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1.
Sci Rep ; 11(1): 24442, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1577650

ABSTRACT

Therapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops, making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as the targeting of host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, reduces RSV protein production and generation of infectious progeny virus. Further, we show that this approach can be generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, mRNA transcription and protein production. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particularly in the absence of antiviral drugs.


Subject(s)
Coronavirus/metabolism , Respiratory Syncytial Virus, Human/metabolism , TOR Serine-Threonine Kinases/metabolism , Viral Proteins/metabolism , A549 Cells , Coronavirus/drug effects , Coronavirus/genetics , Gene Expression Regulation, Viral/drug effects , Humans , Protein Biosynthesis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , RNA Interference , RNA, Small Interfering/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/antagonists & inhibitors , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , Regulatory-Associated Protein of mTOR/antagonists & inhibitors , Regulatory-Associated Protein of mTOR/genetics , Regulatory-Associated Protein of mTOR/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/isolation & purification , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Viral Proteins/genetics
2.
Viruses ; 12(8)2020 07 27.
Article in English | MEDLINE | ID: covidwho-1512665

ABSTRACT

Acute viral bronchiolitis causes significant mortality in the developing world, is the number one cause of infant hospitalisation in the developed world, and is associated with the later development of chronic lung diseases such as asthma. A vaccine against respiratory syncytial virus (RSV), the leading cause of viral bronchiolitis in infancy, remains elusive, and hence new therapeutic modalities are needed to limit disease severity. However, much remains unknown about the underlying pathogenic mechanisms. Neutrophilic inflammation is the predominant phenotype observed in infants with both mild and severe disease, however, a clear understanding of the beneficial and deleterious effects of neutrophils is lacking. In this review, we describe the multifaceted roles of neutrophils in host defence and antiviral immunity, consider their contribution to bronchiolitis pathogenesis, and discuss whether new approaches that target neutrophil effector functions will be suitable for treating severe RSV bronchiolitis.


Subject(s)
Bronchiolitis, Viral/immunology , Bronchiolitis, Viral/pathology , Immunity, Innate , Neutrophils/immunology , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/immunology , Acute Disease , Animals , Clinical Trials as Topic , Humans , Inflammation/virology , Lung/virology , Mice , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus, Human/pathogenicity
3.
Sci Rep ; 11(1): 21519, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500511

ABSTRACT

A high neutrophil to lymphocyte ratio (NLR) is considered an unfavorable prognostic factor in various diseases, including COVID-19. The prognostic value of NLR in other respiratory viral infections, such as Influenza, has not hitherto been extensively studied. We aimed to compare the prognostic value of NLR in COVID-19, Influenza and Respiratory Syncytial Virus infection (RSV). A retrospective cohort of COVID-19, Influenza and RSV patients admitted to the Tel Aviv Medical Center from January 2010 to October 2020 was analyzed. Laboratory, demographic, and clinical parameters were collected. Two way analyses of variance (ANOVA) was used to compare the association between NLR values and poor outcomes among the three groups. ROC curve analyses for each virus was applied to test the discrimination ability of NLR. 722 COVID-19, 2213 influenza and 482 RSV patients were included. Above the age of 50, NLR at admission was significantly lower among COVID-19 patients (P < 0.001). NLR was associated with poor clinical outcome only in the COVID-19 group. ROC curve analysis was performed; the area under curve of poor outcomes for COVID-19 was 0.68, compared with 0.57 and 0.58 for Influenza and RSV respectively. In the COVID-19 group, multivariate logistic regression identified a high NLR (defined as a value above 6.82) to be a prognostic factor for poor clinical outcome, after adjusting for age, sex and Charlson comorbidity score (odds ratio of 2.9, P < 0.001). NLR at admission is lower and has more prognostic value in COVID-19 patients, when compared to Influenza and RSV.


Subject(s)
COVID-19/pathology , Influenza, Human/pathology , Respiratory Syncytial Virus Infections/pathology , Adult , Aged , Aged, 80 and over , Area Under Curve , COVID-19/immunology , COVID-19/virology , Female , Humans , Influenza, Human/immunology , Lymphocytes/cytology , Lymphocytes/metabolism , Male , Middle Aged , Neutrophils/cytology , Neutrophils/metabolism , Prognosis , ROC Curve , Respiratory Syncytial Virus Infections/immunology , Retrospective Studies , SARS-CoV-2/isolation & purification
4.
Eur J Med Chem ; 224: 113684, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1292698

ABSTRACT

Respiratory syncytial virus (RSV) causes serious lower respiratory tract infections. Currently, the only clinical anti-RSV drug is ribavirin, but ribavirin has serious toxic side effect and can only be used by critically ill patients. A series of benzimidazole derivatives were synthesized starting from 1,4:3,6-dianhydro-d-fructose and a variety of o-phenylenediamines. Evaluation of their antiviral activity showed that compound a27 had the highest antiviral activity with a half maximal effective concentration (EC50) of 9.49 µM. Investigation of the antiviral mechanism of compound a27 indicated that it can inhibit the replication of RSV by inhibiting apoptosis and autophagy pathways. Retinoic acid-inducible gene (RIG)-I, TNF receptor associated factor (TRAF)-3, TANK binding kinase (TBK)-1, interferon regulatory factor (IRF)-3, nuclear factor Kappa-B (NF-κB), interferon (IFN)-ß, Toll-like receptor (TLR)-3, interleukin (IL)-6 were suppressed at the cellular level. Mouse lung tissue was subjected to hematoxylin and eosin (HE) staining and immunohistochemistry, which showed that RSV antigen and M gene expression could be reduced by compound a27. Decreased expression of RIG-I, IRF-3, IFN-ß, TLR-3, IL-6, interleukin (IL)-8, interleukin (IL)-10, inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α was also found in vivo.


Subject(s)
Antiviral Agents/chemical synthesis , Benzimidazoles/chemistry , Drug Design , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Apoptosis/drug effects , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Cell Line , Cytokines/metabolism , Humans , Isomerism , Lung/metabolism , Lung/pathology , Mice , Molecular Conformation , Reactive Oxygen Species/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/physiology , Structure-Activity Relationship , Toll-Like Receptor 3/metabolism , Virus Replication/drug effects
5.
PLoS One ; 16(3): e0248932, 2021.
Article in English | MEDLINE | ID: covidwho-1150551

ABSTRACT

Few studies have examined the effects of inbound overseas travelers and meteorological conditions on the shift in human respiratory syncytial virus (HRSV) season in Japan. This study aims to test whether the number of inbound overseas travelers and meteorological conditions are associated with the onset week of HRSV epidemic season. The estimation of onset week for 46 prefectures (except for Okinawa prefecture) in Japan for 4-year period (2014-2017) was obtained from previous papers based on the national surveillance data. We obtained data on the yearly number of inbound overseas travelers and meteorological (yearly mean temperature and relative humidity) conditions from Japan National Tourism Organization (JNTO) and Japan Meteorological Agency (JMA), respectively. Multi-level mixed-effects linear regression analysis showed that every 1 person (per 100,000 population) increase in number of overall inbound overseas travelers led to an earlier onset week of HRSV epidemic season in the year by 0.02 week (coefficient -0.02; P<0.01). Higher mean temperature and higher relative humidity were also found to contribute to an earlier onset week by 0.30 week (coefficient -0.30; P<0.05) and 0.18 week (coefficient -0.18; P<0.01), respectively. Additionally, models that included the number of travelers from individual countries (Taiwan, South Korea, and China) except Australia showed that both the number of travelers from each country and meteorological conditions contributed to an earlier onset week. Our analysis showed the earlier onset week of HRSV epidemic season in Japan is associated with increased number of inbound overseas travelers, higher mean temperature, and relative humidity. The impact of international travelers on seasonality of HRSV can be further extended to investigations on the changes of various respiratory infectious diseases especially after the coronavirus disease 2019 (COVID-19) pandemic.


Subject(s)
Respiratory Syncytial Virus Infections/pathology , Travel , Epidemics , Humans , Humidity , Japan/epidemiology , Models, Theoretical , Respiratory Syncytial Virus Infections/epidemiology , Seasons , Temperature
6.
mSphere ; 5(3)2020 05 27.
Article in English | MEDLINE | ID: covidwho-774837

ABSTRACT

Zinc supplementation in cell culture has been shown to inhibit various viruses, like herpes simplex virus, rotavirus, severe acute respiratory syndrome (SARS) coronavirus, rhinovirus, and respiratory syncytial virus (RSV). However, whether zinc plays a direct antiviral role in viral infections and whether viruses have adopted strategies to modulate zinc homeostasis have not been investigated. Results from clinical trials of zinc supplementation in infections indicate that zinc supplementation may be beneficial in a pathogen- or disease-specific manner, further underscoring the importance of understanding the interaction between zinc homeostasis and virus infections at the molecular level. We investigated the effect of RSV infection on zinc homeostasis and show that RSV infection in lung epithelial cells leads to modulation of zinc homeostasis. The intracellular labile zinc pool increases upon RSV infection in a multiplicity of infection (MOI)-dependent fashion. Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Adding zinc to culture medium after RSV infection led to significant inhibition of RSV titers, whereas depletion of zinc by a zinc chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) led to an increase in RSV titers. The inhibitory effect of zinc was specific, as other divalent cations had no effect on RSV titers. Both RSV infection and zinc chelation by TPEN led to reactive oxygen species (ROS) induction, whereas addition of zinc blocked ROS induction. These results suggest a molecular link between RSV infection, zinc homeostasis, and oxidative-stress pathways and provide new insights for developing strategies to counter RSV infection.IMPORTANCE Zinc deficiency rates in developing countries range from 20 to 30%, and zinc supplementation trials have been shown to correct clinical manifestations attributed to zinc deficiency, but the outcomes in the case of respiratory infections have been inconsistent. We aimed at understanding the role of zinc homeostasis in respiratory syncytial virus (RSV) infection. Infection of lung epithelial cell lines or primary small-airway epithelial cells led to an increase in labile zinc pools, which was due to increased uptake of zinc. Zinc supplementation inhibited RSV replication, whereas zinc chelation had an opposing effect, leading to increases in RSV titers. Increases in labile zinc in RSV-infected cells coincided with induction of reactive oxygen species (ROS). Both zinc depletion and addition of exogenous ROS led to enhanced RSV infection, whereas addition of the antioxidant inhibited RSV, suggesting that zinc is part of an interplay between RSV-induced oxidative stress and the host response to maintain redox balance.


Subject(s)
Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/metabolism , Virus Replication/drug effects , Zinc/metabolism , Zinc/pharmacology , A549 Cells , Adolescent , Cation Transport Proteins/genetics , Cell Line , Child , Child, Preschool , Epithelial Cells/metabolism , Ethylenediamines/pharmacology , Female , Host-Pathogen Interactions , Humans , Lung/cytology , Lung/metabolism , Male , Oxidative Stress/physiology , RNA Interference , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology
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