Human rhinovirus serotypes induces different immune responses
Rhinovirus serotypes induces different immune responses
Different species of human rhinovirus (HRV) can induce varied antiviral and inflammatory responses in human blood macrophages and lower airway epithelium. Although human nasal epithelial cells (HNECs) are a primary infection route of HRV, differences between major and minor groups of HRV in the upper airway epithelium have not been studied in detail. In this study, we investigated viral replications and immune responses of major and minor groups of HRV in the HNECs.
Viral replication, immune responses of IFN-β, IFN-λ, proinflammatory cytokines, and viral receptors, and mRNA expression of transcription factors of HRV16 (major group) and HRV1B (minor group) in the HNECs were assessed.
Compared with HRV16, HRV1B replicated more actively without excessive cell death and produced higher IFN-β, IFN-λ1/3, CXCL10, IL-6, IL-8, and IL-18 levels. Furthermore, low-density lipoprotein receptor (LDLR), TLR3, MDA5, NF-κB, STAT1, and STAT2 mRNA levels increased in HRV1B-infected HNECs.
HRV1B induces a stronger antiviral and inflammatory response from cell entry to downstream signaling compared with HRV16.
Human rhinovirus (HRV) is the most common cause of the common cold. Furthermore, HRV is detected in the nasal lavage and mucosae as well as turbinate epithelial cells of patients with chronic rhinosinusitis (CRS), suggesting a significant association between HRV infection and pathogenesis of CRS [1, 2]. HRV infections can also trigger severe lower airway diseases such as bronchitis, pneumonia, and exacerbations of asthma and chronic obstructive pulmonary disease [3,4,5,6,7].
HRVs are classified phylogenetically into three species (A, B, and C), including around 160 serotypes that differ in their surface proteins . Different receptors between major and minor groups of HRV can elicit different immune and inflammatory responses. The major groups HRV-A and HRV-B enter the respiratory epithelial cells via Inter-Cellular Adhesion Molecule 1 (ICAM-1, CD54), whereas minor group HRV uses the low-density lipoprotein receptor (LDLR) . HRV-C binds to cadherin-related family member 3 . After their internalization via ICAM-1 or LDLR, the RNA genome of HRV crosses the endosome membrane into the cytosol . In the endosome, viral double-stranded RNA (dsRNA) and single-stranded RNA (ssRNA) are recognized by toll-like receptor 3 (TLR3) and TLR7/8, respectively. Newly synthesized viral dsRNA and ssRNA in the cytoplasm are also recognized by retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). TLRs, RIG-1, and MDA-5 stimulate interferon-β (IFN-β) and INF-λ responses and production of proinflammatory cytokines and their gene expression, including C-X-C motif chemokine 10 (CXCL10), interleukin (IL)-6, and IL-8/CXCL8 [11, 12]. In a previous study, HRV16 (major group) and HRV1A (minor group) infections induced phosphorylation of kinases (p38, JNK, ERK5) and transcription factors (ATF-2, CREB, CEBP-alpha) differently in human macrophages derived from blood. Differential activation of these signaling pathways led to altered expression of inflammatory cytokines Chemokine (C–C motif) ligand 20 (CCL20), CCL2, and IL-10 .
Although human nasal epithelial cells (HNECs) are a primary infection route of HRV, there are no reports stating the differences in the inflammatory responses between major and minor groups of HRV in the HNECs. Minor group HRV1B can be infected in the lungs and sinonasal mucosa in Balb/c mice and induce airway inflammation [14, 15]. In our previous studies, it was identified that major group HRV16 induces inflammatory responses and alters tight and adherens junctions in HNECs, which may have deleterious effects on the barrier function of HNECs [16,17,18]. In addition, HRV16 infection up-regulates bacterial adhesion to HNECs, may induce secondary bacterial infections leading to bacterial rhinosinusitis [19,20,21]. In another previous study, HRV-A and HRV-B were detected in the nasal lavage fluid and turbinate epithelial cells of patients with CRS, and only HRV-A in the non-CRS controls . Therefore, we focused on HRV1B (minor group of HRV-A) and HRV16 (major group of HRV-A) in the upper airway epithelium, and studied the immune responses elicited by both HRV16 and HRV1B infected cells, assessed the viral replications and measured the levels of IFN-β, IFN-λ, and proinflammatory cytokines produced by the infected cells.
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