Anti-viral activity of acetylsalicylic acid against human rhinovirus 14 infection involves suppression of VP3 expression and infection-dependent down-regulation of CD54

New Aspects on Human Rhinovirus Infections

Rhinoviruses in the pathogenesis of asthma: The bronchial epithelium as a major disease target

The common cold is most often a result of human rhinovirus (HRV) infection. Common cold symptoms including rhinorrhea and nasal obstruction frequently occur during HRV infection of the upper respiratory tract. Conversely, HRV may also infect the epithelial cells of the lower respiratory tract. Symptom severity associated with HRV infection ranges from mild to potentially serious depending on a person’s susceptibility and pre-existing condition, such as chronic obstructive pulmonary disease. An over active host immune response is believed to be the primary contributor to HRV pathogenesis. Enhanced activity of various host cell cytokines and granulocytes mediate specific cellular pathways inducing many of the symptoms associated with HRV infection. There are over 100 serotypes of HRV which can be further categorized based on the specific characteristics of each type. The two main categories of HRV consist of the major and minor groups. The unique host cell receptor is the distinguishing factor between these two groups. Yet, these viruses may also differ in mechanism of infection and replication. Due to the high frequency of hospital and clinical visits and the corresponding economic burden, novel therapies are of interest. Several different treatment options varying from herbal remedies to anti-viral drugs have been studied. However, the vast number of HRV serotypes complicates the progress of developing a universal treatment for attenuating HRV infection.

Antiviral and anti-inflammatory activity of budesonide against human rhinovirus infection mediated via autophagy activation

Burden of human rhinovirus infections in influenza like illnesses in Kenya

Background: Human rhinovirus (HRV) and human metapneumovirus (hMPV) are common viral causes of pediatric respiratory tract infections. Bacterial co-infections frequently complicate HRV and hMPV illnesses in children, but the interactions between viral and bacterial pathogens and their impacts on disease severity are not well understood. Objectives: The present research aimed to analyze and compare the clinical features of HRV and hMPV mono-infections in hospitalized children and to assess the impact of bacterial co-infection on the disease severity of HRV and hMPV infections. Methods: The present retrospective analytical cross-sectional study was conducted to compare the clinical features between HRV and hMPV mono-infections and HRV and hMPV with bacterial co-infections in hospitalized children aged 14 years or younger. Results: Between January and December 2022, we investigated 1,978 children hospitalized with HRV infection, of which 1,529 had HRV mono-infection and 1,117 hospitalized with hMPV infection, among whom 910 had hMPV mono-infection. Compared to HRV, hMPV mono-infection exhibited more pronounced symptoms of fever, cough, and rales in most age groups, while HRV showed more wheezing. Except in patients ≥ 6 years old, hMPV was more associated with pneumonia and longer hospitalizations. In contrast to HRV mono-infections, children with bacterial co-infections had a higher proportion of coughs (P < 0.001), pneumonia (P < 0.001), pediatric intensive care unit (PICU) admissions (P < 0.001), and longer hospitalizations (P = 0.003). Demographic characteristics, clinical presentation, diagnosis, and treatments showed no significant differences between patients with hMPV mono-infection and co-infection. Conclusions: Among hospitalized children, hMPV mono-infection resulted in more severe respiratory illnesses compared to HRV mono-infection. Bacterial co-infections exacerbated disease severity in HRV infections.

The human airway epithelial cell is the primary site of human rhinovirus (HRV) infection in both the upper and lower airways, but HRV infection does not cause overt epithelial cytotoxicity at either location. Therefore, it is thought that HRV infections induce symptoms of the common cold or exacerbate lower airway diseases, such as asthma and chronic obstructive pulmonary disease, by altering epithelial cell biology. This premise has led to intense investigation of the interactions of HRV with epithelial cells. This article reviews current knowledge regarding how HRV induces epithelial induction of proinflammatory cytokines and chemokines. In addition, the contributions of epithelial cells to host antiviral responses will be reviewed along with evidence that HRV-infected epithelial cells may contribute to the airway remodeling that is a characteristic feature of asthma.

This study aimed to assess the clinical characteristics and T‐helper 1 (Th1)/Th2 profile of human rhinovirus (HRV) infection in children with bronchiolitis and pneumonia, compared with the respiratory syncytial virus (RSV). In September 2013 to August 2014, 335 nasopharyngeal aspirates from children below 14 with bronchiolitis and pneumonia were screened for HRV and 13 other respiratory viruses by PCR or reverse transcription PCR. Interferon (IFN)‐γ, interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, and tumor necrosis factor (TNF)‐α were detected by multiplex enzyme‐linked immunosorbent assay. HRVs were found in 66 cases (19.7%), including 35 bronchiolitis and 31 pneumonia cases. Compared with the RSV alone group, children with pneumonia had more frequent wheezing episodes in HRV (P a = .001) and HRV + non‐RSV (P b = .002) groups, and fever in the HRV (P f = .004) and HRV + RSV (P g = .005) groups. Among patients with bronchiolitis, cases with HRV alone were more likely to present in winter than those with RSV alone (P i = .010) and HRV + non‐RSV (P j = .014), and less numerous in summer compared with HRV + non‐RSV (P h = .005). Children with HRV alone were more susceptible to have a history of eczema than RSV alone among bronchiolitis (P c < .001) and pneumonia (P e = .033) cases. HRV bronchiolitis cases had increased IL‐4/IFN‐γ and decreased TNF‐α/IL‐10 ratios, compared with HRV pneumonia counterparts. HRV is a major non‐RSV pathogen causing hospitalization in children with bronchiolitis and pneumonia and induces an imbalanced Th1/Th2 response in bronchiolitis. Compared with RSV infection, HRV bronchiolitis and pneumonia differ significantly regarding wheezing episodes, susceptibility to eczema, fever occurrence, and seasonal prevalence.

Viral respiratory tract infections and asthma: The course ahead

In mammals, viral infections are detected by innate immune receptors, including Toll-like receptor and retinoic acid inducible gene I (RIG-I)-like receptor (RLR), which activate the type I interferon (IFN) system. IFN essentially activates genes encoding antiviral proteins that inhibit various steps of viral replication as well as facilitate the subsequent activation of acquired immune responses. In this study, we investigated the expression of non-coding RNA upon viral infection or RLR activation. Using a microarray, we identified several microRNAs (miRNA) specifically induced to express by RLR signaling. As suggested by Bioinformatics (miRBase Target Data base), one of the RLR-inducible miRNAs, miR-23b, actually knocked down the expression of very low density lipoprotein receptor (VLDLR) and LDLR-related protein 5 (LRP5). Transfection of miR-23b specifically inhibited infection of rhinovirus 1B (RV1B), which utilizes the low density lipoprotein receptor (LDLR) family for viral entry. Conversely, introduction of anti-miRNA-23b enhanced the viral yield. Knockdown experiments using small interfering RNA (siRNA) revealed that VLDLR, but not LRP5, is critical for an efficient infection by RV1B. Furthermore, experiments with the transfection of infectious viral RNA revealed that miR-23b did not affect post-entry viral replication. Our results strongly suggest that RIG-I signaling results in the inhibitions of infections of RV1B through the miR-23b-mediated down-regulation of its receptor VLDLR.

Human rhinovirus (HRV) infection is an important trigger of exacerbations of chronic obstructive pulmonary disease (COPD) but its role in determining exacerbation frequency phenotype or the time-course of HRV infection in naturally occurring exacerbations is unknown. Sputum samples from 77 patients were analysed by real-time quantitative PCR for both HRV (388 samples), and Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (89 samples). Patients recorded worsening of respiratory symptoms on daily diary cards, from which exacerbations were identified. HRV prevalence and load at exacerbation presentation were significantly higher than in the stable state (prevalence 53.3% versus 17.2%, respectively; p<0.001) but 0% by day 35 post-exacerbation. HRV load was higher in patients with cold symptoms (p=0.046) or sore throats (p=0.006) than those without. 73% of bacterium-negative but HRV-positive exacerbations were bacterium-positive by day 14. Patients with HRV detected at exacerbation had a higher exacerbation frequency (interquartile range) of 3.01 (2.02-5.30) per year compared with patients without HRV (2.51 (2.00-3.51)) (p=0.038). HRV prevalence and load increased at COPD exacerbation, and resolved during recovery. Frequent exacerbators were more likely to experience HRV infection. Secondary bacterial infection is common after HRV infection, and provides a possible mechanism for exacerbation recurrence and a potential target for novel therapies.

Human rhinovirus (HRV) infection is one of the main causes of respiratory injury. Recently, calcitriol has been reported to have protective effect against respiratory infections. In this paper, we aimed to explore the effects and mechanisms of calcitriol on HRV-induced respiratory infection. Participants including pediatric patients diagnosed with HRV-induced respiratory infection (n = 50) and paired healthy controls (n = 40) were recruited at the Weifang People's Hospital between May 2019 and May 2020. The serum 25(OH)D3 level was measured in participants using ELISA kit. The HRV-induced respiratory infection model in human nasal mucosal epithelial cells (hNECs) was adapted, in vitro. HRV infection was measured by real-time PCR analysis of HRV expression. After HRV infection and treatment with calcitriol, the changes of cell viability were detected by MTT assay, the expression of ER stress-induced apoptosis and AMPK-mTOR related proteins by western blot, and the cell apoptosis by flow cytometry assay. In order to confirm whether AMPK-mTOR signal pathway was involved in the ER stress-induced apoptosis of hNECs, cells were pretreated with compound C which was a AMPK inhibitor. The 25-(OH)D3 concentration in serum collected in HRV-infected children was lower than that in controls. In vitro experiments showed that HRV infection decreased cell viability, and this effect was reversed when treated with calcitriol. Additionally, HRV increased levels of apoptosis and ER stress markers (including cleaved-caspase3, Bax, CHOP, nATF6, and BiP), while calcitriol significantly reversed these effects. Furthermore, calcitriol played a protective role by increasing p-AMPK and decreasing p-mTOR level. However, the protective effects of calcitriol could be abolished by compound C. Calcitriol protected HRV-infected hNECs by inhibiting the ER stress-induced apoptosis through the AMPK-mTOR signaling pathway. These protective effects of calcitriol against HRV-induced respiratory infection may provide an experimental basis for the clinical application.

Human rhinovirus (HRV) infections up-regulate proinflammatory mediators and growth factors that are associated with exacerbations of inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Matrix metalloproteinase (MMP)-9 was shown to be increased in the airways of patients with asthma and COPD. We sought to determine whether HRV infection modulated the expression of MMP-9 and its highest-affinity inhibitor, the tissue inhibitor of metalloproteinase (TIMP)-1, and we explored the mechanism by which this modulation occurs. In vitro studies, using RT-PCR, ELISA, zymography, and a fluorescent activity assay, demonstrated that MMP-9 mRNA, protein, and activity were increased upon infection with HRV, whereas TIMP-1 mRNA and protein remained unchanged. These results were verified in vivo, using nasal lavage samples obtained from subjects with confirmed rhinovirus infections. Human rhinovirus infections were shown to up-regulate NF-kappaB, and NF-kappaB has also been reported to play a role in the expression of MMP-9. We therefore investigated the role of NF-kappaB in HRV-induced MMP-9 expression. Using two inhibitors of IkappaBalpha kinase beta, we observed a concentration-dependent decrease in HRV-induced MMP-9 expression. The role of NF-kappaB in HRV-induced MMP-9 expression was further confirmed using MMP-9 promoter luciferase constructs, which demonstrated that an NF-kappaB site at -620/-607 base pairs was necessary for HRV-induced MMP-9 expression. Electrophoretic mobility shift assays and supershift assays confirmed the nuclear translocation and binding of p50/p65 NF-kappaB subunits to an MMP-9-specific NF-kappaB oligonucleotide. This increase in MMP-9 may be a mechanism by which rhinovirus infections contribute to airway inflammation and, potentially, to airway remodeling.

Levocetirizine inhibits rhinovirus-induced ICAM-1 and cytokine expression and viral replication in airway epithelial cells

Human rhinovirus (HRV) infections are a major cause of exacerbations in chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease, but HRV-induced immune responses of the lower airway are poorly understood. Earlier work examining cytokine release following HRV infection has focused on epithelial cells because they serve as the principal site of viral replication, and internalization and replication of viral RNA appear necessary for epithelial cell mediator release. However, during HRV infection, only a small proportion of epithelial cells become infected. As HRV-induced cytokine levels in vivo are markedly elevated, this observation suggests that other mechanisms independent of direct viral infection may induce epithelial cell cytokine release. Our aim was to test for the importance of interactions between human bronchial epithelial cells (HBECs) and monocytic cells in the control of mediator release during HRV exposure. In vitro models of HRV serotype-16 (HRV16) infection of primary HBECs and human monocytic cells, in mono or co-culture, were used. We assessed HRV16-induced CXCL10 and CCL2 protein release via ELISA. Co-culture of human monocytic and bronchial epithelial cells promoted a synergistic augmentation of CXCL10 and CCL2 protein release following HRV16 challenge. Transfer of conditioned media from HRV16-treated monocytic cells to epithelial cultures induced a robust release of CXCL10 by the epithelial cells. This effect was greatly attenuated by type I IFN receptor blocking antibodies, and could be recapitulated by IFN-alpha addition. Our data indicate that epithelial CXCL10 release during HRV infection is augmented by a monocytic cell-dependent mechanism involving type I IFN(s). Our findings support a key role for monocytic cells in the amplification of epithelial cell chemokine production during HRV infection, and help to explain how an inflammatory milieu is created in the lower airways even in the absence of extensive viral replication and epithelial infection.