Fatal outcome of human coronavirus NL63 infection despite successful viral elimination by IFN‐alpha in a patient with newly diagnosed ALL

Mayer, Karin; Nellessen, Cordula; Hahn-Ast, Corinna; Schumacher, Martin; Pietzonka, Sandra; Eis‐Hübinger, Anna Maria; Drosten, Christian; Brossart, Peter; Wolf, Dominik

doi:10.1111/ejh.12744

Cited by 31 publications

(32 citation statements)

References 5 publications

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“…Although the majority of infections with HCoVs cause only mild respiratory tract illness, all HCoVs can also induce fulminant courses of disease, especially but not exclusively in immunosuppressed patients and infants (Konca et al, 2017;Mayer et al, 2016;Oosterhof et al, 2010;van der Hoek, 2007). Beside the occurrence in the respiratory tract, all endemic CoVs can also be detected in stool samples but they do not seem to be a major cause of gastroenteritis (Esper et al, 2010;Paloniemi et al, 2015;Risku et al, 2010).…”

Section: Endemic Human Coronavirus Diseasementioning

confidence: 99%

Hosts and Sources of Endemic Human Coronaviruses

Corman

Muth

Niemeyer

et al. 2018

Advances in Virus Research

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922

835

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The four endemic human coronaviruses HCoV-229E, -NL63, -OC43, and -HKU1 contribute a considerable share of upper and lower respiratory tract infections in adults and children. While their clinical representation resembles that of many other agents of the common cold, their evolutionary histories, and host associations could provide important insights into the natural history of past human pandemics. For two of these viruses, we have strong evidence suggesting an origin in major livestock species while primordial associations for all four viruses may have existed with bats and rodents. HCoV-NL63 and -229E may originate from bat reservoirs as assumed for many other coronaviruses, but HCoV-OC43 and -HKU1 seem more likely to have speciated from rodent-associated viruses. HCoV-OC43 is thought to have emerged from ancestors in domestic animals such as cattle or swine. The bovine coronavirus has been suggested to be a possible ancestor, from which HCoV-OC43 may have emerged in the context of a pandemic recorded historically at the end of the 19th century. New data suggest that HCoV-229E may actually be transferred from dromedary camels similar to Middle East respiratory syndrome (MERS) coronavirus. This scenario provides important ecological parallels to the present prepandemic pattern of host associations of the MERS coronavirus.

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Section: Endemic Human Coronavirus Diseasementioning

confidence: 99%

Hosts and Sources of Endemic Human Coronaviruses

Corman

Muth

Niemeyer

et al. 2018

Advances in Virus Research

Self Cite

922

835

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“…9) and 229E 10 that usually cause only mild respiratory symptoms in otherwise healthy individuals, but are much more widespread than SARS-CoV or MERS-CoV. Therapeutic intervention against alphacoronaviruses is indicated in cases of accompanying disease such as cystic fibrosis 11 or leukemia, 12 or certain other underlying medical conditions. 13 The enteroviruses include pathogens such as EV-D68, the causative agent of the 2014 outbreak of the "summer flu" in the US, 14 EV-A71 and Coxsackievirus A16 (CVA16), the etiological agents of Hand, Foot, and Mouth Disease (HFMD), 15 Coxsackievirus B3 (CVB3), which can cause myocardic inflammation, 16 and human rhinoviruses (HRV), notoriously known to lead to the common cold but also capable of causing exacerbations of asthma and COPD.…”

Section: Introductionmentioning

confidence: 99%

Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

Zhang

Lin

Kusov

et al. 2020

Preprint

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The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain nearequipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued structure-based design of peptidomimetic a-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease:inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the aketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against Middle East Respiratory Syndrome coronavirus.We chose the chemical class of peptidomimetic a-ketoamides to assess the feasibility of achieving antiviral drugs targeting coronaviruses and enteroviruses with near-equipotency. Here we describe the structure-based design, synthesis, and evaluation of inhibitory activity of a series of compounds with broad-spectrum activities afforded by studying the structure-activity relationships mainly with respect to the P2 position of the peptidomimetics. One of the compounds designed and synthesized exhibits excellent activity against MERS-CoV. RESULTS Structure-based design of a-ketoamidesOur efforts to design novel a-ketoamides as broad-spectrum inhibitors of coronavirus M pro s and enterovirus 3C pro s started with a detailed analysis of the following crystal structures of unliganded target enzymes: SARS-CoV M pro (ref. 25-27; PDB entries 1UJ1, 2BX3, 2BX4); bat coronavirus HKU4 M pro as a surrogate for the closely related MERS-CoV protease (our unpublished work (Ma, Xiao et al.; PDB entry 2YNA; see also ref. 27); HCoV-229E M pro (ref. 27,28; PDB entry: 1P9S); Coxsackievirus B3 3C pro (our unpublished work; Tan et al., PDB entry 3ZYD); enterovirus D68 3C pro (ref. 29; PDB entry: 3ZV8); and enterovirus A71 3C pro (ref. 30; PDB entry: 3SJK).During the course of the present study, we determined crystal structures of a number of lead a-ketoamide compounds in complex with SARS-CoV M pro , HCoV-NL63 M pro , and CVB3 3C pro , in support of the design of improvements in the next round of lead optimization. Notably, unexpected differences between alpha-and betacoronavirus M pro were found in this study. The structural foundation of these was elucidated in detail in a subproject involving the M pro of HCoV NL63; because of its volume, this work wil...

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“…The clinical presentation may vary depending on the general health status of the patient. Usually, the virus causes a relatively mild respiratory tract disease, but fatal cases have been reported (2)(3)(4)(5). Furthermore, broad studies on the association between infection and clinical symptoms reveal that HCoV-NL63 is associated with croup in young children (6)(7)(8)(9).…”

mentioning

confidence: 99%

Entry of Human Coronavirus NL63 into the Cell

Milewska

Nowak

Owczarek

et al. 2018

J Virol

182

188

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The first steps of human coronavirus NL63 (HCoV-NL63) infection were previously described. The virus binds to target cells by use of heparan sulfate proteoglycans and interacts with the ACE2 protein. Subsequent events, including virus internalization and trafficking, remain to be elucidated. In this study, we mapped the process of HCoV-NL63 entry into the LLC-Mk2 cell line and three-dimensional (3D) tracheobronchial tissue. Using a variety of techniques, we have shown that HCoV-NL63 virions require endocytosis for successful entry into the LLC-MK2 cells, and interaction between the virus and the ACE2 molecule triggers recruitment of clathrin. Subsequent vesicle scission by dynamin results in virus internalization, and the newly formed vesicle passes the actin cortex, which requires active cytoskeleton rearrangement. Finally, acidification of the endosomal microenvironment is required for successful fusion and release of the viral genome into the cytoplasm. For 3D tracheobronchial tissue cultures, we also observed that the virus enters the cell by clathrin-mediated endocytosis, but we obtained results suggesting that this pathway may be bypassed. Available data on coronavirus entry frequently originate from studies employing immortalized cell lines or undifferentiated cells. Here, using the most advanced 3D tissue culture system mimicking the epithelium of conductive airways, we systematically mapped HCoV-NL63 entry into susceptible cells. The data obtained allow for a better understanding of the infection process and may support development of novel treatment strategies.

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Fatal outcome of human coronavirus NL63 infection despite successful viral elimination by IFN‐alpha in a patient with newly diagnosed ALL

Abstract: This report emphasizes the fatal consequences of common respiratory virus infections in immunocompromised patients. HCoV-NL63 replication can be reduced by treatment with peg-IFN if diagnosed early.

Cited by 31 publications

References 5 publications

Hosts and Sources of Endemic Human Coronaviruses

Hosts and Sources of Endemic Human Coronaviruses

Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication

Entry of Human Coronavirus NL63 into the Cell

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