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Deaths associated with human adenovirus-14p1 infections, Europe, 2009-2010.

ABSTRACT: Human adenovirus (HAdV) serotype 14 is rarely identified. However, an emerging variant, termed HAdV-14p1, recently has been described in the United States in association with outbreaks of acute respiratory disease with high rates of illness and death. We retrospectively analyzed specimens confirmed positive for HAdV by immunofluorescence, virus culture, or real-time PCR during July 1, 2009-July 31, 2010, and describe 9 cases of HAdV-14p1 infection with characteristic mutations in the fiber and E1A genes that are phylogenetically indistinguishable from the viruses previously detected in the United States. Three patients died; 2 were immunocompromised, and 1 was an immunocompetent adult. We propose that surveillance should be increased for HAdV-14p1 and recommend that this virus be considered in the differential diagnosis of sudden-onset acute respiratory disease, particularly fatal infections, for which an etiology is not clear.

SUBMITTER: Carr MJ

PROVIDER: S-EPMC3381588 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Deaths associated with human adenovirus-14p1 infections, Europe, 2009-2010.

Carr Michael J MJ Kajon Adriana E AE Lu Xiaoyan X Dunford Linda L O'Reilly Paul P Holder Paul P De Gascun Cillian F CF Coughlan Suzie S Connell Jeff J Erdman Dean D DD Hall William W WW

Emerging infectious diseases 20110801 8

Human adenovirus (HAdV) serotype 14 is rarely identified. However, an emerging variant, termed HAdV-14p1, recently has been described in the United States in association with outbreaks of acute respiratory disease with high rates of illness and death. We retrospectively analyzed specimens confirmed positive for HAdV by immunofluorescence, virus culture, or real-time PCR during July 1, 2009-July 31, 2010, and describe 9 cases of HAdV-14p1 infection with characteristic mutations in the fiber and E ...[more]

PMID: 21801616

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Project description:BackgroundOnly a few pneumotropic types of the human adenoviruses (e.g. type B14p1) cause severe lower respiratory tract infections like pneumonia and acute respiratory distress syndrome (ARDS) even in immunocompetent patients. By contrast, many other human adenovirus (HAdV) types (e.g. HAdV-C5) are associated mainly with upper respiratory tract infections. This is in accordance with a highly physiological cell culture system consisting of differentiated primary human bronchial epithelial cells which are little susceptible for apical HAdV-C5 infections.Objective and methodsWe hypothesized that a pneumotropic and highly pathogenic HAdV type infects differentiated human bronchial epithelial cells efficiently from the apical surface and also induces proinflammatory cytokines in order to establish ARDS and pneumonia. Therefore, the apical infection of differentiated primary human bronchial epithelial cells with the pneumotropic and virulent type HAdV-B14p1 was investigated in comparison to the less pneumotropic HAdV-C5 as a control.ResultsBinding of HAdV-B14p1 to the apical surface of differentiated human bronchial epithelial cells and subsequent internalization of HAdV DNA was 10 fold higher (p<0.01) compared to the less-pneumotropic HAdV-C5 one hour after infection. Overall, the replication cycle of HAdV-B14p1 following apical infection and including apical release of infectious virus progeny was about 1000-fold more effective compared to the non-pneumotropic HAdV-C5 (p<0.001). HAdV-B14p1 infected cells expressed desmoglein 2 (DSG2), which has been described as potential receptor for HAdV-B14p1. Moreover, HAdV-B14p1 induced proinflammatory chemokines IP-10 and I-Tac as potential virulence factors. Interestingly, IP-10 has already been described as a marker for severe respiratory infections e.g. by influenza virus A H5N1.ConclusionsThe efficient "apical to apical" replication cycle of HAdV-B14p1 can promote endobronchial dissemination of the infection from the upper to the lower respiratory tract. Simultaneous induction of proinflammatory cytokines probably contributes to the high virulence of HAdV-B14p1.

Project description: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-κB-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-κB-dependent macrophage cytokine responses (J. R. Radke, F. Grigera, D. S. Ucker, and J. L. Cook, J Virol 88:2658-2669, 2014, http://dx.doi.org/10.1128/JVI.02372-13). The more virulent, emergent strain of Ad14, Ad14p1, causes increased cytopathology in vitro, which suggested a possible E1B 20K defect. Whether there is a linkage between these observations was unknown. We show that there is markedly reduced expression of E1B 20K in Ad14p1-infected human cells and that this causes an increased proinflammatory cytokine response of human alveolar macrophages and more severe inflammatory lung disease in infected hamsters. This is the first evidence of a clinical relevance of differential expression of the small Ad E1B gene product. The results suggest that there is a low, critical threshold of E1B 19/20K expression that is needed for viral replication and infection transmission but that a higher level of E1B 19/20K expression is required for the usual repression and control of the Ad-triggered host innate immune response.

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Deaths associated with human adenovirus-14p1 infections, Europe, 2009-2010.

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Deaths associated with human adenovirus-14p1 infections, Europe, 2009-2010.

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