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. 2017 Dec 27;217(1):134-146.
doi: 10.1093/infdis/jix519.

Host Transcription Profile in Nasal Epithelium and Whole Blood of Hospitalized Children Under 2 Years of Age With Respiratory Syncytial Virus Infection

Lien Anh Ha Do  1 , Johann Pellet  2 , H Rogier van Doorn  1   3 , Anh Tuan Tran  4 , Bach Hue Nguyen  4 , Thi Thu Loan Tran  5 , Quynh Huong Tran  5 , Quoc Bao Vo  5 , Nguyen Anh Tran Dac  5 , Hong Nhien Trinh  4 , Thi Thanh Hai Nguyen  4 , Bao Tinh Le Binh  4 , Huu Mai Khanh Nguyen  4 , Minh Tien Nguyen  4 , Quang Tung Thai  4 , Thanh Vu Vo  4 , Ngoc Quang Minh Ngo  4 , Thi Kim Huyen Dang  5 , Ngoc Huong Cao  5 , Thu Van Tran  5 , Lu Viet Ho  5 , Bertrand De Meulder  6 , Charles Auffray  6 , Jorrit-Jan Hofstra  7 , Jeremy Farrar  1 , Juliet E Bryant  1   3 , Menno de Jong  1   3   7 , Martin L Hibberd  8   9
Affiliations

Host Transcription Profile in Nasal Epithelium and Whole Blood of Hospitalized Children Under 2 Years of Age With Respiratory Syncytial Virus Infection

Lien Anh Ha Do et al. J Infect Dis. .

Abstract

Background: Most insights into the cascade of immune events after acute respiratory syncytial virus (RSV) infection have been obtained from animal experiments or in vitro models.

Methods: In this study, we investigated host gene expression profiles in nasopharyngeal (NP) swabs and whole blood samples during natural RSV and rhinovirus (hRV) infection (acute versus early recovery phase) in 83 hospitalized patients <2 years old with lower respiratory tract infections.

Results: Respiratory syncytial virus infection induced strong and persistent innate immune responses including interferon signaling and pathways related to chemokine/cytokine signaling in both compartments. Interferon-α/β, NOTCH1 signaling pathways and potential biomarkers HIST1H4E, IL7R, ISG15 in NP samples, or BCL6, HIST2H2AC, CCNA1 in blood are leading pathways and hub genes that were associated with both RSV load and severity. The observed RSV-induced gene expression patterns did not differ significantly in NP swab and blood specimens. In contrast, hRV infection did not as strongly induce expression of innate immunity pathways, and significant differences were observed between NP swab and blood specimens.

Conclusions: We conclude that RSV induced strong and persistent innate immune responses and that RSV severity may be related to development of T follicular helper cells and antiviral inflammatory sequelae derived from high activation of BCL6.

Keywords: children under 2 years old; host expression profile; lower respiratory tract infections; respiratory syncytial virus; rhinovirus.

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Figures

Figure 1.
Figure 1.
Comparison of differentially expressed genes obtained with nasopharyngeal (NP) swabs and blood samples. Abbreviations: hRV, rhinovirus; RSV, respiratory syncytial virus; RSVco, RSV coinfection group; RSVsi, single-RSV group.
Figure 2. (a)
Figure 2. (a)
Pathway enriched in differentially expressed genes (DEGs) of nasopharyngeal (NP) swabs and blood in respiratory syncytial virus (RSV) infection using InnateDB. (b) Pathway enriched in DEGs of NP swabs and blood in rhinovirus infection. (a and b) The module-trait relationships with the correlation coefficients and P values. The strength of the correlation is colored by different intensities of red (positive correlation) and blue (negative correlation).
Figure 2. (a)
Figure 2. (a)
Pathway enriched in differentially expressed genes (DEGs) of nasopharyngeal (NP) swabs and blood in respiratory syncytial virus (RSV) infection using InnateDB. (b) Pathway enriched in DEGs of NP swabs and blood in rhinovirus infection. (a and b) The module-trait relationships with the correlation coefficients and P values. The strength of the correlation is colored by different intensities of red (positive correlation) and blue (negative correlation).
Figure 3. (a)
Figure 3. (a)
Weighted gene coexpression network analysis (WGCNA) heatmap for gene coexpression network analysis in respiratory syncytial virus (RSV) nasopharyngeal (NP) arrays: identified modules and clinical trait. (b) WGCNA heatmap for gene coexpression network analysis in RSV blood arrays: identified modules and clinical trait. Each box represents the module and clinical trait relationships with the correlation coefficients and P values. The strength of the correlation is colored by different intensities of red (positive correlation) and blue (negative correlation). The x-axis represents clinical traits and the y-axis represents coexpressed modules. (*) shows the selected modules that were significantly correlated with the course of illness, ie, acute versus early recovery, and with at least 3 clinical traits related to severity, RSV subgroup, and RSV load.
Figure 3. (a)
Figure 3. (a)
Weighted gene coexpression network analysis (WGCNA) heatmap for gene coexpression network analysis in respiratory syncytial virus (RSV) nasopharyngeal (NP) arrays: identified modules and clinical trait. (b) WGCNA heatmap for gene coexpression network analysis in RSV blood arrays: identified modules and clinical trait. Each box represents the module and clinical trait relationships with the correlation coefficients and P values. The strength of the correlation is colored by different intensities of red (positive correlation) and blue (negative correlation). The x-axis represents clinical traits and the y-axis represents coexpressed modules. (*) shows the selected modules that were significantly correlated with the course of illness, ie, acute versus early recovery, and with at least 3 clinical traits related to severity, RSV subgroup, and RSV load.
Figure 4. (a)
Figure 4. (a)
Analysis of acute network in nasopharyngeal (NP). Network analysis using common genes between modules positively correlated with respiratory syncytial virus (RSV) load/severity and those differentially expressed genes (DEGs) identified between acute versus early recovery phase. Red and green nodes represent genes showing increased and decreased expression, respectively. Nodes in gray are direct interaction partners. The size of nodes is proportional to their degree values. (b) Analysis of acute network in blood. Network analysis using common genes between modules positively correlated with RSV load/severity and those DEGs identified between acute versus early recovery phase. Nodes in gray are direct interaction partners. The size of nodes is proportional to their degree values, and the color of nodes are proportional to their betweenness centrality values.
Figure 4. (a)
Figure 4. (a)
Analysis of acute network in nasopharyngeal (NP). Network analysis using common genes between modules positively correlated with respiratory syncytial virus (RSV) load/severity and those differentially expressed genes (DEGs) identified between acute versus early recovery phase. Red and green nodes represent genes showing increased and decreased expression, respectively. Nodes in gray are direct interaction partners. The size of nodes is proportional to their degree values. (b) Analysis of acute network in blood. Network analysis using common genes between modules positively correlated with RSV load/severity and those DEGs identified between acute versus early recovery phase. Nodes in gray are direct interaction partners. The size of nodes is proportional to their degree values, and the color of nodes are proportional to their betweenness centrality values.
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