Adenovirus Serotype 14 Infection, New Brunswick, Canada, 2011

Girouard, Gabriel; Garceau, Richard; Thibault, Louise; Oussedik, Youcef; Bastien, Nathalie; Li, Yan

doi:10.3201/eid1901.120423

Cited by 28 publications

(26 citation statements)

References 11 publications

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“…Specifically, there were no time points along the continuum through 2 weeks after infection where the inflammatory responses to Ad14 infection ever approached the intensity of the responses observed to Ad14p1 infection (unpublished data). The patchy bronchopneumonia observed in Ad14p1-infected hamsters is similar to the pattern of lung pathology described for human infection (4). These data provided the first link between altered viral gene expression during infection with Ad14p1 and increased lung immunopathology of this emergent Ad strain.…”

Section: Ad14p1 Isolates Exhibit Large-plaque and Cytocidal Phenotypessupporting

confidence: 74%

“…6H and I) and can cause increased lung pathology (Fig. 6) and more severe clinical illness (1,4,6,(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

“…Sequencing of the isolates determined that the strains were 100% identical in the coding regions and differed by just 0.3% from the prototype Ad14 deWit strain (2). Currently, Ad14p1 is circulating worldwide and has been identified as the causative agent in numerous cases of acute respiratory distress syndrome (ARDS); these strains are also highly homologous to the military isolates (3)(4)(5)(6). However, it is unclear why Ad14p1 infection can cause more severe forms of respiratory illness than the wild-type (wt) deWit strain of Ad14.…”

mentioning

confidence: 99%

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Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis

Radke

Yong

Cook

2016

J Virol

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Adenovirus 14p1 (Ad14p1) is an emergent variant of Ad serotype 14 (Ad14) that has caused increased severity of respiratory illnesses during globally distributed outbreaks, including cases of acute respiratory distress syndrome and death. We found that human cell infection with Ad14p1 results in markedly decreased expression of the E1B 20-kilodalton (20K) protein compared to that with infection with wild-type (wt) Ad14. This reduced Ad14p1 E1B 20K expression caused a loss-of-function phenotype of Ad-infected cell corpses that, in contrast to cells infected with wt Ad14, either failed to repress or increased NF-B-dependent, proinflammatory cytokine responses of responder human alveolar macrophages. A small-animal model of Ad14-induced lung infection was used to test the translational relevance of these in vitro observations. Intratracheal infection of Syrian hamsters with Ad14p1 caused a marked, patchy bronchopneumonia, whereas hamster infection with wt Ad14 caused minimal peribronchial inflammation. These results suggest that this difference in E1B 20K gene expression during Ad14p1 infection and its modulating effect on the interactions between Ad14-infected cells and the host innate immune response could explain the increased immunopathogenic potential and associated increase in clinical illness in some people infected with the Ad14p1 outbreak strain. IMPORTANCE We previously reported that Ad-infected human cells exhibit E1B 19K-dependent repression of virally induced, NF-B-depen-

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Section: Ad14p1 Isolates Exhibit Large-plaque and Cytocidal Phenotypessupporting

confidence: 74%

“…6H and I) and can cause increased lung pathology (Fig. 6) and more severe clinical illness (1,4,6,(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis

Radke

Yong

Cook

2016

J Virol

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“…Based on epidemiological data, the newly emerged strain, Ad14P1, is considered more pathogenic/virulent than the parental strain (Ad14) (22)(23)(24). In an attempt to experimentally support this, we studied the effect of Ad14 and Ad14P1 on tumor growth in a xenograft model with epithelial tumors derived from A549 cells (Fig.…”

Section: Shedding Of the Dsg2 Extracellular Domain Triggered By Ad3mentioning

confidence: 99%

“…Thirty-eight percent of these patients were hospitalized, including 17% who were admitted to intensive care units; 5% of patients died. Outbreaks of Ad14P1 infection were subsequently detected in other five bases and in civilian populations in Washington (19), Oregon (20), Alaska (21), Wisconsin, and Pennsylvania (22,23), as well as in Canada (24), China (25), and South Korea (26). At this point, the molecular basis for the high pathogenicity and/or virulence of Ad14P1 is unclear.…”

mentioning

confidence: 99%

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Wang

Ducournau

Saydaminova

et al. 2015

J Virol

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We recently discovered that desmoglein 2 (DSG2) is a receptor for human adenovirus species B serotypes Ad3, Ad7, Ad11, and Ad14. Ad3 is considered to be a widely distributed human pathogen. Ad3 binding to DSG2 triggers the transient opening of epithelial junctions. Here, we further delineate the mechanism that leads to DSG2-mediated epithelial junction opening in cells exposed to Ad3 and recombinant Ad3 fiber proteins. We identified an Ad3 fiber knob-dependent pathway that involves the phosphorylation of mitogen-activated protein (MAP) kinases triggering the activation of the matrix-metalloproteinase ADAM17. ADAM17, in turn, cleaves the extracellular domain of DSG2 that links epithelial cells together. The shed DSG2 domain can be detected in cell culture supernatant and also in serum of mice with established human xenograft tumors. We then extended our studies to Ad14 and Ad14P1. Ad14 is an important research and clinical object because of the recent appearance of a new, more pathogenic strain (Ad14P1). In a human epithelial cancer xenograft model, Ad14P1 showed more efficient viral spread and oncolysis than Ad14. Here, we tested the hypothesis that a mutation in the Ad14P1 fiber knob could account for the differences between the two strains. While our X-ray crystallography studies suggested an altered three-dimensional (3D) structure of the Ad14P1 fiber knob in the F-G loop region, this did not significantly change the fiber knob affinity to DSG2 or the intracellular signaling and DSG2 shedding in epithelial cancer cells. IMPORTANCE A number of widely distributed adenoviruses use the epithelial junction protein DSG2 as a receptor for infection and lateral spread. Interaction with DSG2 allows the virus not only to enter cells but also to open epithelial junctions which form a physicalbarrier to virus spread. Our study elucidates the mechanism beyond virus-triggered junction opening with a focus on adenovirus serotype 3. Ad3 binds to DSG2 with its fiber knob domain and triggers intracellular signaling that culminates in the cleavage of the extracellular domain of DSG2, thereby disrupting DSG2 homodimers between epithelial cells. We confirmed this pathway with a second DSG2-interacting serotype, Ad14, and its recently emerged strain Ad14P1. These new insights in basic adenovirus biology can be employed to develop novel drugs to treat adenovirus infection as well as be used as tools for gene delivery into epithelial tissues or epithelial tumors. W e recently discovered that desmoglein 2 (DSG2) is a receptor for human adenovirus species B serotypes Ad3, Ad7, Ad11, and Ad14 (1-3). DSG2 is a calcium-binding transmembrane glycoprotein belonging to the cadherin protein family. In epithelial cells of the respiratory, gastrointestinal, and urinary tracts, DSG2 is a component of the cell-cell adhesion structure (4). It is well established that in addition to maintaining cell adhesion, DSG2 is also involved in intracellular signaling (5). Its cytoplasmic tail interacts with a series of proteins, including plakoglobi...

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Case 17. A 6-Year-Old Girl with Fever for 1 Week, Productive Cough, Running Nose, Decreased Appetite, and Activity: Severe Lower Respiratory Tract Infection Due to Adenovirus

Lin¹,

Huang²

2023

Paediatric Infectious Diseases

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Adenovirus Serotype 14 Infection, New Brunswick, Canada, 2011

Cited by 28 publications

References 11 publications

Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis

Low-Level Expression of the E1B 20-Kilodalton Protein by Adenovirus 14p1 Enhances Viral Immunopathogenesis

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Case 17. A 6-Year-Old Girl with Fever for 1 Week, Productive Cough, Running Nose, Decreased Appetite, and Activity: Severe Lower Respiratory Tract Infection Due to Adenovirus

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