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Article ; Online: Monkeypox virus infection of human astrocytes causes gasdermin B cleavage and pyroptosis.

Miranzadeh Mahabadi, Hajar / Lin, Y C James / Ogando, Natacha S / Moussa, Eman W / Mohammadzadeh, Nazanin / Julien, Olivier / Alto, Neal M / Noyce, Ryan S / Evans, David H / Power, Christopher

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 8, Page(s) e2315653121

Abstract: Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the virus penetrates the brain. Pyroptosis is an inflammatory type of regulated cell death, resulting from plasma membrane ... ...

Abstract	Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the virus penetrates the brain. Pyroptosis is an inflammatory type of regulated cell death, resulting from plasma membrane rupture (PMR) due to oligomerization of cleaved gasdermins to cause membrane pore formation. Herein, we investigated the human neural cell tropism of MPXV compared to another orthopoxvirus, vaccinia virus (VACV), as well as its effects on immune responses and cell death. Astrocytes were most permissive to MPXV (and VACV) infections, followed by microglia and oligodendrocytes, with minimal infection of neurons based on plaque assays. Aberrant morphological changes were evident in MPXV-infected astrocytes that were accompanied with viral protein (I3) immunolabelling and detection of over 125 MPXV-encoded proteins in cell lysates by mass spectrometry. MPXV- and VACV-infected astrocytes showed increased expression of immune gene transcripts (
MeSH term(s)	Animals ; Humans ; Monkeypox virus/physiology ; Mpox (monkeypox) ; Pyroptosis ; Astrocytes ; Gasdermins
Chemical Substances	Gasdermins
Language	English
Publishing date	2024-02-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2315653121
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Article ; Online: Characterizing long-COVID brain fog: a retrospective cohort study.

Lam, Grace Y / Damant, Ronald W / Ferrara, Giovanni / Lim, Rachel K / Stickland, Michael K / Ogando, Natacha S / Power, Christopher / Smith, Maeve P

Journal of neurology

2023 Volume 270, Issue 10, Page(s) 4640–4646

Abstract: Background: Long COVID or post-COVID condition (PCC) is a common complication following acute COVID-19 infection. PCC is a multi-systems disease with neurocognitive impairment frequently reported regardless of age. Little is known about the risk factors, ...

Abstract	Background: Long COVID or post-COVID condition (PCC) is a common complication following acute COVID-19 infection. PCC is a multi-systems disease with neurocognitive impairment frequently reported regardless of age. Little is known about the risk factors, associated biomarkers and clinical trajectory of patients with this symptom. Objective: To determine differences in clinical risk factors, associated biochemical markers and longitudinal clinical trajectories between patients with PCC with subjective neurocognitive symptoms (NC+) or without (NC-). Methods: A retrospective longitudinal cohort study was performed using a well-characterized provincial database of patients with clinically confirmed PCC separated into NC+ and NC- cohorts. Demographical, clinical and biochemical differences at initial consultation between the two patient cohorts were analyzed in cross-section. Multivariate regression analyses were conducted to identify independent risk factors for neurocognitive impairment. Determination of the recovery trajectory was performed using serial assessments of the patient-reported health-related quality of life (HR-QoL) metric Eq-5D-5L-vas score. Findings: Women, milder acute infection and pre-existing mental health diagnoses were independently associated with subjective neurocognitive impairment at 8 months post-infection. NC + patients demonstrated lower levels of IgG, IgG1 and IgG3 compared to NC- patients. The NC + cohort had poorer HR-QoL at initial consultation 8 months post-infection with gradual improvement over 20 months post-infection. Conclusions: Neurocognitive impairment represents a severe phenotype of PCC, associated with unique risk factors, aberrancy in immune response and a delayed recovery trajectory. Those with risk factors for neurocognitive impairment can be identified early in the disease trajectory for more intense medical follow-up.
MeSH term(s)	Humans ; Female ; Quality of Life ; Retrospective Studies ; Post-Acute COVID-19 Syndrome ; Longitudinal Studies ; COVID-19/complications ; Brain
Language	English
Publishing date	2023-08-09
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-11913-w
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Article: The Curious Case of the Nidovirus Exoribonuclease: Its Role in RNA Synthesis and Replication Fidelity.

Ogando, Natacha S / Ferron, Francois / Decroly, Etienne / Canard, Bruno / Posthuma, Clara C / Snijder, Eric J

Frontiers in microbiology

2019 Volume 10, Page(s) 1813

Abstract: Among RNA viruses, the ... ...

Abstract	Among RNA viruses, the order
Keywords	covid19
Language	English
Publishing date	2019-08-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2019.01813
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Article ; Online: Deubiquitinating activity of SARS-CoV-2 papain-like protease does not influence virus replication or innate immune responses in vivo.

van Huizen, Mariska / Bloeme-Ter Horst, Jonna R / de Gruyter, Heidi L M / Geurink, Paul P / van der Heden van Noort, Gerbrand J / Knaap, Robert C M / Nelemans, Tessa / Ogando, Natacha S / Leijs, Anouk A / Urakova, Nadya / Mark, Brian L / Snijder, Eric J / Myeni, Sebenzile K / Kikkert, Marjolein

PLoS pathogens

2024 Volume 20, Issue 3, Page(s) e1012100

Abstract: The coronavirus papain-like protease (PLpro) is crucial for viral replicase polyprotein processing. Additionally, PLpro can subvert host defense mechanisms by its deubiquitinating (DUB) and deISGylating activities. To elucidate the role of these ... ...

Abstract	The coronavirus papain-like protease (PLpro) is crucial for viral replicase polyprotein processing. Additionally, PLpro can subvert host defense mechanisms by its deubiquitinating (DUB) and deISGylating activities. To elucidate the role of these activities during SARS-CoV-2 infection, we introduced mutations that disrupt binding of PLpro to ubiquitin or ISG15. We identified several mutations that strongly reduced DUB activity of PLpro, without affecting viral polyprotein processing. In contrast, mutations that abrogated deISGylating activity also hampered viral polyprotein processing and when introduced into the virus these mutants were not viable. SARS-CoV-2 mutants exhibiting reduced DUB activity elicited a stronger interferon response in human lung cells. In a mouse model of severe disease, disruption of PLpro DUB activity did not affect lethality, virus replication, or innate immune responses in the lungs. This suggests that the DUB activity of SARS-CoV-2 PLpro is dispensable for virus replication and does not affect innate immune responses in vivo. Interestingly, the DUB mutant of SARS-CoV replicated to slightly lower titers in mice and elicited a diminished immune response early in infection, although lethality was unaffected. We previously showed that a MERS-CoV mutant deficient in DUB and deISGylating activity was strongly attenuated in mice. Here, we demonstrate that the role of PLpro DUB activity during infection can vary considerably between highly pathogenic coronaviruses. Therefore, careful considerations should be taken when developing pan-coronavirus antiviral strategies targeting PLpro.
MeSH term(s)	Humans ; Animals ; Mice ; Coronavirus Papain-Like Proteases/genetics ; COVID-19 ; SARS-CoV-2/metabolism ; Immunity, Innate ; Papain/genetics ; Papain/metabolism ; Peptide Hydrolases/metabolism ; Virus Replication ; Polyproteins
Chemical Substances	papain-like protease, SARS-CoV-2 (EC 3.4.22.2) ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; Papain (EC 3.4.22.2) ; Peptide Hydrolases (EC 3.4.-) ; Polyproteins
Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1012100
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Article ; Online: Impact of Changes in Human Airway Epithelial Cellular Composition and Differentiation on SARS-CoV-2 Infection Biology.

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

Journal of innate immunity

2023 Volume 15, Issue 1, Page(s) 562–580

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 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 not only 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 the 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.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Respiratory System ; Epithelial Cells ; Biology
Language	English
Publishing date	2023-03-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000530374
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Article ; Online: Potent Inhibition of SARS-CoV-2 nsp14

Ahmed-Belkacem, Rostom / Hausdorff, Marcel / Delpal, Adrien / Sutto-Ortiz, Priscila / Colmant, Agathe M G / Touret, Franck / Ogando, Natacha S / Snijder, Eric J / Canard, Bruno / Coutard, Bruno / Vasseur, Jean-Jacques / Decroly, Etienne / Debart, Françoise

Journal of medicinal chemistry

2022 Volume 65, Issue 8, Page(s) 6231–6249

Abstract: Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs, and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the design and ... ...

Abstract	Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs, and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the design and synthesis of nucleoside-derived inhibitors against the SARS-CoV-2 nsp14 (
MeSH term(s)	COVID-19/virology ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/chemistry ; Humans ; Methyltransferases ; Molecular Docking Simulation ; RNA, Viral/genetics ; S-Adenosylmethionine ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Sulfonamides/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; COVID-19 Drug Treatment
Chemical Substances	RNA, Viral ; Sulfonamides ; Viral Nonstructural Proteins ; S-Adenosylmethionine (7LP2MPO46S) ; Methyltransferases (EC 2.1.1.-) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-)
Language	English
Publishing date	2022-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c00120
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Article ; Online: The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.

Ogando, Natacha S / Metscher, Erik / Moes, Dirk Jan A R / Arends, Eline J / Tas, Ali / Cross, Jennifer / Snijder, Eric J / Teng, Y K Onno / de Vries, Aiko P J / van Hemert, Martijn J

Transplant international : official journal of the European Society for Organ Transplantation

2022 Volume 35, Page(s) 10369

Abstract: Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory ... ...

Abstract	Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI's in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Calcineurin Inhibitors/pharmacology ; Calcineurin Inhibitors/therapeutic use ; Cell Culture Techniques ; Cyclophilins ; Cyclosporine/pharmacology ; Humans ; Immunosuppressive Agents/adverse effects ; SARS-CoV-2 ; Tacrolimus/pharmacology
Chemical Substances	Antiviral Agents ; Calcineurin Inhibitors ; Immunosuppressive Agents ; voclosporin (2PN063X6B1) ; Cyclosporine (83HN0GTJ6D) ; Cyclophilins (EC 5.2.1.-) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2022-06-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	639435-8
ISSN	1432-2277 ; 0934-0874
ISSN (online)	1432-2277
ISSN	0934-0874
DOI	10.3389/ti.2022.10369
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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 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
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Article ; Online: Voclosporin and the Antiviral Effect Against SARS-CoV-2 in Immunocompromised Kidney Patients.

Arends, Eline J / Meziyerh, Soufian / Moes, Dirk Jan A R / Kamerling, Sylvia W A / van der Kooy, Sandra / Ogando, Natacha S / Snijder, Eric J / van Hemert, Martijn / Visser, Leo G / Feltkamp, Mariet C W / Claas, Eric C J / Rabelink, Ton J / van Kooten, Cees / de Vries, Aiko P J / Teng, Y K Onno

Kidney international reports

2023 Volume 8, Issue 12, Page(s) 2654–2664

Abstract: Introduction: Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus ...

Abstract	Introduction: Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus Methods: First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a Results: The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8-28) and tacrolimus-treated KTRs (median 12 days, IQR 4-16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (ΔCt 7.7 [3.4-10.7]) compared to tacrolimus-treated KTRs (ΔCt 2.7 [2.0-4.3]; Conclusion: This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2023.09.003
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Article ; Online: The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2.

Ogando, Natacha S / Zevenhoven-Dobbe, Jessika C / van der Meer, Yvonne / Bredenbeek, Peter J / Posthuma, Clara C / Snijder, Eric J

Journal of virology

2020 Volume 94, Issue 23

Abstract: Coronaviruses (CoVs) stand out for their large RNA genome and complex RNA-synthesizing machinery comprising 16 nonstructural proteins (nsps). The bifunctional nsp14 contains 3'-to-5' exoribonuclease (ExoN) and guanine-N7-methyltransferase (N7-MTase) ... ...

Abstract	Coronaviruses (CoVs) stand out for their large RNA genome and complex RNA-synthesizing machinery comprising 16 nonstructural proteins (nsps). The bifunctional nsp14 contains 3'-to-5' exoribonuclease (ExoN) and guanine-N7-methyltransferase (N7-MTase) domains. While the latter presumably supports mRNA capping, ExoN is thought to mediate proofreading during genome replication. In line with such a role, ExoN knockout mutants of mouse hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus (SARS-CoV) were previously reported to have crippled but viable hypermutation phenotypes. Remarkably, using reverse genetics, a large set of corresponding ExoN knockout mutations has now been found to be lethal for another betacoronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV). For 13 mutants, viral progeny could not be recovered, unless-as happened occasionally-reversion had first occurred. Only a single mutant was viable, likely because its E191D substitution is highly conservative. Remarkably, a SARS-CoV-2 ExoN knockout mutant was found to be unable to replicate, resembling observations previously made for alpha- and gammacoronaviruses, but starkly contrasting with the documented phenotype of ExoN knockout mutants of the closely related SARS-CoV. Subsequently, we established
MeSH term(s)	Animals ; Betacoronavirus/enzymology ; Betacoronavirus/genetics ; Betacoronavirus/physiology ; Catalytic Domain ; Cell Line ; Exoribonucleases/chemistry ; Exoribonucleases/genetics ; Exoribonucleases/metabolism ; Fluorouracil/pharmacology ; Gene Knockout Techniques ; Genome, Viral ; Humans ; Methylation ; Middle East Respiratory Syndrome Coronavirus/enzymology ; Middle East Respiratory Syndrome Coronavirus/genetics ; Middle East Respiratory Syndrome Coronavirus/physiology ; Mutation ; RNA, Viral/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; SARS-CoV-2 ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Viral Plaque Assay ; Virus Replication ; Zinc Fingers
Chemical Substances	RNA, Viral ; Recombinant Proteins ; Viral Nonstructural Proteins ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-) ; Fluorouracil (U3P01618RT)
Keywords	covid19
Language	English
Publishing date	2020-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01246-20
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