels which may increase the risk of developing SAEs. This may be one piece in the puzzle of the pathophysiology of YEL-AVD. TRIAL REGISTRATION: Trialregitser.nl NTR1040.
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification and characterization of the host protein DNAJC14 as a broadly active flavivirus replication modulator.

Zhigang Yi / Lindsey Sperzel / Cindy Nürnberger / Peter J Bredenbeek / Kirk J Lubick / Sonja M Best / Cristina T Stoyanov / Lok Man J Law / Zhenghong Yuan / Charles M Rice / Margaret R MacDonald

PLoS Pathogens, Vol 7, Iss 1, p e

2011 Volume 1001255

Abstract: Viruses in the Flavivirus genus of the Flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against ... ...

Abstract	Viruses in the Flavivirus genus of the Flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against flaviviruses, we screened a cDNA library using an iterative approach. We identified a mammalian Hsp40 chaperone protein (DNAJC14) that when overexpressed was able to mediate protection from yellow fever virus (YFV)-induced cell death. Further studies revealed that DNAJC14 inhibits YFV at the step of viral RNA replication. Since replication of bovine viral diarrhea virus (BVDV), a member of the related Pestivirus genus, is also known to be modulated by DNAJC14, we tested the effect of this host factor on diverse Flaviviridae family members. Flaviviruses, including the pathogenic Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a Hepacivirus, hepatitis C virus (HCV), all were inhibited by overexpression of DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain, which mediates self-interaction, are required for anti-YFV activity. We found that DNAJC14 does not block YFV nor HCV NS2-3 cleavage, and using non-inhibitory mutants demonstrate that DNAJC14 is recruited to YFV replication complexes. Immunofluorescence analysis demonstrated that endogenous DNAJC14 rearranges during infection and is found in replication complexes identified by dsRNA staining. Interestingly, silencing of endogenous DNAJC14 results in impaired YFV replication suggesting a requirement for DNAJC14 in YFV replication complex assembly. Finally, the antiviral activity of overexpressed DNAJC14 occurs in a time- and dose-dependent manner. DNAJC14 overexpression may disrupt the proper stoichiometry resulting in inhibition, which can be overcome upon restoration of the optimal ratios due to the accumulation of viral nonstructural proteins. Our findings, together with previously published work, suggest that the members of the Flaviviridae family have evolved in ...
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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