Cytokines in the Respiratory Airway as Biomarkers of Severity and Prognosis for Respiratory Syncytial Virus Infection: An Update

Abstract

The human respiratory syncytial virus (hRSV) is one of the most important causes of upper and lower respiratory tract infections in children and the main cause of bronchiolitis worldwide. Disease manifestations caused by hRSV may vary from mild to severe, occasionally requiring admission and hospitalization in intensive care units. Despite the high morbidity rates associated to bronchiolitis, treatment options against hRSV are limited and there are no current vaccination strategies to prevent infection. Importantly, the early identification of high-risk patients can help improve disease management and prevent complications associated with hRSV infection. Recently, the characterization of pro- and anti-inflammatory cytokine patterns produced during hRSV-related inflammatory processes has allowed the identification of potential prognosis biomarkers. A suitable biomarker should allow predicting the severity of the infection in a simple and opportune manner and should ideally be obtained from non-invasive samples. Among the cytokines associated with hRSV disease severity, IL-8, interferon-alpha (IFN-alpha), and IL-6, as well as the Th2-type cytokines thymic stromal lymphopoietin (TSLP), IL-3, and IL-33 have been highlighted as molecules with prognostic value in hRSV infections. In this review, we discuss current studies that describe molecules produced by patients during hRSV infection and their potential as biomarkers to anticipate the severity of the disease caused by this virus.

Keywords: LRTI; biomarker; cytokines; hRSV; prognosis; severity.

Figures

Figure 1

Pathogenesis of hRSV and molecules with a biomarker potential induced in the airways during hRSV infection. (A) HRSV attaches to airway epithelial cells and this binding is mediated by the interaction between the fusion (F) or glycoprotein (G) protein of hRSV. Toll-like receptor 4 (TLR4) is expressed on AECs and it is involved in the hRSV entry. When hRSV F protein binds to TLR4, this triggers a cascade of signaling, where the protein myeloid differentiation primary response 88 (MyD88) is activated. The activation of MyD88 leads to activation of mitogen-activated protein kinase (MAPK), and the NF-kB transcription factor. Activated NF-kB translocates to the nucleus and promotes the production of Th1 cytokines (like as TNF-α, IL-6, and IL-8). Nucleolin is a protein located on the cell surface that is also involved in the entry process of hRSV, which generates a fusion between host cell membrane and the virus. This fusion allows the entry of the viral genetic material to the cell, and the binding of dsRNA to TLR3. TLR3 triggers a cascade of signaling by the TIR-domain-containing adapter-inducing interferon-β (TRIF), MAPKs and NF-kB transcription factor. This signaling pathway promotes the IL-33 and TSLP production. HRSV also can infect Dendritic Cells (DCs) and the virus mediates its entry by TLR4 receptor, present on the surface of the DC. DCs are then infected and the genetic material of the virus enters the cell. dsRNA binds TLR7 receptor, present in the endosome produced by the fusion, which one TLR3 triggers a cascade of signaling by the MyD88 protein, MAPKs and NF-kB transcription factor or interferon-regulatory factor (IRF). Those signaling pathways promote the IL-12 and IFN-α production, respectively. (B) Infected AECs secrete several cytokines and chemokines that have been described as potential biomarkers. High IL-33 levels are produced by AECs and cells expressing ST2 receptor, such as ILC2s, respond to IL-33 through the production of IL-5 and IL-13, which promote the recruitment of eosinophils that generate disease exacerbation and is associated to ventilation requirement. The mast cells also express the ST2 receptor and when IL-33 binds to these receptors the production of IL-3 is promoted. AECs produce high levels of IL-8, promoting the recruitment neutrophils to the infection site, that could generate a degree of hypoxia, ventilation requirement and asthma development. TSLP production is mediate by AECs. This cytokine is recognized by the receptor TSLPR, which is expressed by macrophages, generating an exacerbation of the disease and asthma. Periostin is produced by AECs or eosinophils. This protein increases the expression of inflammatory mediators. Deposits of periostin in the lung is associated with increased severity of asthma. IL-6 is produced by AECs and promotes a Th2 response. This cytokine is involved in the promotion of naïve differentiation to CD4+ and CD8+ T cell. CD4+ T cells trigger the IL-13 production and Th2 overreaction response. CD8+ T cells increase the disease severity. IFN-α is produced by pDCs and AECs. At late times of infection, high levels of this cytokine produce high IL-10 levels by T cells. IL-12 is produced by pDCs and promotes the differentiation of naive T cells into Th1 cells and induces weak IFN-γ-production by T cells. This low IFN-γ-production generate a Th2 overreaction response. IL-3 promotes basophil and eosinophil production, triggering inflammatory and allergic diseases as asthma. IL-13 is produced by ILC2 cells and CD4+ T cells, among other. High IL-13 levels result in a Th2 overreaction response and the recruitment of eosinophils that generate exacerbated mucus production, airway hyperreactivity and inflammation. Different lines (dotted and solid) were used to facilitate understanding of the figure and the different signaling pathways involved.