Effects of rhinovirus species on viral replication and cytokine production

Nakagome, Kazuyuki; Bochkov, Yury A.; Ashraf, Shamaila; Brockman-Schneider, Rebecca; Evans, Michael D.; Pasic, Thomas R.; Gern, James E.

doi:10.1016/j.jaci.2014.01.029

Cited by 98 publications

(95 citation statements)

References 55 publications

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“…Recent data from the University of Wisconsin (UW) COAST (Childhood Origins of Asthma) study associated certain RV-A and RV-C isolates with more severe respiratory illnesses in infants than the equivalent RV-B isolates (32). Moreover, sinus epithelial cells differentiated at the air-liquid interface, tested with recombinant A16, A36, B52, B72, C2, C15, or C41 viruses, also showed that the RV-B types have correspondingly slower replication and lower cytotoxicity and cytokine/chemokine production than the RV-A and RV-C viruses (33). Since the RVs infect only a small subset of airway epithelial cells, virusinduced lysis cannot be the singular cause of observed damage to the epithelial cell lining (34).…”

Section: Discussionmentioning

confidence: 96%

“…Were this to translate into patient infections, it is conceivable that some antiviral signaling might then occur with these viruses before full nuclear transport shutoff, thus promoting proinflammatory immune responses that could cause the more severe illness symptoms observed with RV-A and RV-C infections (33). Indeed, the nuclear cycling of NF-B, when measured in a new reporter cell line, was dependent upon the type of RV that infected the cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases

Watters

İnankur

Gardiner

et al. 2017

J Virol

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The RNA rhinoviruses (RV) encode 2A proteases (2A pro ) that contribute essential polyprotein processing and host cell shutoff functions during infection, including the cleavage of Phe/Gly-containing nucleoporin proteins (Nups) within nuclear pore complexes (NPC). Within the 3 RV species, multiple divergent genotypes encode diverse 2A pro sequences that act differentially on specific Nups. Since only subsets of Phe/Gly motifs, particularly those within Nup62, Nup98, and Nup153, are recognized by transport receptors (karyopherins) when trafficking large molecular cargos through the NPC, the processing preferences of individual 2A pro predict RV genotype-specific targeting of NPC pathways and cargos. To test this idea, transformed HeLa cell lines were created with fluorescent cargos (mCherry) for the importin ␣/␤, transportin 1, and transportin 3 import pathways and the Crm1-mediated export pathway. Live-cell imaging of single cells expressing recombinant RV 2A pro (A16, A45, B04, B14, B52, C02, and C15) showed disruption of each pathway with measurably different efficiencies and reaction rates. The B04 and B52 proteases preferentially targeted Nups in the import pathways, while B04 and C15 proteases were more effective against the export pathway. Virus-type-specific trends were also observed during infection of cells with A16, B04, B14, and B52 viruses or their chimeras, as measured by NF-B (p65/Rel) translocation into the nucleus and the rates of virus-associated cytopathic effects. This study provides new tools for evaluating the host cell response to RV infections in real time and suggests that differential 2A pro activities explain, in part, strain-dependent host responses and diverse RV disease phenotypes.IMPORTANCE Genetic variation among human rhinovirus types includes unexpected diversity in the genes encoding viral proteases (2A pro ) that help these viruses achieve antihost responses. When the enzyme activities of 7 different 2A pro were measured comparatively in transformed cells programed with fluorescent reporter systems and by quantitative cell imaging, the cellular substrates, particularly in the nuclear pore complex, used by these proteases were indeed attacked at different rates and with different affinities. The importance of this finding is that it provides a mechanistic explanation for how different types (strains) of rhinoviruses may elicit different cell responses that directly or indirectly lead to distinct disease phenotypes.KEYWORDS 2A, live-cell imaging, nuclear export, nuclear localization, nuclear trafficking, protease, rhinovirus T he controlled trafficking of protein and RNA across the nuclear membrane is essential for many eukaryotic cellular processes. Nuclear pore complexes (NPC) are large proteinaceous channels embedded in the nuclear envelope that restrict and

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases

Watters

İnankur

Gardiner

et al. 2017

J Virol

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“…Nakagome et al 9 recently showed that HRV-B types isolated from clinical samples have lower replication rates in differentiated primary epithelial cells compared with HRV-A and HRV-C types.…”

Section: Discussionmentioning

confidence: 99%

Human Rhinovirus Types and Association with Respiratory Symptoms During the First Year of Life

Müller

Mack

Tapparel

et al. 2015

Pediatric Infectious Disease Journal

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The most effective management strategy for viral infections is prevention through vaccines, as reported in a pilot study of herpes zoster vaccination in 10 adult SLE patients older than 50 years of age, 12 but the efficacy and safety of this live-attenuated virus vaccine in a large SLE population is unknown.In conclusion, lupus in children has a higher susceptibility to HZI and is characterized by a shorter disease duration, disease activity and lower frequency of postherpetic neuralgia than in adults with SLE. Both groups have a comparable and good overall outcome. H uman rhinoviruses (HRV) are the most common respiratory viruses identified in humans with respiratory infections, 1 and they play a major role in respiratory morbidity of children. ACKNOWLEDGMENT2,3 HRVinduced wheezing during early life is strongly associated with the later development of asthma. 4 Based on their genetic divergence, HRVs are divided into 3 species: HRV-A, HRV-B and HRV-C, of which HRV-A and HRV-C are thought to cause most severe symptoms.5 For each HRV species, various types are known. Despite the high frequency of HRV infections, detailed information is lacking on prevalence of HRV types and their association with presence and severity of respiratory symptoms, especially in early infancy of otherwise healthy children. Therefore, we analyzed weekly nasal swabs for HRV presence, sequenced positive samples for HRV typing and compared the results with respiratory symptoms. METHODSIn a subsample of 20 healthy infants (9 female, 11 male) nested in the prospective Basel-Bern-Infant-Lung-Development cohort study, 6 we analyzed the presence of HRV RNA by onestep real-time polymerase chain reaction in nasal swabs collected weekly during the first year of life. HRV-positive samples were further sequenced to determine HRV types (for method see Tapparel et al 7 ). Signs of respiratory symptoms (cough, wheeze and breathing difficulties) were assessed based on a standardized symptom score by weekly telephone interviews with the parents. 6 The study was approved by the Ethics Committee Bern, Switzerland and written informed consent was obtained from the parents. RESULTS Prevalence of HRV Species and TypesHRV was detected in 266 of 831 nasal swabs (32%). HRV-A and HRV-C were almost equally frequent (38% and 39%, respectively), followed by HRV-B (12%). Ten percent of the samples were untypable (because of poor sample quality or undetectable viral load). In total, 74 different HRV types were identified (30 HRV-A, 8 HRV-B and 36 HRV-C). Twelve HRV types of all 3 species were particularly frequent and found in 5 or more samples: A78 (detected in 17 samples), A16 (in nine samples), B6 (in 8 samples), A56, A89 (both in 7 samples), A101, C1, C9 (all in 6 samples), A12, C22, C26 and C39 (all in 5 samples). Those HRV types were identified in samples of 1 (A12), 3 (B6, A89, C1), 4 (A16, A56, Association of HRV Prevalence and Respiratory SymptomsIn total, half of HRV-positive episodes were accompanied by respiratory symptoms, with slight differences among ...

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“…The protocol was approved by the University of Wisconsin-Madison Human Subjects Committee. Primary airway epithelial cells were cultured submerged (undifferentiated monolayers) or at the ALI (fully differentiated), as previously described (13,40).…”

Section: Methodsmentioning

confidence: 99%

“…Recombinant RV-C15, RV-C15-GFP, RV-C2, RV-C41, RV-A16, and RV-B52 were produced by transfecting viral RNA synthesized in vitro from linearized infectious cDNA clones into WisL cells, as previously described (11,40). Cells grown in 12-well plates (monolayers) or in Transwell polycarbonate inserts (0.4-μm pore size; Corning) (ALI cultures) were inoculated with RV at 10 6 PFUe per well or insert (unless other dose indicated), incubated for 2-4 h at 34°C, and washed three times with PBS to remove unattached input virus.…”

Section: Methodsmentioning

confidence: 99%

Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Bochkov¹,

Watters

Ashraf³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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345

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Members of rhinovirus C (RV-C) species are more likely to cause wheezing illnesses and asthma exacerbations compared with other rhinoviruses. The cellular receptor for these viruses was heretofore unknown. We report here that expression of human cadherin-related family member 3 (CDHR3) enables the cells normally unsusceptible to RV-C infection to support both virus binding and replication. A coding single nucleotide polymorphism (rs6967330, C529Y) was previously linked to greater cell-surface expression of CDHR3 protein, and an increased risk of wheezing illnesses and hospitalizations for childhood asthma. Compared with wild-type CDHR3, cells transfected with the CDHR3-Y529 variant had about 10-fold increases in RV-C binding and progeny yields. We developed a transduced HeLa cell line (HeLa-E8) stably expressing CDHR3-Y529 that supports RV-C propagation in vitro. Modeling of CDHR3 structure identified potential binding sites that could impact the virus surface in regions that are highly conserved among all RV-C types. Our findings identify that the asthma susceptibility gene product CDHR3 mediates RV-C entry into host cells, and suggest that rs6967330 mutation could be a risk factor for RV-C wheezing illnesses.

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Effects of rhinovirus species on viral replication and cytokine production

Cited by 98 publications

References 55 publications

Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases

Differential Disruption of Nucleocytoplasmic Trafficking Pathways by Rhinovirus 2A Proteases

Human Rhinovirus Types and Association with Respiratory Symptoms During the First Year of Life

Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

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