Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children

Esposito, Susanna; Molteni, Claudio Giuseppe; Giliani, Silvia; Mazza, Cinzia; Scala, Alessia; Tagliaferri, L.; Pelucchi, Claudio; Fossali, Emilio F.; Plebani, Alessandro; Principi, Nicola

doi:10.1186/1743-422x-9-270

Cited by 67 publications

(70 citation statements)

References 34 publications

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“…In contrast, TLR3−/− mice have no survival advantage when infected with a 2009 pandemic H1N1 virus (Leung et al, 2014). A common polymorphism in the TLR3 gene has been associated with severe disease upon infection with 2009 pandemic H1N1 virus (Esposito et al, 2012). Thus, TLR3 may contribute to either pathogenesis or viral suppression during IAV infection of the alveoli.…”

Section: Resultsmentioning

confidence: 99%

Proteomic analysis reveals down-regulation of surfactant protein B in murine type II pneumocytes infected with influenza A virus

et al. 2015

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Infection of type II alveolar epithelial (ATII) cells by influenza A viruses (IAV) correlates with severe respiratory disease in humans and mice. To understand pathogenic mechanisms during IAV infection of ATII cells, murine ATII cells were cultured to maintain a differentiated phenotype, infected with IAV-PR8, which causes severe lung pathology in mice, and proteomics analyses were performed using liquid chromatography-mass spectrometry. PR8 infection increased levels of proteins involved in interferon signaling, antigen presentation, and cytoskeleton regulation. Proteins involved in mitochondrial membrane permeability, energy metabolism, and chromatin formation had reduced levels in PR8-infected cells. Phenotypic markers of ATII cells in vivo were identified, confirming the differentiation status of the cultures. Surfactant protein B had decreased levels in PR8-infected cells, which was confirmed by immunoblotting and immunofluorescence assays. Analysis of ATII cell protein profiles will elucidate cellular processes in IAV pathogenesis, which may provide insight into potential therapies to modulate disease severity.

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Section: Resultsmentioning

confidence: 99%

Proteomic analysis reveals down-regulation of surfactant protein B in murine type II pneumocytes infected with influenza A virus

et al. 2015

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“…However, it has been demonstrated that TLR3 also contributes to pulmonary damage through the induction of pro-inflammatory molecules and the recruitment of leukocytes, during IAV virus infection [7, 42–46]. Furthermore, TLR3 polymorphisms have been shown to be related to severe cases of influenza infection in humans and mice [42, 47, 48] and its upregulation has been associated with severe pulmonary lesions in the ferret model after IAV infection [42, 46–49]. Moreover, it is known that TLR3 signalling is not required for the initial cell-autonomous recognition of viral infection or the induction of IFNα, which is induced via viral recognition by RIG-I [50].…”

Section: Discussionmentioning

confidence: 99%

Involvement of the different lung compartments in the pathogenesis of pH1N1 influenza virus infection in ferrets

Vidaña

Martínez

Martorell

et al. 2016

Vet Res

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Severe cases after pH1N1 infection are consequence of interstitial pneumonia triggered by alveolar viral replication and an exacerbated host immune response, characterized by the up-regulation of pro-inflammatory cytokines and the influx of inflammatory leukocytes to the lungs. Different lung cell populations have been suggested as culprits in the unregulated innate immune responses observed in these cases. This study aims to clarify this question by studying the different induction of innate immune molecules by the distinct lung anatomic compartments (vascular, alveolar and bronchiolar) of ferrets intratracheally infected with a human pH1N1 viral isolate, by means of laser microdissection techniques. The obtained results were then analysed in relation to viral quantification in the different anatomic areas and the histopathological lesions observed. More severe lung lesions were observed at 24 h post infection (hpi) correlating with viral antigen detection in bronchiolar and alveolar epithelial cells. However, high levels of viral RNA were detected in all anatomic compartments throughout infection. Bronchiolar areas were the first source of IFN-α and most pro-inflammatory cytokines, through the activation of RIG-I. In contrast, vascular areas contributed with the highest induction of CCL2 and other pro-inflammatory cytokines, through the activation of TLR3.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-016-0395-0) contains supplementary material, which is available to authorized users.

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“…Several potential genetic determinants associated with A(H1N1)pdm09 infection have been described, including TNF (Antonopoulou et al, 2012), IFN-inducible transmembrane (Everitt et al, 2012), killer-cell immunoglobulin-like receptor (Aranda-Romo et al, 2012), complement regulatory protein CD55 (Zhou et al, 2012) and Toll-like receptor 3 (Esposito et al, 2012). Data relating to the role of chemokine receptor 5 (CCR5) in severe A(H1N1)pdm09-infected patients are contradictory and have been debated (Keynan et al, 2010;Rodriguez et al, 2013;Sironi et al, 2014).…”

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confidence: 99%

CCR5 deficiency predisposes to fatal outcome in influenza virus infection

Falcón

Cuevas

Rodríguez-Frandsen

et al. 2015

Journal of General Virology

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Influenza epidemics affect all age groups, although children, the elderly and those with underlying medical conditions are the most severely affected. Whereas co-morbidities are present in 50 % of fatal cases, 25-50 % of deaths are in apparently healthy individuals. This suggests underlying genetic determinants that govern infection severity. Although some viral factors that contribute to influenza disease are known, the role of host genetic factors remains undetermined. Data for small cohorts of influenza-infected patients are contradictory regarding the potential role of chemokine receptor 5 deficiency (CCR5-D32 mutation, a 32 bp deletion in the CCR5 gene) in the outcome of influenza virus infection. We tested 171 respiratory samples from influenza patients (2009 pandemic) for CCR5-D32 and evaluated its correlation with patient mortality. CCR5-D32 patients (17.4 %) showed a higher mortality rate than WT individuals (4.7 %; P50.021), which indicates that CCR5-D32 patients are at higher risk than the normal population of a fatal outcome in influenza infection. Influenza A viruses are a major source of acute respiratory infections and continue to be an important cause of acute illness and death worldwide. They cause annual epidemics and occasional pandemics with potentially fatal outcome. The mean global burden of seasonal influenza is more than 600 million cases, with 3 million cases of severe illness and almost 500 000 deaths per year worldwide (http://www. who.int/en/). A new H1N1 subtype influenza A virus emerged in 2009 [A(H1N1)pdm09], which was highly transmissible with relatively low virulence and caused the first pandemic of the 21st century (Neumann et al., 2009).Differences in disease severity can be due to pre-existing health conditions, predisposing host genetic factors, differences in the virulence of circulating viruses or a combination of these factors. The co-morbid conditions for A(H1N1)pdm09 include chronic metabolic disease, primarily diabetes mellitus and renal disease, chronic lung and cardiac disease, immunosuppressive conditions, neoplasms, obesity and pregnancy (Falagas et al., 2011; Louie et al., 2011;Singanayagam et al., 2011).Although co-morbidities are present in half of fatal cases, one-third of fatal cases have no co-morbid conditions (http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm), suggesting that host genetic variation accounts for the distinct disease severity of A(H1N1)pdm09 infection. Several potential genetic determinants associated with A(H1N1)pdm09 infection have been described, including TNF (Antonopoulou et al., 2012), IFN-inducible transmembrane (Everitt et al., 2012), killer-cell immunoglobulin-like receptor (Aranda-Romo et al., 2012), complement regulatory protein CD55 (Zhou et al., 2012) and Toll-like receptor 3 (Esposito et al., 2012). Data relating to the role of chemokine receptor 5 (CCR5) in severe A(H1N1)pdm09-infected patients are contradictory and have been debated (Keynan et al., 2010;Rodriguez et al., 2013;Sironi et al., 2014).CCR5 regulates various aspec...

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Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children

Cited by 67 publications

References 34 publications

Proteomic analysis reveals down-regulation of surfactant protein B in murine type II pneumocytes infected with influenza A virus

Proteomic analysis reveals down-regulation of surfactant protein B in murine type II pneumocytes infected with influenza A virus

Involvement of the different lung compartments in the pathogenesis of pH1N1 influenza virus infection in ferrets

CCR5 deficiency predisposes to fatal outcome in influenza virus infection

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