Spread of Adenovirus to Geographically Dispersed Military Installations, May–October 2007

Trei, Jill S.; Johns, Natalie M.; Garner, Jason L.; Noel, Lawrence B.; Ortman, Brian; Ensz, Kari L.; Johns, Matthew C.; Bunning, Michel L.; Gaydos, Joel C.

doi:10.3201/eid1605.091633

Cited by 46 publications

(50 citation statements)

References 13 publications

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“…Thirty-eight percent of these patients were hospitalized, including 17% who were admitted to intensive care units; 5% of patients died. Outbreaks of HAdVB14p1 were subsequently detected in the other 5 bases and in civilian populations in Washington, Oregon (32), Alaska (33), Wisconsin, and Pennsylvania (7,9), as well as in Canada (8), China (34), and South Korea (35). At this point, the molecular basis for the high pathogenicity and/or virulence of Ad14p1 is unclear.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

Wang

Yumul

Cao

et al. 2013

J Virol

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f Human adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14, as well as a recently emerged strain of Ad14 (Ad14p1), use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. Unlike Ad interaction with CAR and CD46, structural details for Ad binding to DSG2 are still elusive. Using an approach based on Escherichia coli expression libraries of random Ad3 and Ad14p1 fiber knob mutants, we identified amino acid residues that, when mutated individually, ablated or reduced Ad knob binding to DSG2. These residues formed three clusters inside one groove at the extreme distal end of the fiber knob. The Ad3 fiber knob mutant library was also used to identify variants with increased affinity to DSG2. We found a number of mutations within or near the EF loop of the Ad3 knob that resulted in affinities to DSG2 that were several orders of magnitude higher than those to the wild-type Ad3 knob. Crystal structure analysis of one of the mutants showed that the introduced mutations make the EF loop more flexible, which might facilitate the interaction with DSG2. We recently identified DSG2 as the main receptor for a group of species B adenoviruses, including adenovirus serotype 3 (Ad3), a serotype which is widely distributed in the human population (1). We found that the DSG2-interacting domain(s) within Ad3 is formed by several fiber knobs (2). This specific mode of Ad3 fiber knob-DSG2 interaction provides a high avidity and is functionally relevant for opening of epithelial junctions (1, 2). The latter involves clustering of DSG2 and activation of pathways that are reminiscent of an epithelial-to-mesenchymal transition, including the phosphorylation of mitogen-activated protein kinase (MAPK) and the downregulation of junction protein expression (1,3,4). The ability to open epithelial junctions appears to be important for Ad3 penetration into and spread within airway epithelial cells (1, 2, 4). In a recent study, we attempted to find the minimal moiety within the Ad3 capsid that confers efficient binding to DSG2 (2). We generated a small recombinant protein which contains the Ad3 fiber knob and a domain that allows for the self-dimerization of trimeric Ad3 fiber knobs (JO-1) (2). JO-1 can be readily produced in Escherichia coli and purified by affinity chromatography. In polarized epithelial cell cultures, JO-1 triggered the opening of intercellular junctions, while intravenous injection of JO-1 into mice with epithelial tumors allowed for better penetration of anti-cancer drugs (3, 5).The first goal of the present study was to further delineate structural features of the Ad3 fiber knob-DSG2 interaction. This included identifying the amino acid residues within the Ad3 fiber knob that are involved in binding to DSG2 and creating JO-1 mutants with reduced and ablated binding to DSG2. The second goal of this study, which has translational relevance, was to further improve JO-1 by enhancing its affinity to DSG2, thereby increasing its therapeutic effect. This was done by identifying mutants with increased b...

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

Wang

Yumul

Cao

et al. 2013

J Virol

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“…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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“…All patients were young, previously healthy soldiers. Although several studies have described the clinical features of adenovirus infection among military personnel (7)(8)(9)(10)(11)(12)(13), few studies have compared the clinical characteristics of pneumonic and non-pneumonic adenovirus cases or evaluated the risk factors associated with military training courses. Furthermore, few reports have provided detailed descriptions of the radiological features of adenovirus infections by means such as thinsection computed tomography (CT) (7,9).…”

Section: Introductionmentioning

confidence: 99%

Outbreak of Febrile Respiratory Illness Caused by Adenovirus at a South Korean Military Training Facility: Clinical and Radiological Characteristics of Adenovirus Pneumonia

Hwang

Park²,

Yong³

et al. 2013

Jpn J Infect Dis

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SUMMARY: Adenovirus often causes respiratory disease outbreaks in military training soldiers. Compared with adenovirus pneumonia in young military adults, symptoms arising from febrile respiratory illness (FRI) caused by adenovirus have not been previously evaluated in Korean soldiers. We conducted an event-based outbreak investigation involving 712 male soldiers aged 19 to 21 years from March 14 to 30, 2012 to evaluate the epidemiological and clinical characteristics of patients with pneumonia and FRI caused by adenovirus. We described the laboratory and radiological characteristics of patients with adenovirus pneumonia. Among these, 407 cases of FRI and 15 cases of pneumonia were identified through active surveillance (attack rate of FRI, 57.16z; attack rate of pneumonia, 2.11z). Fire training and march training may present environmental risk factors for adenovirus-associated outbreaks. Most symptoms were mild. The most frequent symptom in patients with pneumonia and FRI was cough. Patients with pneumonia were associated with an increased incidence of dizziness (crude odds ratio [cOR], 9.65; 95z confidence interval [CI], 2.38-37.15) and a decreased incidence of rhinorrhea (cOR, 0.15; 95z CI, 0.04-0.53) during adenovirus-associated outbreaks. Differential leukocyte count revealed high monocytes, low lymphocytes, and low eosinophils, and chest computed tomography revealed a consolidation pattern and right lobar pneumonia. These findings warrant a high level of suspicion for adenovirus pneumonia.

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Spread of Adenovirus to Geographically Dispersed Military Installations, May–October 2007

Abstract: Adenovirus serotype B14 spread readily to other sites after an initial outbreak at a military basic training facility.

Cited by 46 publications

References 13 publications

Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

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

Outbreak of Febrile Respiratory Illness Caused by Adenovirus at a South Korean Military Training Facility: Clinical and Radiological Characteristics of Adenovirus Pneumonia

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