Date Published: March 7, 2019
Publisher: Public Library of Science
Author(s): Sandra E. Vieira, Silvia Y. Bando, Milena de Paulis, Danielle B. L. Oliveira, Luciano M. Thomazelli, Edison L. Durigon, Marina B. Martinez, Carlos Alberto Moreira-Filho, Ralph A. Tripp.
Human respiratory syncytial virus (HRSV) is the main cause of bronchiolitis during the first year of life, when infections by other viruses, such as rhinovirus, also occur and are clinically indistinguishable from those caused by HRSV. In hospitalized infants with bronchiolitis, the analysis of gene expression profiles from peripheral blood mononuclear cells (PBMC) may be useful for the rapid identification of etiological factors, as well as for developing diagnostic tests, and elucidating pathogenic mechanisms triggered by different viral agents. In this study we conducted a comparative global gene expression analysis of PBMC obtained from two groups of infants with acute viral bronchiolitis who were infected by HRSV (HRSV group) or by HRV (HRV group). We employed a weighted gene co-expression network analysis (WGCNA) which allows the identification of transcriptional modules and their correlations with HRSV or HRV groups. This approach permitted the identification of distinct transcription modules for the HRSV and HRV groups. According to these data, the immune response to HRSV infection—comparatively to HRV infection—was more associated to the activation of the interferon gamma signaling pathways and less related to neutrophil activation mechanisms. Moreover, we also identified host-response molecular markers that could be used for etiopathogenic diagnosis. These results may contribute to the development of new tests for respiratory virus identification. The finding that distinct transcriptional profiles are associated to specific host responses to HRSV or to HRV may also contribute to the elucidation of the pathogenic mechanisms triggered by different respiratory viruses, paving the way for new therapeutic strategies.
Viral bronchiolitis is frequent and has an important impact on the children’s health care due to the high rates of hospitalization and mortality, especially of young infants [1, 2]. Human respiratory syncytial virus (HRSV) is the predominant etiological agent, but infections by other respiratory viruses, such as human rhinovirus (HRV), metapneumovirus, parainfluenza, influenza, adenovirus, and coronavirus, also occur. These infections with different respiratory virus present similar clinical characteristics, so etiological diagnosis can be carried out in clinical practice only by virus identification, either by molecular tests, immunofluorescence or culture methods [1–5]. Although the current guidelines do not indicate routine tests to identify the etiologic agent in infants with bronchiolitis, the etiological diagnosis may contribute to the prevention of nosocomial acquisition, since the transmission mechanisms diverge among respiratory viruses. Knowledge on molecular epidemiology also contributes to programming and organizing prophylactic strategies, such as the use of monoclonal antibodies to HRSV and influenza vaccination [3, 6]. Etiological diagnosis may also contribute for developing specific therapeutic approaches for each agent.
Transcriptional analysis revealed that 283 out of 6,615 GO annotated genes were differentially expressed (DE, fold-change ≥ 2.0) when compared between the HRSV and HRV groups. In the HRSV group most of the DE genes (204 genes) were hyper-expressed and only 79 genes were hypo-expressed when compared with the HRV group. The gene CCDC177 (C14orf162) presented the highest fold-change value (16.3). Moreover, 22 genes were differentially expressed and presented high fold-change values between 16.3 and 4.0 (S1 Fig). Table 2 lists these high fold-change DE genes, where 21 genes were hyper-expressed and one was hypo-expressed in HRSV group.
Bronchiolitis is frequently caused by HRSV but HRV is also an important etiological agent. Infections by these two viruses present similar clinical features, thus rendering etiological diagnosis difficult. Moreover, no vaccines or effective/specific therapies are available. The identification of the etiology in infant bronchiolitis by obtaining peripheral blood samples and performing molecular marker analyses would be of great utility in clinical practice. These methods are non-invasive and reflect quite well the host’s immunological response , thus allowing a better understanding of the molecular mechanisms involved in the pathogenesis of HRSV infection.
The PBMC transcriptional profiles of hospitalized infants with HRSV or HRV bronchiolitis are different and probably correlated with distinctive etiopathogenic mechanisms. Additionally, the infants with HRSV had leukopenia and they usually demand more hospitalization days. The immune response to HRSV infection, comparatively to the response to HRV infection, appears to be more associated to the activation of the IFNγ signaling pathways and less related to neutrophil activation. Moreover, we also identified potential host-response molecular markers that could be used for HRSV or HRV etiopathogenic diagnosis. These results may contribute to the development of future tests for respiratory virus identification. Additionally, a better understanding of PBMC specific host responses to HRSV or HRV—here disclosed by different gene expression profiles—may serve to elucidate the pathogenic mechanisms triggered by different viral agents and, therefore, contribute to the development of new therapeutic approaches.