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Mamun TI, Ali MA, Hosen MN, Rahman J, Islam MA, Akib MG, Zaman K, Rahman MM, Hossain FMA, Ibenmoussa S, Bourhia M, Dawoud TM. Designing a multi-epitope vaccine candidate against human rhinovirus C utilizing immunoinformatics approach. Front Immunol 2025; 15:1364129. [PMID: 39840071 PMCID: PMC11747413 DOI: 10.3389/fimmu.2024.1364129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 12/04/2024] [Indexed: 01/30/2025] Open
Abstract
Human rhinovirus C (HRV-C) is a significant contributor to respiratory tract infections in children and is implicated in asthma exacerbations across all age groups. Despite its impact, there is currently no licensed vaccine available for HRV-C. Here, we present a novel approach to address this gap by employing immunoinformatics techniques for the design of a multi-epitope-based vaccine against HRV-C. The sequences of the chosen structural proteins VP1 and VP2, along with the non-structural protein 2C of HRV-C, were downloaded in FASTA format from the NCBI server for further analysis. Through an exhaustive analysis of HRV-C genomic sequences, we identified highly conserved immunogenic regions capable of eliciting a protective immune response. Leveraging advanced immunoinformatics tools, we predicted epitopes for B-cells, Cytotoxic T lymphocytes, and Helper T lymphocytes, ensuring broad coverage across different HRV-C strains. The vaccine candidate was constructed by integrating selected antigens with immunogenic epitopes and adjuvants, employing optimal linkers. Three vaccine constructs were developed, with V2 being the most promising, consisting of 480 amino acids residues. V2 exhibited strong antigenicity, non-allergenicity, and solubility, with a solubility score greater than 0.550, and demonstrated excellent structural stability, with 91.9% of residues in the most favorable regions of the Ramachandran plot. Molecular dynamics and simulation studies revealed a stable Vaccine-TLR8 complex, with a binding energy of -296.15 and consistent RMSD values. Furthermore, in silico cloning and sequence optimization ensured efficient expression in E. coli, with a Codon Adaptation Index of 0.99 and GC content of 54.58%. The minimum free energy of the RNA secondary structure was -494.90 kcal/mol. While our findings suggest the potential effectiveness of the designed vaccine candidate against HRV-C, further in vitro and in vivo investigations are warranted to validate its safety and efficacy.
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Affiliation(s)
- Tajul Islam Mamun
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet, Bangladesh
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Md. Ahad Ali
- Department Of Chemistry, University of Rajshahi, Rajshahi, Bangladesh
| | - Md. Nazmul Hosen
- Department of Pharmacology and Toxicology, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Jillur Rahman
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Md. Anwarul Islam
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Md. Golam Akib
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Kamruz Zaman
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Md. Masudur Rahman
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
- Department of Pathology, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Ferdaus Mohd Altaf Hossain
- Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
- Department of Dairy Science, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Samir Ibenmoussa
- Laboratory of Therapeutic and Organic Chemistry, Faculty of Pharmacy, University of Montpellier, Montpellier, France
| | - Mohammed Bourhia
- Department of Chemistry and Biochemistry, Faculty of Medicine and Pharmacy, Ibn Zohr University, Laayoune, Morocco
| | - Turki M. Dawoud
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
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2
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Ganjian H, Sajjan U. Laboratory Protocol for Propagation and Purification of Rhinovirus A and B Suitable for In Vitro and In Vivo Infection. Methods Mol Biol 2025; 2903:9-19. [PMID: 40016454 DOI: 10.1007/978-1-0716-4410-2_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
H1HeLa cell line has become the most utilized cell culture system for in vitro studies of the rhinovirus life cycle. These cells are also widely used to propagate the rhinovirus to study host responses. Unlike other viruses, high-titer virus is required for studies focusing on understanding the host responses to rhinovirus infection in vivo and in vitro. Therefore, after propagation of rhinovirus, H1HeLa cells should be concentrated and purified. In this chapter, we describe the methods used for the propagation of rhinovirus A and B that are adapted to H1HeLa cells.
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Affiliation(s)
- Haleh Ganjian
- Centre for Inflammation and Lung Research, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA
| | - Umadevi Sajjan
- Centre for Inflammation and Lung Research, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA.
- Department of Microbiology, Immunology and Inflammation, Temple University, Philadelphia, PA, USA.
- Department of Thoracic Medicine and Surgery, Temple University, Philadelphia, PA, USA.
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Tabasi M. Detection of Rhinovirus in Clinical Samples by PCR. Methods Mol Biol 2025; 2903:1-7. [PMID: 40016453 DOI: 10.1007/978-1-0716-4410-2_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Rhinovirus is a prevalent respiratory pathogen responsible for a significant proportion of upper and lower respiratory tract infections. Its ability to cause a range of illnesses, from mild common cold symptoms to more severe respiratory diseases, underscores the importance of accurate and timely detection. Detecting rhinovirus in clinical samples is an important diagnostic process for identifying and diagnosing respiratory infections caused by this common virus. This chapter of the book provides a comprehensive overview of the methodologies and techniques employed in the detection of rhinovirus in clinical samples.
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Affiliation(s)
- Mohsen Tabasi
- Centre for Inflammation and Lung Research, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA.
- Department of Microbiology, Immunology and Inflammation, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA.
- Department of Thoracic Medicine and Surgery, Lewis Katz Medical School, Temple University, Philadelphia, PA, USA.
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Li C, Yu Y, Wan Z, Chiu MC, Huang J, Zhang S, Zhu X, Lan Q, Deng Y, Zhou Y, Xue W, Yue M, Cai JP, Yip CCY, Wong KKY, Liu X, Yu Y, Huang L, Chu H, Chan JFW, Clevers H, Yuen KY, Zhou J. Human respiratory organoids sustained reproducible propagation of human rhinovirus C and elucidation of virus-host interaction. Nat Commun 2024; 15:10772. [PMID: 39738014 DOI: 10.1038/s41467-024-55076-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 11/26/2024] [Indexed: 01/01/2025] Open
Abstract
The lack of a robust system to reproducibly propagate HRV-C, a family of viruses refractory to cultivation in standard cell lines, has substantially hindered our understanding of this common respiratory pathogen. We sought to develop an organoid-based system to reproducibly propagate HRV-C, and characterize virus-host interaction using respiratory organoids. We demonstrate that airway organoids sustain serial virus passage with the aid of CYT387-mediated immunosuppression, whereas nasal organoids that more closely simulate the upper airway achieve this without any intervention. Nasal organoids are more susceptible to HRV-C than airway organoids. Intriguingly, upon HRV-C infection, we observe an innate immune response that is stronger in airway organoids than in nasal organoids, which is reproduced in a Poly(I:C) stimulation assay. Treatment with α-CDHR3 and antivirals significantly reduces HRV-C viral growth in airway and nasal organoids. Additionally, an organoid-based immunofluorescence assay is established to titrate HRV-C infectious particles. Collectively, we develop an organoid-based system to reproducibly propagate the poorly cultivable HRV-C, followed by a comprehensive characterization of HRV-C infection and innate immunity in physiologically active respiratory organoids. The organoid-based HRV-C infection model can be extended for developing antiviral strategies. More importantly, our study has opened an avenue for propagating and studying other uncultivable human and animal viruses.
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Affiliation(s)
- Cun Li
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yifei Yu
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Zhixin Wan
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Man Chun Chiu
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
| | - Jingjing Huang
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
| | - Shuxin Zhang
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Xiaoxin Zhu
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
| | - Qiaoshuai Lan
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
| | - Yanlin Deng
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
| | - Ying Zhou
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wei Xue
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Ming Yue
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Jian-Piao Cai
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Cyril Chik-Yan Yip
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kenneth Kak-Yuen Wong
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Queen Mary Hospital, Hong Kong, China
| | - Xiaojuan Liu
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Yang Yu
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | | | - Hin Chu
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
| | - Jasper Fuk-Woo Chan
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Hans Clevers
- Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), and University Medical Center (UMC) Utrecht, Utrecht, the Netherlands
- Roche Pharmaceutical Research and Early Development, Basel, Switzerland
| | - Kwok Yung Yuen
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Jie Zhou
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
- Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China.
- BiomOrgan Ltd, Hong Kong, China.
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.
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Asri N, Mohammadi S, Jahdkaran M, Rostami-Nejad M, Rezaei-Tavirani M, Mohebbi SR. Viral infections in celiac disease: what should be considered for better management. Clin Exp Med 2024; 25:25. [PMID: 39731690 DOI: 10.1007/s10238-024-01542-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024]
Abstract
Following a gluten-free diet (GFD) is known as the main effective therapy available for celiac disease (CD) patients, which in some cases is not enough to heal all patients presentations completely. Accordingly, emerging researchers have focused on finding novel therapeutic/preventive strategies for this disorder. Moreover, previous studies have shown that celiac patients, especially untreated subjects, are at increased risk of developing viral and bacterial infections, which can become a challenge for the clinician. Viruses, such as Rotavirus, Reovirus, Adenovirus, Enterovirus, Rhinovirus, Astrovirus, Hepatitis virus, COVID-19, Norovirus, and Herpesvirus, have been related to CD pathogenesis. Therefore, clinicians need to pay more attention to evaluate CD patients' viral infection history (especially nonresponders to the GFD), to look for effective preventive strategies and educate patients about important risk factors. In addition, there are still viruses whose role in CD pathogenesis has not been fully studied. In this review, current information on the association between CD and various viral infections was gathered to improve knowledge in this subject area and draw researchers'/clinicians' attention to unstudied/less studied viruses in CD pathogenesis, which might guide future prevention approaches.
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Affiliation(s)
- Nastaran Asri
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahnaz Mohammadi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahtab Jahdkaran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Das NK, Vogt J, Patel A, Banna HA, Koirala D. Structural basis for a highly conserved RNA-mediated enteroviral genome replication. Nucleic Acids Res 2024; 52:11218-11233. [PMID: 39036953 PMCID: PMC11472160 DOI: 10.1093/nar/gkae627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/28/2024] [Accepted: 07/05/2024] [Indexed: 07/23/2024] Open
Abstract
Enteroviruses contain conserved RNA structures at the extreme 5' end of their genomes that recruit essential proteins 3CD and PCBP2 to promote genome replication. However, the high-resolution structures and mechanisms of these replication-linked RNAs (REPLRs) are limited. Here, we determined the crystal structures of the coxsackievirus B3 and rhinoviruses B14 and C15 REPLRs at 1.54, 2.2 and 2.54 Å resolution, revealing a highly conserved H-type four-way junction fold with co-axially stacked sA-sD and sB-sC helices that are stabilized by a long-range A•C•U base-triple. Such conserved features observed in the crystal structures also allowed us to predict the models of several other enteroviral REPLRs using homology modeling, which generated models almost identical to the experimentally determined structures. Moreover, our structure-guided binding studies with recombinantly purified full-length human PCBP2 showed that two previously proposed binding sites, the sB-loop and 3' spacer, reside proximally and bind a single PCBP2. Additionally, the DNA oligos complementary to the 3' spacer, the high-affinity PCBP2 binding site, abrogated its interactions with enteroviral REPLRs, suggesting the critical roles of this single-stranded region in recruiting PCBP2 for enteroviral genome replication and illuminating the promising prospects of developing therapeutics against enteroviral infections targeting this replication platform.
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Affiliation(s)
- Naba Krishna Das
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Jeff Vogt
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Alisha Patel
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Hasan Al Banna
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
| | - Deepak Koirala
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
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de Campos GM, Santos HDO, Lima ARJ, Leite AB, Ribeiro G, Todão Bernardino JDS, do Nascimento JPM, Souza JVC, de Lima LPO, Lima MBZ, de Araújo MA, Giovanetti M, Kallas EG, Sampaio SC, Elias MC, Slavov SN. Unveiling viral pathogens in acute respiratory disease: Insights from viral metagenomics in patients from the State of Alagoas, Brazil. PLoS Negl Trop Dis 2024; 18:e0012536. [PMID: 39312587 PMCID: PMC11460670 DOI: 10.1371/journal.pntd.0012536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/08/2024] [Accepted: 09/13/2024] [Indexed: 09/25/2024] Open
Abstract
BACKGROUND Respiratory illness affects individuals across all age demographics on a global scale, often precipitated by viral infections. The symptomatic manifestations of these diseases bear clinical resemblance, complicating the accurate determination of their etiological origins. Furthermore, the diagnostic panels for respiratory pathogens used within local medical practices, may not encompass the full spectrum of viral agents responsible for such ailments. Consequently, a significant number of clinically important viral pathogens may remain undetected. METHODS AND FINDINGS In the light of this, we conducted a metagenomic examination of 66 nasopharyngeal swab specimens, obtained from patients presenting with acute respiratory conditions yet tested negative by the standard diagnostic panels available locally. These specimens were obtained from the Public Health Laboratory, Maceio, State of Alagoas. Our findings indicate a predominant diagnostic escape of rhinoviruses and notably enterovirus D68. Moreover, our study identified a substantial quantity of sequence reads attributed to human respirovirus 3 (human parainfluenza 3) along with various herpresviruses including human herpesvirus-1, Epstein-Barr virus (Human herpesvirus-4), Human herpesviruses 6 and 7 and human parvovirus B19 (B19V). Notably, the metagenomic analysis uncovered a widespread presence of the emerging human vientovirus FB in most of sample pools, though its clinical importance remains to be elucidated. CONCLUSIONS The obtained results in this study underscore the invaluable role of viral metagenomics in the identification of underrecognized viruses bearing clinical relevance. Furthermore, it offers insights into the dissemination of these pathogens within the studied area, thereby informing public health strategies aimed at enhancing diagnostic accuracy and improving patient care.
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Affiliation(s)
- Gabriel Montenegro de Campos
- Post-Graduation Program of Clinical Oncology, Stem-Cells and Cell Therapy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | | | | | - Anderson Brandão Leite
- Central Public Health Laboratory (LACEN) of the State of Alagoas, Maceio, Alagoas, Brazil
| | - Gabriela Ribeiro
- Center for Viral Surveillance and Serologic Evaluation (CeVIVAS), Butantan Institute, São Paulo, Brazil
| | | | | | | | | | - Marlon Breno Zampieri Lima
- Post-Graduation Program of Clinical Oncology, Stem-Cells and Cell Therapy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | | | - Marta Giovanetti
- Department of Sciences and Technologies for Sustainable Development and One Health, Universita Campus Bio-Medico di Roma, Rome, Italy
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
- Climate Amplified Diseases and Epidemics (CLIMADE), Rio de Janeiro, Brazil, United States of America
| | - Esper Georges Kallas
- Center for Viral Surveillance and Serologic Evaluation (CeVIVAS), Butantan Institute, São Paulo, Brazil
| | - Sandra Coccuzzo Sampaio
- Center for Viral Surveillance and Serologic Evaluation (CeVIVAS), Butantan Institute, São Paulo, Brazil
| | - Maria Carolina Elias
- Center for Viral Surveillance and Serologic Evaluation (CeVIVAS), Butantan Institute, São Paulo, Brazil
| | - Svetoslav Nanev Slavov
- Center for Viral Surveillance and Serologic Evaluation (CeVIVAS), Butantan Institute, São Paulo, Brazil
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Xiao M, Banu A, Jia Y, Chang M, Wang G, An J, Huang Y, Hu X, Tang C, Li Z, Niu Y, Tian X, Deng W, Tang C, Du J, Cui X, Chan JFW, Peng R, Yin F. Circulation pattern and genetic variation of rhinovirus infection among hospitalized children on Hainan Island, before and after the dynamic zero-COVID policy, from 2021 to 2023. J Med Virol 2024; 96:e29755. [PMID: 38922896 DOI: 10.1002/jmv.29755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/17/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
Throughout the COVID-19 pandemic, rhinovirus (RV) remained notable persistence, maintaining its presence while other seasonal respiratory viruses were largely suppressed by pandemic restrictions during national lockdowns. This research explores the epidemiological dynamics of RV infections among pediatric populations on Hainan Island, China, specifically focusing on the impact before and after the zero-COVID policy was lifted. From January 2021 to December 2023, 19 680 samples were collected from pediatric patients hospitalized with acute lower respiratory tract infections (ARTIs) at the Hainan Maternal and Child Health Hospital. The infection of RV was detected by tNGS. RV species and subtypes were identified in 32 RV-positive samples representing diverse time points by analyzing the VP4/VP2 partial regions. Among the 19 680 pediatric inpatients with ARTIs analyzed, 21.55% were found to be positive for RV infection, with notable peaks observed in April 2021 and November 2022. A gradual annual decline in RV infections was observed, alongside a seasonal pattern of higher prevalence during the colder months. The highest proportion of RV infections was observed in the 0-1-year age group. Phylogenetic analysis on 32 samples indicated a trend from RV-A to RV-C in 2022. This observation suggests potential evolving dynamics within the RV species although further studies are needed due to the limited sample size. The research emphasizes the necessity for ongoing surveillance and targeted management, particularly for populations highly susceptible to severe illnesses caused by RV infections.
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Affiliation(s)
- Meifang Xiao
- Department of Clinical Laboratory, Center for Laboratory Medicine, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, Hainan, China
- Department of Microbiology, Faculty of Medicine, Lincoln University College, Petaling Jaya, Malaysia
| | - Afreen Banu
- Department of Microbiology, Faculty of Medicine, Lincoln University College, Petaling Jaya, Malaysia
| | - Yibo Jia
- Medical Administration Division, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
- International School of Public Health and One Health, Hainan Medical College, Haikou, Hainan, China
| | - Meng Chang
- Department of Clinical Laboratory, Center for Laboratory Medicine, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, Hainan, China
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Gaoyu Wang
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Jing An
- Department of Clinical Laboratory, Center for Laboratory Medicine, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, Hainan, China
| | - Yi Huang
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Xiaoyuan Hu
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Chuanning Tang
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Zihan Li
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Yi Niu
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Xiuying Tian
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Wanxin Deng
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Cheng Tang
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Jiang Du
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiuji Cui
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
- Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan, China
| | - Jasper Fuk-Woo Chan
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
- State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, and Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China
- Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Ruoyan Peng
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
| | - Feifei Yin
- Department of Clinical Laboratory, Center for Laboratory Medicine, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou, Hainan, China
- Academician Workstation of Hainan Province, Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, Hainan, China
- Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan, China
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Yang H, Zhu R, Zhou Z, Chen H, Wu Y, Zhang D, Liu C, Xia N, Xu L, Cheng T. Construction and characterization of an infectious cDNA clone of human rhinovirus A89. Heliyon 2024; 10:e27214. [PMID: 38463855 PMCID: PMC10920733 DOI: 10.1016/j.heliyon.2024.e27214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 02/05/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Rhinoviruses (RVs) are major causes of the common cold and are related to severe respiratory tract diseases, leading to a considerable economic burden and impacts on public health. Available and stable viral resources of rhinoviruses for laboratory use are important for promoting studies on rhinoviruses and further vaccine or therapeutic drug development. Reverse genetic technology can be useful to produce rhinoviruses and will help to promote studies on their pathogenesis and virulence. In this study, rhinovirus A89, an RV-A species that has been found to be highly involved in hospitalization triggered by RV infections, was selected to construct an infectious clone based on its sequence as a representative. The viral mRNA produced by a T7 RNA transcript system was transfected into H1-HeLa cells, and the rescued RV-A89 viruses were harvested and confirmed by sequencing. The rescued RV-A89 induced a similar cytopathic effect (CPE) and shared almost identical growth kinetics curves with parental RV-A89. Moreover, 9A7, a prescreened monoclonal antibody against the parental RV-A89, had a good and specific reaction with the rescued RV-A89, and further characterization showed almost the same morphology and protein composition of both viruses; thus, recombinant RV-A89 with similar biological characterization and virulence to the parental virus was obtained. In summary, the infectious clone of RV-A89 was successfully established, and the development of reverse genetic technology for rhinovirus will provide a framework for further studies on rhinoviruses.
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Affiliation(s)
| | | | - Zhenhong Zhou
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Hao Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Yuanyuan Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Dongqing Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Che Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Longfa Xu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
| | - Tong Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, PR China
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10
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Ljubin-Sternak S, Meštrović T. Rhinovirus—A True Respiratory Threat or a Common Inconvenience of Childhood? Viruses 2023; 15:v15040825. [PMID: 37112805 PMCID: PMC10144685 DOI: 10.3390/v15040825] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/22/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
A decade-long neglect of rhinovirus as an important agent of disease in humans was primarily due to the fact that they were seen as less virulent and capable of causing only mild respiratory infections such as common cold. However, with an advent of molecular diagnostic methods, an increasing number of reports placed them among the pathogens found in the lower respiratory tract and recognized them as important risk factors for asthma-related pathology in childhood. As the spread of rhinovirus was not severely affected by the implementation of social distancing and other measures during the coronavirus disease 2019 (COVID-19) pandemic, its putative pathogenic role has become even more evident in recent years. By concentrating on children as the most vulnerable group, in this narrative review we first present classification and main traits of rhinovirus, followed by epidemiology and clinical presentation, risk factors for severe forms of the disease, long-term complications and the pathogenesis of asthma, as well as a snapshot of treatment trials and studies. Recent evidence suggests that the rhinovirus is a significant contributor to respiratory illness in both high-risk and low-risk populations of children.
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11
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Ai J, Zhu Y, Duan Y, Zhang M, Lu G, Sun Y, Jin R, Shang Y, Li C, Xu B, Chen X, Xie Z. A multicenter study on molecular epidemiology of rhinovirus isolated from children with community acquired pneumonia in China during 2017-2019. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 106:105384. [PMID: 36396029 DOI: 10.1016/j.meegid.2022.105384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 11/16/2022]
Abstract
Rhinoviruses (RVs) are a major pathogen of community acquired pneumonia in children. To investigate the prevalence and genetic characteristics of RVs in China, we performed a molecular epidemiological study during 2017-2019 in community acquired pneumonia (CAP) in pediatric patients. In this multicenter study, 109 RV-A, 20 RV-B and 80 RV-C were identified. Among them, RV-A12, RV-A101, RV-A78, RV-A49, RV-A22, RV-B52, RV-C2, RV-C53 and RV-C5 were the common genotypes in the study. A total of 23 complete genome of RVs including 4 RV-A, 1 RV-B and 18 RV-C were obtained. Furthermore, in the RV-C isolates, one RV-C5 and five RV-C53 genotypes were found, which have a limited number in the GenBank. Phylogenetic analysis of the complete genome showed that most of the RVs isolated in the study have high nucleotide sequence identities (>95%) compared with the corresponding reference sequence in the GenBank. In RV-A9, RV-A28, RV-A61 and RV-B52, amino acid mutations were found in the potential neutralizing immunogenic (Nim) sites (Nim-1a and Nim-1b) of the VP1. In RV-B52, one of RV-C2 and RV-C5 isolates, amino acid mutations were found in the P1a peptide of the VP1. However, no recombination events were found in the study. In conclusion, RV-A was the predominant specie of RVs followed by RV-C in the study. The complete genomes of one RV-C5 and five RV-C53 genotypes were obtained which have a limited number sequence in the GenBank. High nucleotide sequence identities (>95%) were found among the complete genome obtained in the study and the corresponding reference sequence in the GenBank. Amino acid mutations were found in the potential Nim-1a, Nim-1b sites and P1a peptide region of the VP1 in parts of RVs.
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Affiliation(s)
- Junhong Ai
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Yun Zhu
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Yali Duan
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Meng Zhang
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China
| | - Gen Lu
- Guangzhou Women and Children's Medical Center, Guangzhou 510623, China
| | - Yun Sun
- Yinchuan Maternal and Child Health Hospital, Yinchuan 750001, China
| | - Rong Jin
- Guiyang Maternal and Child Health Hospital, Guiyang 550003, China
| | - Yunxiao Shang
- Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Changchong Li
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Baoping Xu
- Department of Respiratory Diseases I, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing 100045, China
| | - Xiangpeng Chen
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
| | - Zhengde Xie
- Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, Research Unit of Critical Infection in Children, Chinese Academy of Medical Sciences, 2019RU016, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
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12
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Lee HS, Volpe SJ, Chang EH. The Role of Viruses in the Inception of Chronic Rhinosinusitis. Clin Exp Otorhinolaryngol 2022; 15:310-318. [PMID: 36455880 PMCID: PMC9723285 DOI: 10.21053/ceo.2022.01004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 11/22/2022] Open
Abstract
Chronic rhinosinusitis (CRS) is a complex inflammatory disorder that affects between 2% and 16% of adults in the United States, with estimated healthcare costs between 4 and 12 million USD. Viruses are a common etiologic factor for URIs, are frequently identified in the sinuses of patients with CRS, and trigger CRS exacerbations. Therefore, investigating the role of viruses provides an opportunity to identify their role in the pathogenesis of CRS. In this review, we identified the viruses frequently isolated in patients with CRS, as well as their associated immunologic responses and contributions to inflammation. Rhinovirus, parainfluenza virus, influenza virus, and respiratory syncytial virus are the viruses commonly found in patients with CRS. This information allows us to target pathways early in the pathogenesis of CRS, thereby playing a significant role in slowing the progression of this chronic disease.
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Affiliation(s)
- Hyeon Seung Lee
- Department of Otolaryngology, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Sophia J Volpe
- Department of Otolaryngology, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Eugene H Chang
- Department of Otolaryngology, University of Arizona College of Medicine, Tucson, AZ, USA
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13
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Microarray-Based Analyses of Rhinovirus Species-Specific Antibody Responses in Exacerbated Pediatric Asthma in a German Pediatric Cohort. Viruses 2022; 14:v14091857. [PMID: 36146664 PMCID: PMC9502376 DOI: 10.3390/v14091857] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 02/05/2023] Open
Abstract
Rhinoviruses (RV) account for a significant number of asthma exacerbations, and RV species C may be associated with a severe course in vulnerable patient groups. Despite important evidence on the role of RV reported by clinicians and life scientists, there are still unanswered questions regarding their influence on asthma exacerbation in young patients. Thus, we measured the RVspecies-specific IgG titers in our German pediatric exacerbation cohort using a microarray-based technology. For this approach, human sera of patients with exacerbated asthma and wheeze, as well as healthy control subjects (n = 136) were included, and correlation analyses were performed. Concordantly with previously published results, we observed significantly higher cumulative levels of RV species A-specific IgG (p = 0.011) and RV-C-specific IgG (p = 0.051) in exacerbated asthma group compared to age-matched controls. Moreover, atopic wheezers had increased RV-specific IgG levels for species A (p = 0.0011) and species C (p = 0.0009) compared to non-atopic wheezers. Hypothesizing that bacterial infection positively correlates with immune memory against RV, we included nasopharyngeal swab results in our analyses and detected limited correlations. Interestingly, the eosinophil blood titer positively correlated with RV-specific IgG levels. With these observations, we add important observations to the existing data regarding exacerbation in pediatric and adolescent medicine. We propose that scientists and clinicians should pay more attention to the relevance of RV species in susceptible pediatric patients.
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14
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Molecular epidemiology and clinical characterization of human rhinoviruses circulating in Shanghai, 2012-2020. Arch Virol 2022; 167:1111-1123. [PMID: 35303167 PMCID: PMC8931777 DOI: 10.1007/s00705-022-05405-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 01/22/2022] [Indexed: 12/30/2022]
Abstract
Human rhinoviruses (HRVs) cause acute upper and lower respiratory tract infections and aggravation of asthma and chronic obstructive pulmonary disease. The 5’ untranslated region (5' UTR) and the VP4/VP2 region are widely used for genotyping of HRVs. Members of the species Rhinovirus A and Rhinovirus C have been reported to be more frequently associated with severe disease than members of the species Rhinovirus B. We report the clinical and molecular epidemiological characteristics of HRVs circulating from 2012 to 2020 in Shanghai. A total of 5832 nasopharyngeal swabs from patients with acute respiratory infections were collected. A real-time reverse transcription polymerase chain reaction assay was used for virus detection. The 5' untranslated region and VP4/VP2 region were amplified and sequenced for genotyping and phylogenetic analysis. The overall rate of rhinovirus detection was 2.74% (160/5832), with members of species A, B, and C accounting for 68.13% (109/160), 20.00% (32/160), and 11.88% (19/160) of the total, respectively. A peak of HRV infection was observed in autumn (5.34%, 58/1087). Patients in the 3- to 14-year-old age group were the most susceptible to HRV infection (χ2 = 23.88, P = 0.017). Influenza virus and Streptococcus pneumoniae were detected more frequently than other pathogens in cases of coinfection. Recombination events were identified in 10 strains, which were successfully genotyped by phylogenetic analysis based on the 5’ UTR-VP4/VP2 region but not the 5’ UTR region alone. We observed a high degree of variability in the relative distribution of HRV genotypes and the prevalence of HRV infection in Shanghai and found evidence of recombination events in the portion of the genome containing the 5’ UTR and the VP4/VP2 region between HRV-C strains and HRV-A-like strains. This study is important for surveillance of the spread of HRVs and the emergence of new variants.
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15
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Esneau C, Duff AC, Bartlett NW. Understanding Rhinovirus Circulation and Impact on Illness. Viruses 2022; 14:141. [PMID: 35062345 PMCID: PMC8778310 DOI: 10.3390/v14010141] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/08/2022] [Accepted: 01/10/2022] [Indexed: 01/27/2023] Open
Abstract
Rhinoviruses (RVs) have been reported as one of the main viral causes for severe respiratory illnesses that may require hospitalization, competing with the burden of other respiratory viruses such as influenza and RSV in terms of severity, economic cost, and resource utilization. With three species and 169 subtypes, RV presents the greatest diversity within the Enterovirus genus, and despite the efforts of the research community to identify clinically relevant subtypes to target therapeutic strategies, the role of species and subtype in the clinical outcomes of RV infection remains unclear. This review aims to collect and organize data relevant to RV illness in order to find patterns and links with species and/or subtype, with a specific focus on species and subtype diversity in clinical studies typing of respiratory samples.
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Affiliation(s)
| | | | - Nathan W. Bartlett
- Hunter Medical Research Institute, College of Health Medicine and Wellbeing, University of Newcastle, New Lambton Heights, NSW 2305, Australia; (C.E.); (A.C.D.)
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16
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Watkinson RL, Looi K, Laing IA, Cianferoni A, Kicic A. Viral Induced Effects on a Vulnerable Epithelium; Lessons Learned From Paediatric Asthma and Eosinophilic Oesophagitis. Front Immunol 2021; 12:773600. [PMID: 34912343 PMCID: PMC8666438 DOI: 10.3389/fimmu.2021.773600] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/05/2021] [Indexed: 01/07/2023] Open
Abstract
The epithelium is integral to the protection of many different biological systems and for the maintenance of biochemical homeostasis. Emerging evidence suggests that particular children have epithelial vulnerabilities leading to dysregulated barrier function and integrity, that resultantly contributes to disease pathogenesis. These epithelial vulnerabilities likely develop in utero or in early life due to various genetic, epigenetic and environmental factors. Although various epithelia are uniquely structured with specific function, prevalent allergic-type epithelial diseases in children potentially have common or parallel disease processes. These include inflammation and immune response dysregulation stemming from atypical epithelial barrier function and integrity. Two diseases where aetiology and pathogenesis are potentially linked to epithelial vulnerabilities include Paediatric Asthma and Eosinophilic Oesophagitis (EoE). For example, rhinovirus C (RV-C) is a known risk factor for paediatric asthma development and is known to disrupt respiratory epithelial barrier function causing acute inflammation. In addition, EoE, a prevalent atopic condition of the oesophageal epithelium, is characterised by similar innate immune and epithelial responses to viral injury. This review examines the current literature and identifies the gaps in the field defining viral-induced effects on a vulnerable respiratory epithelium and resulting chronic inflammation, drawing from knowledge generated in acute wheezing illness, paediatric asthma and EoE. Besides highlighting the importance of epithelial structure and barrier function in allergic disease pathogenesis regardless of specific epithelial sub-types, this review focuses on the importance of examining other parallel allergic-type disease processes that may uncover commonalities driving disease pathogenesis. This in turn may be beneficial in the development of common therapeutics for current clinical management and disease prevention in the future.
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Affiliation(s)
- Rebecca L Watkinson
- Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA, Australia.,Wal-Yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia
| | - Kevin Looi
- Wal-Yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia.,School of Public Health, Curtin University, Bentley, WA, Australia
| | - Ingrid A Laing
- Division of Paediatrics, Medical School, The University of Western Australia, Nedlands, WA, Australia.,Wal-Yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia
| | - Antonella Cianferoni
- Pediatrics Department, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Anthony Kicic
- Wal-Yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia.,School of Public Health, Curtin University, Bentley, WA, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Medicine, The University of Western Australia, Nedlands, WA, Australia
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17
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Zhang YM. Orosomucoid-like protein 3, rhinovirus and asthma. World J Crit Care Med 2021; 10:170-182. [PMID: 34616654 PMCID: PMC8462028 DOI: 10.5492/wjccm.v10.i5.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also plays pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
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Affiliation(s)
- You-Ming Zhang
- Section of Genomic and Environmental Medicine, National Heart and Lung Institute, Molecular Genetics Group, Division of Respiratory Sciences, Imperial College London, London SW3 6LY, United Kingdom
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18
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Real-Hohn A, Blaas D. Rhinovirus Inhibitors: Including a New Target, the Viral RNA. Viruses 2021; 13:1784. [PMID: 34578365 PMCID: PMC8473194 DOI: 10.3390/v13091784] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/21/2021] [Accepted: 09/03/2021] [Indexed: 12/18/2022] Open
Abstract
Rhinoviruses (RVs) are the main cause of recurrent infections with rather mild symptoms characteristic of the common cold. Nevertheless, RVs give rise to enormous numbers of absences from work and school and may become life-threatening in particular settings. Vaccination is jeopardised by the large number of serotypes eliciting only poorly cross-neutralising antibodies. Conversely, antivirals developed over the years failed FDA approval because of a low efficacy and/or side effects. RV species A, B, and C are now included in the fifteen species of the genus Enteroviruses based upon the high similarity of their genome sequences. As a result of their comparably low pathogenicity, RVs have become a handy model for other, more dangerous members of this genus, e.g., poliovirus and enterovirus 71. We provide a short overview of viral proteins that are considered potential drug targets and their corresponding drug candidates. We briefly mention more recently identified cellular enzymes whose inhibition impacts on RVs and comment novel approaches to interfere with infection via aggregation, virus trapping, or preventing viral access to the cell receptor. Finally, we devote a large part of this article to adding the viral RNA genome to the list of potential drug targets by dwelling on its structure, folding, and the still debated way of its exit from the capsid. Finally, we discuss the recent finding that G-quadruplex stabilising compounds impact on RNA egress possibly via obfuscating the unravelling of stable secondary structural elements.
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Affiliation(s)
- Antonio Real-Hohn
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Dr. Bohr Gasse 9/3, A-1030 Vienna, Austria
| | - Dieter Blaas
- Center for Medical Biochemistry, Vienna Biocenter, Max Perutz Laboratories, Medical University of Vienna, Dr. Bohr Gasse 9/3, A-1030 Vienna, Austria
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19
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Utility of Three Nebulizers in Investigating the Infectivity of Airborne Viruses. Appl Environ Microbiol 2021; 87:e0049721. [PMID: 34085856 DOI: 10.1128/aem.00497-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Laboratory-generated bioaerosols are widely used in aerobiology studies of viruses; however, few comparisons of alternative nebulizers exist. We compared aerosol production and virus survival for a Collison nebulizer, vibrating mesh nebulizer (VMN), and hydraulic spray atomizer (HSA). We also measured the dry size distribution of the aerosols produced and calculated the droplet sizes before evaporation and the dry size distribution from normal saline solution. Dry count median diameters of 0.11, 0.22, and 0.30 μm were found for normal saline from the Collison nebulizer, VMN, and HSA, respectively. The volume median diameters were 0.323, 1.70, and 1.30 μm, respectively. The effect of nebulization on the viability of two influenza A viruses (IAVs) (H1N1 and H3N2) and human rhinovirus 16 (HRV-16) was assessed by nebulization into an SKC BioSampler. The HSA had the least impact on surviving fractions (SFs) of H1N1 and H3N2 (89% ± 3% and 94% ± 2%, respectively), followed by the Collison nebulizer (83% ± 1% and 82% ± 2%, respectively). The VMN yielded SFs of 78% ± 2% and 76% ± 2%, respectively. Conversely, for HRV-16, the VMN produced higher SFs (87% ± 8%). Our findings indicate that there were no statistical differences between SFs of the viruses nebulized by these nebulizers. However, VMN produced higher aerosol concentrations within the airborne size range, making it more suitable where high aerosol mass production is required. IMPORTANCE Viral respiratory tract infections cause millions of lost days of work and physician visits globally, accounting for significant morbidity and mortality. Respiratory droplets and droplet nuclei from infected hosts are the potential carriers of such viruses within indoor environments. Laboratory-generated bioaerosols are applied in understanding the transmission and infection of viruses, modeling the physiological aspects of bioaerosol generation in a controlled environment. However, little comparative characterization exists for nebulizers used in infectious disease aerobiology, including Collison nebulizer, vibrating mesh nebulizer, and hydraulic spray atomizer. This study characterized the physical features of aerosols generated by laboratory nebulizers and their performance in producing aerosols at a size relevant to airborne transmission used in infectious disease aerobiology. We also determined the impact of nebulization mechanisms of these nebulizers on the viability of human respiratory viruses, including IAV H1N1, IAV H3N2, and HRV-16.
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20
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Isaacs SR, Foskett DB, Maxwell AJ, Ward EJ, Faulkner CL, Luo JYX, Rawlinson WD, Craig ME, Kim KW. Viruses and Type 1 Diabetes: From Enteroviruses to the Virome. Microorganisms 2021; 9:microorganisms9071519. [PMID: 34361954 PMCID: PMC8306446 DOI: 10.3390/microorganisms9071519] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022] Open
Abstract
For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.
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Affiliation(s)
- Sonia R. Isaacs
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Dylan B. Foskett
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Anna J. Maxwell
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Emily J. Ward
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Faculty of Medicine and Health, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Clare L. Faulkner
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Jessica Y. X. Luo
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - William D. Rawlinson
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Faculty of Medicine and Health, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
- Faculty of Science, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Maria E. Craig
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Institute of Endocrinology and Diabetes, Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Ki Wook Kim
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Correspondence: ; Tel.: +61-2-9382-9096
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21
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Rhinovirus and Cell Death. Viruses 2021; 13:v13040629. [PMID: 33916958 PMCID: PMC8067602 DOI: 10.3390/v13040629] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/29/2021] [Accepted: 03/29/2021] [Indexed: 12/27/2022] Open
Abstract
Rhinoviruses (RVs) are the etiological agents of upper respiratory tract infections, particularly the common cold. Infections in the lower respiratory tract is shown to cause severe disease and exacerbations in asthma and COPD patients. Viruses being obligate parasites, hijack host cell pathways such as programmed cell death to suppress host antiviral responses and prolong viral replication and propagation. RVs are non-enveloped positive sense RNA viruses with a lifecycle fully contained within the cytoplasm. Despite decades of study, the details of how RVs exit the infected cell are still unclear. There are some diverse studies that suggest a possible role for programmed cell death. In this review, we aimed to consolidate current literature on the impact of RVs on cell death to inform future research on the topic. We searched peer reviewed English language literature in the past 21 years for studies on the interaction with and modulation of cell death pathways by RVs, placing it in the context of the broader knowledge of these interconnected pathways from other systems. Our review strongly suggests a role for necroptosis and/or autophagy in RV release, with the caveat that all the literature is based on RV-A and RV-B strains, with no studies to date examining the interaction of RV-C strains with cell death pathways.
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22
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Porto BN, Moraes TJ. The triad: respiratory microbiome - virus - immune response in the pathophysiology of pulmonary viral infections. Expert Rev Respir Med 2021; 15:635-648. [PMID: 33605840 DOI: 10.1080/17476348.2021.1893168] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The longstanding dogma that the healthy lung is sterile has been refuted by recent advances in culture-independent analyses of airway samples. The respiratory microbiome comprises all airway and lung tissue-associated microbes. These micro-organisms occur throughout the upper and lower respiratory tracts, with different populations and distinct burdens at specific sites and can be classified as pathogenic or commensal. AREAS COVERED The majority of studies investigating the respiratory microbiome have focused on bacteria; however, emerging evidence has revealed the composition of the lung virome, the global viral communities present in the lung tissue. In this review, we searched PubMed and used keywords such as airway microbiome. We restricted outputs to English language and did not limit by any dates. We summarize the up-to-date knowledge on how the microbiome interacts with the host immune system and influences the pathogenesis of pulmonary viral infections. EXPERT OPINION The relationship between colonizing microbes and the host is complex and various factors need to be considered in order to appreciate its pathophysiological consequences. Understanding these intricate mechanisms of interaction among the respiratory microbiome, viruses and the immune response may lead to the development of better therapies to treat or prevent respiratory viral infections.
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Affiliation(s)
- Bárbara N Porto
- Program in Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Theo J Moraes
- Program in Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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23
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Solution NMR Determination of the CDHR3 Rhinovirus-C Binding Domain, EC1. Viruses 2021; 13:v13020159. [PMID: 33499226 PMCID: PMC7911512 DOI: 10.3390/v13020159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/22/2022] Open
Abstract
Cadherin Related Family Member 3 (CDHR3) is the identified and required cellular receptor for all virus isolates in the rhinovirus-C species (RV-C). Cryo-EM determinations recently resolved the atomic structure of RV-C15a, and subsequently, a complex of this virus bound to CDHR3 extracellular domain 1 (EC1), the N-terminal portion of this receptor responsible for virus interactions. The EC1 binds to a hypervariable sequence footprint on the virus surface, near the 3-fold axis of icosahedral symmetry. The key contacts involve discontinuous residues from 3 viral proteins, VP1, VP2 and VP3. That single cryo-EM EC1 structure, however, could not resolve whether the virus-receptor interface was structurally adaptable to accommodate multiple virus sequences. We now report the solution NMR determination of CDHR3 EC1, showing that this protein, in fact, is mostly inflexible, particularly in the virus-binding face. The new, higher resolution dataset identifies 3 cis-Pro residues in important loop regions, where they can influence both rigidity and overall protein conformation. The data also provide clarification about the residues involved in essential calcium ion binding, and a potential CDHR3 surface groove feature that may be involved in native protein interactions with cellular partners.
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24
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Genome sequencing and phylogenetic reconstruction reveal a potential fourth rhinovirus species and its worldwide distribution. Arch Virol 2020; 166:225-229. [PMID: 33084935 DOI: 10.1007/s00705-020-04855-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/14/2020] [Indexed: 01/30/2023]
Abstract
Genome sequences of members of a potential fourth rhinovirus (RV) species, provisionally denoted as rhinovirus A clade D, from patients with acute respiratory infection were determined. Bayesian coalescent analysis estimated that clade D emerged around the 1940s and diverged further around 2006-2007 into two distinctive sublineages (RV-A8-like and RV-A45-like) that harbored unique "clade-defining" substitutions. Similarity plots and bootscan mapping revealed a recombination breakpoint located in the 5'-UTR region of members of the RV-A8-like sublineage. Phylogenetic reconstruction revealed the distribution of clade D viruses in the Asia Pacific region and in Europe, underlining its worldwide distribution.
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25
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Liu Y, Bochkov YA, Eickhoff JC, Hu T, Zumwalde NA, Tan JW, Lopez C, Fichtinger PS, Reddy TR, Overmyer KA, Gumperz JE, Coon J, Mathur SK, Gern JE, Smith JA. Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells. Am J Respir Cell Mol Biol 2020; 62:783-792. [PMID: 32078788 DOI: 10.1165/rcmb.2019-0237oc] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Polymorphism at the 17q21 gene locus and wheezing responses to rhinovirus (RV) early in childhood conspire to increase the risk of developing asthma. However, the mechanisms mediating this gene-environment interaction remain unclear. In this study, we investigated the impact of one of the 17q21-encoded genes, ORMDL3 (orosomucoid-like 3), on RV replication in human epithelial cells. ORMDL3 knockdown inhibited RV-A16 replication in HeLa, BEAS-2B, A549, and NCI-H358 epithelial cell lines and primary nasal and bronchial epithelial cells. Inhibition varied by RV species, as both minor and major group RV-A subtypes RV-B52 and RV-C2 were inhibited but not RV-C15 or RV-C41. ORMDL3 siRNA did not affect expression of the major group RV-A receptor ICAM-1 or initial internalization of RV-A16. The two major outcomes of ORMDL3 activity, SPT (serine palmitoyl-CoA transferase) inhibition and endoplasmic reticulum (ER) stress induction, were further examined: silencing ORMDL3 decreased RV-induced ER stress and IFN-β mRNA expression. However, pharmacologic induction of ER stress and concomitant increased IFN-β inhibited RV-A16 replication. Conversely, blockade of ER stress with tauroursodeoxycholic acid augmented replication, pointing to an alternative mechanism for the effect of ORMDL3 knockdown on RV replication. In comparison, the SPT inhibitor myriocin increased RV-A16 but not RV-C15 replication and negated the inhibitory effect of ORMDL3 knockdown. Furthermore, lipidomics analysis revealed opposing regulation of specific sphingolipid species (downstream of SPT) by myriocin and ORMDL3 siRNA, correlating with the effect of these treatments on RV replication. Together, these data revealed a requirement for ORMDL3 in supporting RV replication in epithelial cells via SPT inhibition.
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Affiliation(s)
| | | | | | | | | | | | | | - Paul S Fichtinger
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | | | - Katherine A Overmyer
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin; and.,Morgridge Institute for Research, Madison, Wisconsin
| | | | - Joshua Coon
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin; and.,Morgridge Institute for Research, Madison, Wisconsin
| | - Sameer K Mathur
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | | | - Judith A Smith
- Department of Pediatrics.,Department of Medical Microbiology and Immunology, and
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26
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Stimulator of interferon genes (STING) is an essential proviral host factor for human rhinovirus species A and C. Proc Natl Acad Sci U S A 2020; 117:27598-27607. [PMID: 33060297 PMCID: PMC7959528 DOI: 10.1073/pnas.2014940117] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We show here that efficient replication of RV-A and RV-C viruses, common respiratory pathogens with positive-strand RNA genomes, requires STING, a host protein with canonical function in innate immune responses to DNA viruses. STING is enriched in PI4P-containing membranes of RV-A replication organelles and is essential for a step in replication of the viral RNA genome. Its host factor activity is highly species-specific, and adaptation of the RV-16 virus to murine STING promotes RV-16 replication in cells of murine origin. These findings add substantially to the current understanding of essential host factors that restrict the host species range of RVs and limit the development of small animal models. Human rhinoviruses (RVs) are positive-strand RNA viruses that cause respiratory tract disease in children and adults. Here we show that the innate immune signaling protein STING is required for efficient replication of members of two distinct RV species, RV-A and RV-C. The host factor activity of STING was identified in a genome-wide RNA interference (RNAi) screen and confirmed in primary human small airway epithelial cells. Replication of RV-A serotypes was strictly dependent on STING, whereas RV-B serotypes were notably less dependent. Subgenomic RV-A and RV-C RNA replicons failed to amplify in the absence of STING, revealing it to be required for a step in RNA replication. STING was expressed on phosphatidylinositol 4-phosphate (PI4P)-enriched membranes and was enriched in RV-A16 compared with RV-B14 replication organelles isolated in isopycnic gradients. The host factor activity of STING was species-specific, as murine STING (mSTING) did not rescue RV-A16 replication in STING-deficient cells. This species specificity mapped primarily to the cytoplasmic, ligand-binding domain of STING. Mouse-adaptive mutations in the RV-A16 2C protein allowed for robust replication in cells expressing mSTING, suggesting a role for 2C in recruiting STING to RV-A replication organelles. Palmitoylation of STING was not required for RV-A16 replication, nor was the C-terminal tail of STING that mediates IRF3 signaling. Despite co-opting STING to promote its replication, interferon signaling in response to STING agonists remained intact in RV-A16 infected cells. These data demonstrate a surprising requirement for a key host mediator of innate immunity to DNA viruses in the life cycle of a small pathogenic RNA virus.
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27
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Affiliation(s)
- Kazuhiro Ito
- National Heart and Lung InstituteImperial College LondonLondon, United Kingdom
| | - Youming Zhang
- National Heart and Lung InstituteImperial College LondonLondon, United Kingdom
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28
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Ganjian H, Rajput C, Elzoheiry M, Sajjan U. Rhinovirus and Innate Immune Function of Airway Epithelium. Front Cell Infect Microbiol 2020; 10:277. [PMID: 32637363 PMCID: PMC7316886 DOI: 10.3389/fcimb.2020.00277] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022] Open
Abstract
Airway epithelial cells, which lines the respiratory mucosa is in direct contact with the environment. Airway epithelial cells are the primary target for rhinovirus and other inhaled pathogens. In response to rhinovirus infection, airway epithelial cells mount both pro-inflammatory responses and antiviral innate immune responses to clear the virus efficiently. Some of the antiviral responses include the expression of IFNs, endoplasmic reticulum stress induced unfolded protein response and autophagy. Airway epithelial cells also recruits other innate immune cells to establish antiviral state and resolve the inflammation in the lungs. In patients with chronic lung disease, these responses may be either defective or induced in excess leading to deficient clearing of virus and sustained inflammation. In this review, we will discuss the mechanisms underlying antiviral innate immunity and the dysregulation of some of these mechanisms in patients with chronic lung diseases.
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Affiliation(s)
- Haleh Ganjian
- Department of Thoracic Medicine and Surgery, Lewis Katz Medical School, Temple University, Philadelphia, PA, United States
| | - Charu Rajput
- Department of Thoracic Medicine and Surgery, Lewis Katz Medical School, Temple University, Philadelphia, PA, United States
| | - Manal Elzoheiry
- Department of Thoracic Medicine and Surgery, Lewis Katz Medical School, Temple University, Philadelphia, PA, United States
| | - Umadevi Sajjan
- Department of Thoracic Medicine and Surgery, Lewis Katz Medical School, Temple University, Philadelphia, PA, United States
- Department of Physiology, Lewis Katz Medical School, Temple University, Philadelphia, PA, United States
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29
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Behzadi MA, Choi A, Duehr J, Feyznezhad R, Upadhyay C, Schotsaert M, Palese P, Nachbagauer R. A cross-reactive mouse monoclonal antibody against rhinovirus mediates phagocytosis in vitro. Sci Rep 2020; 10:9750. [PMID: 32546721 PMCID: PMC7297972 DOI: 10.1038/s41598-020-66600-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 05/22/2020] [Indexed: 12/20/2022] Open
Abstract
Rhinoviruses (RVs) are the main cause of the common cold worldwide. To date, more than 160 types of the virus have been recognized, categorized into three major species - A, B, and C. There are currently no approved vaccines available to prevent infection with RVs. To elicit antibodies against conserved regions located on capsid proteins of RV A viruses, mice were sequentially vaccinated with DNA plasmids encoding capsid proteins of different RV A types. After a final boost with whole virus, antibody-expressing hybridomas were generated. After isotyping, 11 monoclonal antibodies (mAbs) expressing an IgG subtype Fc-domain were selected for further expansion and purification. Three mAbs showed cross-reactivity against multiple strains of RV A viruses by ELISA, including strains A1A, A1B, A15, A16 and A49. Other mAbs had strain-specific binding patterns, with the majority of mAbs showing reactivity to RV-A15, the strain used for the final vaccination. We found that the RV-A15-specific mAbs, but not the cross-reactive mAbs, had neutralizing activity against RV-A15. An antibody dependent cellular phagocytosis (ADCP) assay revealed substantial ADCP activity for one of the cross-reactive mAbs. Epitope mapping of the neutralizing mAbs via escape mutant virus generation revealed a shared binding epitope on VP1 of RV-A15 for several neutralizing mAbs. The epitope of the ADCP-active, non-neutralizing mAb was determined by microarray analysis of peptides generated from the VP1 capsid protein. VP1-specific, cross-reactive antibodies, especially those with ADCP activity, could contribute to protection against RV infections.
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Affiliation(s)
- Mohammad Amin Behzadi
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Angela Choi
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - James Duehr
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Roya Feyznezhad
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Chitra Upadhyay
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Peter Palese
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raffael Nachbagauer
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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30
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Meng B, Lan K, Xie J, Lerner RA, Wilson IA, Yang B. Inhibitory antibodies identify unique sites of therapeutic vulnerability in rhinovirus and other enteroviruses. Proc Natl Acad Sci U S A 2020; 117:13499-13508. [PMID: 32467165 PMCID: PMC7306783 DOI: 10.1073/pnas.1918844117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The existence of multiple serotypes renders vaccine development challenging for most viruses in the Enterovirus genus. An alternative and potentially more viable strategy for control of these viruses is to develop broad-spectrum antivirals by targeting highly conserved proteins that are indispensable for the virus life cycle, such as the 3C protease. Previously, two single-chain antibody fragments, YDF and GGVV, were reported to effectively inhibit human rhinovirus 14 proliferation. Here, we found that both single-chain antibody fragments target sites on the 3C protease that are distinct from its known drug site (peptidase active site) and possess different mechanisms of inhibition. YDF does not block the active site but instead noncompetitively inhibits 3C peptidase activity through an allosteric effect that is rarely seen for antibody protease inhibitors. Meanwhile, GGVV antagonizes the less-explored regulatory function of 3C in genome replication. The interaction between 3C and the viral genome 5' noncoding region has been reported to be important for enterovirus genome replication. Here, the interface between human rhinovirus 14 3C and its 5' noncoding region was probed by hydrogen-deuterium exchange coupled mass spectrometry and found to partially overlap with the interface between GGVV and 3C. Consistently, prebinding of GGVV completely abolishes interaction between human rhinovirus 14 3C and its 5' noncoding region. The epitopes of YDF and GGVV, therefore, represent two additional sites of therapeutic vulnerability in rhinovirus. Importantly, the GGVV epitope appears to be conserved across many enteroviruses, suggesting that it is a promising target for pan-enterovirus inhibitor screening and design.
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Affiliation(s)
- Bing Meng
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, People's Republic of China
| | - Keke Lan
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, People's Republic of China
- School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, People's Republic of China
| | - Jia Xie
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037
| | - Richard A Lerner
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037
| | - Ian A Wilson
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, People's Republic of China;
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037
- Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037
| | - Bei Yang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, People's Republic of China;
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31
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Megremis S, Niespodziana K, Cabauatan C, Xepapadaki P, Kowalski ML, Jartti T, Bachert C, Finotto S, West P, Stamataki S, Lewandowska-Polak A, Lukkarinen H, Zhang N, Zimmermann T, Stolz F, Neubauer A, Akdis M, Andreakos E, Valenta R, Papadopoulos NG. Rhinovirus Species-Specific Antibodies Differentially Reflect Clinical Outcomes in Health and Asthma. Am J Respir Crit Care Med 2020; 198:1490-1499. [PMID: 30134114 DOI: 10.1164/rccm.201803-0575oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Rationale: Rhinoviruses (RVs) are major triggers of common cold and acute asthma exacerbations. RV species A, B, and C may have distinct clinical impact; however, little is known regarding RV species-specific antibody responses in health and asthma.Objectives: To describe and compare total and RV species-specific antibody levels in healthy children and children with asthma, away from an acute event.Methods: Serum samples from 163 preschool children with mild to moderate asthma and 72 healthy control subjects from the multinational Predicta cohort were analyzed using the recently developed PreDicta RV antibody chip.Measurements and Main Results: RV antibody levels varied, with RV-C and RV-A being higher than RV-B in both groups. Compared with control subjects, asthma was characterized by significantly higher levels of antibodies to RV-A and RV-C, but not RV-B. RV antibody levels positively correlated with the number of common colds over the previous year in healthy children, and wheeze episodes in children with asthma. Antibody levels also positively correlated with asthma severity but not with current asthma control.Conclusions: The variable humoral response to RV species in both groups suggests a differential infectivity pattern between RV species. In healthy preschoolers, RV antibodies accumulate with colds. In asthma, RV-A and RV-C antibodies are much higher and further increase with disease severity and wheeze episodes. Higher antibody levels in asthma may be caused by a compromised innate immune response, leading to increased exposure of the adaptive immune response to the virus. Importantly, there is no apparent protection with increasing levels of antibodies.
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Affiliation(s)
| | - Katarzyna Niespodziana
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Clarissa Cabauatan
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
| | - Paraskevi Xepapadaki
- Allergy Department, 2nd Pediatric Clinic, National and Kapodistrian University of Athens, Athens, Greece
| | - Marek L Kowalski
- Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland
| | - Tuomas Jartti
- Department of Paediatrics, Turku University Hospital, University of Turku, Turku, Finland
| | - Claus Bachert
- Upper Airways Research Laboratory, Ghent University, Ghent, Belgium
| | - Susetta Finotto
- Department of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Peter West
- Division of Infection, Immunity and Respiratory Medicine and
| | - Sofia Stamataki
- Athens General Children's Hospital "Pan & Aglaia Kyriakou," Athens, Greece
| | - Anna Lewandowska-Polak
- Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Lodz, Poland
| | - Heikki Lukkarinen
- Department of Paediatrics, Turku University Hospital, University of Turku, Turku, Finland
| | - Nan Zhang
- Upper Airways Research Laboratory, Ghent University, Ghent, Belgium
| | - Theodor Zimmermann
- Department of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | | | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research, University of Zurich, Zurich, Switzerland
| | | | - Rudolf Valenta
- Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria.,NRC Institute of Immunology FMBA of Russia, Moscow, Russia
| | - Nikolaos G Papadopoulos
- Division of Infection, Immunity and Respiratory Medicine and.,Division of Immunopathology, Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
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Parikh V, Scala J, Patel R, Corbi C, Lo D, Bochkov YA, Kennedy JL, Kurten RC, Liggett SB, Gern JE, Koziol-White CJ. Rhinovirus C15 Induces Airway Hyperresponsiveness via Calcium Mobilization in Airway Smooth Muscle. Am J Respir Cell Mol Biol 2020; 62:310-318. [PMID: 31533004 PMCID: PMC7055698 DOI: 10.1165/rcmb.2019-0004oc] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 09/18/2019] [Indexed: 12/18/2022] Open
Abstract
Rhinovirus (RV) exposure evokes exacerbations of asthma that markedly impact morbidity and mortality worldwide. The mechanisms by which RV induces airway hyperresponsiveness (AHR) or by which specific RV serotypes differentially evoke AHR remain unknown. We posit that RV infection evokes AHR and inflammatory mediator release, which correlate with degrees of RV infection. Furthermore, we posit that rhinovirus C-induced AHR requires paracrine or autocrine mediator release from epithelium that modulates agonist-induced calcium mobilization in human airway smooth muscle. In these studies, we used an ex vivo model to measure bronchoconstriction and mediator release from infected airways in human precision cut lung slices to understand how RV exposure alters airway constriction. We found that rhinovirus C15 (RV-C15) infection augmented carbachol-induced airway narrowing and significantly increased release of IP-10 (IFN-γ-induced protein 10) and MIP-1β (macrophage inflammatory protein-1β) but not IL-6. RV-C15 infection of human airway epithelial cells augmented agonist-induced intracellular calcium flux and phosphorylation of myosin light chain in co-cultured human airway smooth muscle to carbachol, but not after histamine stimulation. Our data suggest that RV-C15-induced structural cell inflammatory responses are associated with viral load but that inflammatory responses and alterations in agonist-mediated constriction of human small airways are uncoupled from viral load of the tissue.
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Affiliation(s)
- Vishal Parikh
- Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Jacqueline Scala
- Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Riva Patel
- Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Corinne Corbi
- Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Dennis Lo
- Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Yury A. Bochkov
- Department of Pediatrics, University of Wisconsin–Madison, Madison, Wisconsin
| | | | - Richard C. Kurten
- Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and
| | - Stephen B. Liggett
- Department of Molecular Pharmacology and Physiology and
- Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - James E. Gern
- Department of Pediatrics, University of Wisconsin–Madison, Madison, Wisconsin
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Denlinger LC, Heymann P, Lutter R, Gern JE. Exacerbation-Prone Asthma. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2019; 8:474-482. [PMID: 31765853 DOI: 10.1016/j.jaip.2019.11.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 10/28/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023]
Abstract
Patients who are prone to exacerbations of asthma experience significant costs in terms of missed work and school, acute care visits, and hospitalizations. Exacerbations are largely driven by environmental exposures including pollutants, stress, and viral and bacterial pathogens. These exposures are most likely to induce acute severe "asthma attacks" in high-risk patients. These personal risk factors for exacerbations can vary with the phenotype of asthma and age of the patient. In children, allergic sensitization is a strong risk factor, especially for those children who develop sensitization early in life. Airway inflammation is an important risk factor, and biomarkers are under evaluation for utility in detecting eosinophilic and type 2 inflammation and neutrophilic inflammation as indicators of risk for recurrent exacerbations. Insights into inflammatory mechanisms have led to new approaches to prevent exacerbations using mAb-based biologics that target specific type 2 pathways. Challenges remain in developing an evidence base to support precision interventions with these effective yet expensive therapies, and in determining whether these treatments will be safe and effective in young children. Unfortunately, there has been less progress in developing treatments for acute exacerbations. Hopefully, greater understanding of mechanisms relating airway viruses, bacteria, mucin production, and neutrophilic inflammatory responses will lead to additional treatment options for patients experiencing acute exacerbations.
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Affiliation(s)
- Loren C Denlinger
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wis.
| | - Peter Heymann
- Department of Pediatrics, University of Virginia, Charlottesville, Va
| | - Rene Lutter
- Departments of Respiratory Medicine and Experimental Immunology, Amsterdam University Centers, University of Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, The Netherlands
| | - James E Gern
- Department of Pediatrics, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wis
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34
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Joshi PU, Turpeinen DG, Weiss M, Escalante-Corbin G, Schroeder M, Heldt CL. Tie line framework to optimize non-enveloped virus recovery in aqueous two-phase systems. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1126-1127:121744. [DOI: 10.1016/j.jchromb.2019.121744] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/18/2019] [Accepted: 08/02/2019] [Indexed: 01/01/2023]
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35
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Morobe JM, Nyiro JU, Brand S, Kamau E, Gicheru E, Eyase F, Otieno GP, Munywoki PK, Agoti CN, Nokes DJ. Human rhinovirus spatial-temporal epidemiology in rural coastal Kenya, 2015-2016, observed through outpatient surveillance. Wellcome Open Res 2019; 3:128. [PMID: 30483602 PMCID: PMC6234744 DOI: 10.12688/wellcomeopenres.14836.2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2019] [Indexed: 12/22/2022] Open
Abstract
Background: Human rhinovirus (HRV) is the predominant cause of upper respiratory tract infections, resulting in a significant public health burden. The virus circulates as many different types (168), each generating strong homologous, but weak heterotypic, immunity. The influence of these features on transmission patterns of HRV in the community is understudied. Methods: Nasopharyngeal swabs were collected from patients with symptoms of acute respiratory infection (ARI) at nine out-patient facilities across a Health and Demographic Surveillance System between December 2015 and November 2016. HRV was diagnosed by real-time RT-PCR, and the VP4/VP2 genomic region of the positive samples sequenced. Phylogenetic analysis was used to determine the HRV types. Classification models and G-test statistic were used to investigate HRV type spatial distribution. Demographic characteristics and clinical features of ARI were also compared. Results: Of 5,744 NPS samples collected, HRV was detected in 1057 (18.4%), of which 817 (77.3%) were successfully sequenced. HRV species A, B and C were identified in 360 (44.1%), 67 (8.2%) and 390 (47.7%) samples, respectively. In total, 87 types were determined: 39, 10 and 38 occurred within species A, B and C, respectively. HRV types presented heterogeneous temporal patterns of persistence. Spatially, identical types occurred over a wide distance at similar times, but there was statistically significant evidence for clustering of types between health facilities in close proximity or linked by major road networks. Conclusion: This study records a high prevalence of HRV in out-patient presentations exhibiting high type diversity. Patterns of occurrence suggest frequent and independent community invasion of different types. Temporal differences of persistence between types may reflect variation in type-specific population immunity. Spatial patterns suggest either rapid spread or multiple invasions of the same type, but evidence of similar types amongst close health facilities, or along road systems, indicate type partitioning structured by local spread.
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Affiliation(s)
- John Mwita Morobe
- Institute of Biotechnology Research, Jomo Kenyatta University of Agriculture and Technology, Juja, +254, Kenya.,Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya
| | - Joyce U Nyiro
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya
| | - Samuel Brand
- Zeeman Institute of Systems Biology and Infectious Disease Research (SBIDER), University of Warwick, Coventry, UK.,School of Life Sciences, University of Warwick, Coventry, UK
| | - Everlyn Kamau
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya
| | - Elijah Gicheru
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya
| | - Fredrick Eyase
- Institute of Biotechnology Research, Jomo Kenyatta University of Agriculture and Technology, Juja, +254, Kenya
| | - Grieven P Otieno
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya
| | - Patrick K Munywoki
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya.,Public Health, Pwani University, Kilifi, +254, Kenya
| | - C N Agoti
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya.,Public Health, Pwani University, Kilifi, +254, Kenya
| | - D J Nokes
- Epidemiology and Demography Department, KEMRI-Wellcome Trust Research Programme, Kilifi, +254, Kenya.,Zeeman Institute of Systems Biology and Infectious Disease Research (SBIDER), University of Warwick, Coventry, UK.,School of Life Sciences, University of Warwick, Coventry, UK.,Public Health, Pwani University, Kilifi, +254, Kenya
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36
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Scully EJ, Basnet S, Wrangham RW, Muller MN, Otali E, Hyeroba D, Grindle KA, Pappas TE, Thompson ME, Machanda Z, Watters KE, Palmenberg AC, Gern JE, Goldberg TL. Lethal Respiratory Disease Associated with Human Rhinovirus C in Wild Chimpanzees, Uganda, 2013. Emerg Infect Dis 2019; 24:267-274. [PMID: 29350142 PMCID: PMC5782908 DOI: 10.3201/eid2402.170778] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We describe a lethal respiratory outbreak among wild chimpanzees in Uganda in 2013 for which molecular and epidemiologic analyses implicate human rhinovirus C as the cause. Postmortem samples from an infant chimpanzee yielded near-complete genome sequences throughout the respiratory tract; other pathogens were absent. Epidemiologic modeling estimated the basic reproductive number (R0) for the epidemic as 1.83, consistent with the common cold in humans. Genotyping of 41 chimpanzees and examination of 24 published chimpanzee genomes from subspecies across Africa showed universal homozygosity for the cadherin-related family member 3 CDHR3-Y529 allele, which increases risk for rhinovirus C infection and asthma in human children. These results indicate that chimpanzees exhibit a species-wide genetic susceptibility to rhinovirus C and that this virus, heretofore considered a uniquely human pathogen, can cross primate species barriers and threatens wild apes. We advocate engineering interventions and prevention strategies for rhinovirus infections for both humans and wild apes.
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37
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Development of a respiratory disease model for enterovirus D68 in 4-week-old mice for evaluation of antiviral therapies. Antiviral Res 2018; 162:61-70. [PMID: 30521834 DOI: 10.1016/j.antiviral.2018.11.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/07/2018] [Accepted: 11/22/2018] [Indexed: 02/07/2023]
Abstract
Enterovirus D68 (EV-D68) is a non-polio enterovirus that affects the respiratory system and can cause serious complications, especially in children and older people with weakened immune systems. As an emerging virus, there are no current antiviral therapies or vaccines available. Our goal was to develop a mouse model of human EV-D68 infection that mimicked the disease observed in humans and could be used for evaluation of experimental therapeutics. This is the first report of a respiratory disease model for EV-D68 infection in mice. We adapted the virus by 30 serial passages in AG129 mice, which are deficient in IFN- α/β and -γ receptors. Despite a lack of weight loss or mortality in mice, lung function measured by plethysmography, showed an increase in enhanced pause (Penh) on days 6 and 7 post-infection. In addition, as virus adapted to mice, virus titer in the lungs increased 50-fold, and the pro-inflammatory cytokines MCP-1 and RANTES increased 15-fold and 2-fold in the lung, respectively. In addition, a time course of mouse-adapted EV-D68 infection was determined in lung, blood, liver, kidney, spleen, leg muscle, spinal cord and brain. Virus in the lung replicated rapidly after intranasal inoculation of adapted virus, 106 CCID50/mL by 4 h and 108.3 CCID50/mL by 24 h. Virus then spread to the blood and other tissues, including spinal cord and brain. This mouse model for EV-D68 infection includes enhanced pause (Penh) as an indicator of morbidity, and viremia, virus titers and proinflammatory cytokines in the lung, and lung histopathology as indicators of disease. Our mouse-adapted virus has a similar antiviral profile to the original isolate as well as another respiratory picornavirus, rhinovirus-14. This model will be valuable in evaluating experimental therapies in the future.
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38
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Ling KM, Garratt LW, Lassmann T, Stick SM, Kicic A. Elucidating the Interaction of CF Airway Epithelial Cells and Rhinovirus: Using the Host-Pathogen Relationship to Identify Future Therapeutic Strategies. Front Pharmacol 2018; 9:1270. [PMID: 30464745 PMCID: PMC6234657 DOI: 10.3389/fphar.2018.01270] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/17/2018] [Indexed: 01/07/2023] Open
Abstract
Chronic lung disease remains the primary cause of mortality in cystic fibrosis (CF). Growing evidence suggests respiratory viral infections are often more severe in CF compared to healthy peers and contributes to pulmonary exacerbations (PEx) and deterioration of lung function. Rhinovirus is the most prevalent respiratory virus detected, particularly during exacerbations in children with CF <5 years old. However, even though rhinoviral infections are likely to be one of the factors initiating the onset of CF lung disease, there is no effective targeted treatment. A better understanding of the innate immune responses by CF airway epithelial cells, the primary site of infection for viruses, is needed to identify why viral infections are more severe in CF. The aim of this review is to present the clinical impact of virus infection in both young children and adults with CF, focusing on rhinovirus infection. Previous in vitro and in vivo investigations looking at the mechanisms behind virus infection will also be summarized. The review will finish on the potential of transcriptomics to elucidate the host-pathogen responses by CF airway cells to viral infection and identify novel therapeutic targets.
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Affiliation(s)
- Kak-Ming Ling
- Paediatrics, Medical School, Faculty of Healthy and Medical Science, University of Western Australia, Nedlands, WA, Australia.,Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Luke W Garratt
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Timo Lassmann
- Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia
| | - Stephen M Stick
- Paediatrics, Medical School, Faculty of Healthy and Medical Science, University of Western Australia, Nedlands, WA, Australia.,Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, WA, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, Australia
| | - Anthony Kicic
- Paediatrics, Medical School, Faculty of Healthy and Medical Science, University of Western Australia, Nedlands, WA, Australia.,Telethon Kids Institute, University of Western Australia, Nedlands, WA, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, WA, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA, Australia.,Occupation and Environment, School of Public Health, Curtin University, Bentley, WA, Australia
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39
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Morobe JM, Nyiro JU, Brand S, Kamau E, Gicheru E, Eyase F, Otieno GP, Munywoki PK, Agoti C, Nokes D. Human rhinovirus spatial-temporal epidemiology in rural coastal Kenya, 2015-2016, observed through outpatient surveillance. Wellcome Open Res 2018; 3:128. [DOI: 10.12688/wellcomeopenres.14836.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/26/2018] [Indexed: 01/02/2023] Open
Abstract
Background: Human rhinovirus (HRV) is the predominant cause of upper respiratory tract infections, resulting in a significant public health burden. The virus circulates as many different types (~160), each generating strong homologous, but weak heterotypic, immunity. The influence of these features on transmission patterns of HRV in the community is understudied. Methods: Nasopharyngeal swabs were collected from patients with symptoms of acute respiratory infection (ARI) at nine out-patient facilities across a Health and Demographic Surveillance System between December 2015 and November 2016. HRV was diagnosed by real-time RT-PCR, and the VP4/VP2 genomic region of the positive samples sequenced. Phylogenetic analysis was used to determine the HRV types. Classification models and G-test statistic were used to investigate HRV type spatial distribution. Demographic characteristics and clinical features of ARI were also compared. Results: Of 5,744 NPS samples collected, HRV was detected in 1057 (18.4%), of which 817 (77.3%) were successfully sequenced. HRV species A, B and C were identified in 360 (44.1%), 67 (8.2%) and 390 (47.7%) samples, respectively. In total, 87 types were determined: 39, 10 and 38 occurred within species A, B and C, respectively. HRV types presented heterogeneous temporal patterns of persistence. Spatially, identical types occurred over a wide distance at similar times, but there was statistically significant evidence for clustering of types between health facilities in close proximity or linked by major road networks. Conclusion: This study records a high prevalence of HRV in out-patient presentations exhibiting high type diversity. Patterns of occurrence suggest frequent and independent community invasion of different types. Temporal differences of persistence between types may reflect variation in type-specific population immunity. Spatial patterns suggest either rapid spread or multiple invasions of the same type, but evidence of similar types amongst close health facilities, or along road systems, indicate type partitioning structured by local spread.
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40
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Abstract
Rhinoviruses are the most common cause of upper respiratory tract infections. However, they can induce exacerbations of chronic obstructive pulmonary disease and asthma, bronchiolitis in infants, and significant lower respiratory tract infections in children, the immunosuppressed, and the elderly. The large number of rhinovirus strains (currently about 160) and their antigenic diversity are significant obstacles in vaccine development. The phenotype of immune responses induced during rhinovirus infection can affect disease severity. Recognition of rhinovirus and a balance of innate responses are important factors in rhinovirus-induced morbidity. Immune responses to rhinovirus infections in healthy individuals are typically of the T helper type 1 (Th1) phenotype. However, rhinovirus-driven asthma exacerbations are additionally characterised by an amplified Th2 immune response and airway neutrophilia. This commentary focuses on recent advances in understanding immunity toward rhinovirus infection and how innate and adaptive immune responses drive rhinovirus-induced asthma exacerbations.
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Affiliation(s)
- Spyridon Makris
- National Heart and Lung Institute, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK
| | - Sebastian Johnston
- National Heart and Lung Institute, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, UK
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41
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Martin ET, Kuypers J, Chu HY, Foote S, Hashikawa A, Fairchok MP, Englund JA. Heterotypic Infection and Spread of Rhinovirus A, B, and C among Childcare Attendees. J Infect Dis 2018; 218:848-855. [PMID: 29684211 PMCID: PMC7107396 DOI: 10.1093/infdis/jiy232] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 04/17/2018] [Indexed: 11/25/2022] Open
Abstract
Background Despite the frequency of human rhinovirus (HRV), data describing the molecular epidemiology of HRV in the community are limited. Childcare centers are optimal settings to characterize heterotypic HRV cocirculation. Methods HRV specimens were prospectively obtained from a cohort of childcare attendees at enrollment and weekly during respiratory illness. The 5' noncoding region sequences were used to determine HRV species (A, B, C) and genotypes. Results Among 225 children followed, sequence data were available for 92 HRV infections: HRV-A (n = 80; 59%) was most common, followed by HRV-C (n = 52, 39%), and HRV-B (n = 3, 2%). Forty-one genotypes were identified and cocirculation was common. Frequent spread between classrooms occurred with 2 HRV-A genotypes. Repeated detections within single illnesses were a combination of persistent (n = 7) and distinct (n = 7) genotypes. Prevalence of HRV among asymptomatic children was 41%. HRV-C was clinically similar to HRV-A and HRV-B. Conclusions HRV epidemiology in childcare consists of heterotypic cocirculation of genotypes with periodic spread within and among classrooms. Based on our finding of multiple genotypes evident during the course of single illnesses, the use of sequence-based HRV type determination is critical in longitudinal studies of HRV epidemiology and transmission.
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Affiliation(s)
- Emily T Martin
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor
| | - Jane Kuypers
- Department of Laboratory Medicine, University of Washington, Seattle
| | - Helen Y Chu
- Department of Medicine, University of Washington, Seattle
| | - Sydney Foote
- Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor
| | - Andrew Hashikawa
- Department of Emergency Medicine, Michigan Medicine at University of Michigan, Ann Arbor
| | - Mary P Fairchok
- Infectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland
- Madigan Army Medical Center, Tacoma, Washington
| | - Janet A Englund
- Department of Pediatrics, University of Washington, Seattle
- Seattle Children’s Research Institute, Washington
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42
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Wark PAB, Ramsahai JM, Pathinayake P, Malik B, Bartlett NW. Respiratory Viruses and Asthma. Semin Respir Crit Care Med 2018; 39:45-55. [PMID: 29427985 PMCID: PMC7117086 DOI: 10.1055/s-0037-1617412] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recognized, though remains incompletely understood. In this article, we will address key issues around this relationship. These will include the crucial role virus infection plays in early life, as a potential risk factor for the development of asthma and lung disease. We will assess the impact that virus infection has on those with established asthma as a trigger for acute disease and how this may influence asthma throughout life. Finally, we will explore the complex interaction that occurs between the airway and the immune responses that make those with asthma so susceptible to the effects of virus infection.
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Affiliation(s)
- Peter A B Wark
- Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, New South Wales, Australia.,Department of Respiratory and Sleep Medicine, John Hunter Hospital, New South Wales, Australia
| | - James Michael Ramsahai
- Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, New South Wales, Australia.,Department of Respiratory and Sleep Medicine, John Hunter Hospital, New South Wales, Australia
| | - Prabuddha Pathinayake
- Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, New South Wales, Australia.,Department of Respiratory and Sleep Medicine, John Hunter Hospital, New South Wales, Australia
| | - Bilal Malik
- Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, New South Wales, Australia
| | - Nathan W Bartlett
- Centre for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, New South Wales, Australia.,School of Biomedical Sciences, The University of Newcastle, New South Wales, Australia
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43
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Abstract
Rhinoviruses (RV) are ubiquitous respiratory tract pathogens. They affect both the upper and lower respiratory tract and cause colds but have also been associated with wheezing, asthma exacerbations and pneumonia. New blood transcription profiling techniques of the host immune response are becoming available to characterise the pathogenesis of RV in humans. This review will outline the clinical impact of RVs in children.
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Affiliation(s)
- Simon B Drysdale
- Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Level 2, Children's Hospital, Oxford OX3 9DU, UK.
| | - Asuncion Mejias
- Division of Pediatric Infectious Diseases and Centre for Vaccines and Immunity, Nationwide Children's Hospital, USA and The Ohio State University, USA.
| | - Octavio Ramilo
- Division of Pediatric Infectious Diseases and Centre for Vaccines and Immunity, Nationwide Children's Hospital, USA and The Ohio State University, USA.
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44
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Morrey JD, Wang H, Hurst BL, Zukor K, Siddharthan V, Van Wettere AJ, Sinex DG, Tarbet EB. Causation of Acute Flaccid Paralysis by Myelitis and Myositis in Enterovirus-D68 Infected Mice Deficient in Interferon αβ/γ Receptor Deficient Mice. Viruses 2018; 10:E33. [PMID: 29329211 PMCID: PMC5795446 DOI: 10.3390/v10010033] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 01/04/2018] [Accepted: 01/08/2018] [Indexed: 11/16/2022] Open
Abstract
Enterovirus D68 (EV-D68) caused a large outbreak in the summer and fall of 2014 in the United States. It causes serious respiratory disease, but causation of associated paralysis is controversial, because the virus is not routinely identified in cerebrospinal fluid. To establish clinical correlates with human disease, we evaluated EV-D68 infection in non-lethal paralysis mouse models. Ten-day-old mice lacking interferon responses were injected intraperitoneally with the virus. Paralysis developed in hindlimbs. After six weeks of paralysis, the motor neurons were depleted due to viral infection. Hindlimb muscles were also infected and degenerating. Even at the earliest stage of paralysis, muscles were still infected and were degenerating, in addition to presence of virus in the spinal cord. To model natural respiratory infection, five-day-old mice were infected intranasally with EV-D68. Two of the four infected mice developed forelimb paralysis. The affected limbs had muscle disease, but no spinal cord infection was detected. The unique contributions of this study are that EV-D68 causes paralysis in mice, and that causation by muscle disease, with or without spinal cord disease, may help to resolve the controversy that the virus can cause paralysis, even if it cannot be identified in cerebrospinal fluid.
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Affiliation(s)
- John D Morrey
- Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322, USA.
| | - Hong Wang
- Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322, USA.
| | - Brett L Hurst
- Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322, USA.
| | - Katherine Zukor
- Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322, USA.
| | - Venkatraman Siddharthan
- Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322, USA.
| | - Arnaud J Van Wettere
- Utah Veterinary Diagnostics Laboratory, Department of Animal, Dairy, and Veterinary Sciences, 950 East 1400 North, Utah State University, Logan, UT 84341, USA.
| | - Donal G Sinex
- Department of Communication Disorders and Deaf Education, 2800 Old Main Hill, Utah State University, Logan, UT 84322, USA.
| | - E Bart Tarbet
- Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322, USA.
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A chip-based rapid genotyping assay to discriminate between rhinovirus species A, B and C. J Clin Virol 2017; 99-100:10-14. [PMID: 29268148 DOI: 10.1016/j.jcv.2017.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 12/01/2017] [Accepted: 12/06/2017] [Indexed: 11/20/2022]
Abstract
BACKGROUND Human rhinoviruses (RVs) are increasingly associated with severe disease of the respiratory tract. Multiple studies highlighted the clinical significance of different RV species; RV-C is linked to asthma exacerbations and increased disease severity in children, whereas RV-B seems to correlate with milder disease. OBJECTIVES Current typing strategies for differentiation of RV species are time consuming and require extensive equipment. Here we present a novel genotyping tool to discriminate RV species A, B and C. STUDY DESIGN The method encompasses a VP4/VP2 polymerase chain reaction (PCR), followed by hybridization of the product on a macro array with probes covering RV-A, B, and C, produced by Chipron as custom array. Validation was performed with respiratory specimens submitted for diagnostic evaluation to the Academic Medical Center. A selection of RV PCR-positive samples genotyped based on VP4/VP2 sequencing was evaluated. Diagnostic performance was tested on respiratory samples positive for RV in an in-house multiplex respiratory PCR from January 2016 to January 2017. In-house primers and additional genotype-specific primers were used for sequencing to investigate array-negative and array-double-positive samples. RESULTS The majority of samples pretyped RVs (n = 135) were classified correctly, except for one that was assigned RV-C instead of RV-A, and 3 samples tested negative. The array gave four double-positive results; the presence of more than one genotype was confirmed in two samples. In 173/187 (92.5%) RV-positive tested patient samples from 2016, the test resulted in a designated species. RV species A was identified in 109 specimens (58.3%), RV-B in 26 (13.9%), and RV-C in 56 (29.9%) samples. Sequencing of the probe region of 14 (7.6%) negative samples revealed up to 3 mismatches to the probes for 12 samples; in 2 cases no PCR product was generated. Notably, in 18 samples the chip detected more than one species, of which 16 were confirmed by sequencing. DISCUSSION The Chipron LCD RV array provides a fast and highly sensitive method for discrimination between rhinovirus species, and has the power to detect dual infections.
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Stobart CC, Nosek JM, Moore ML. Rhinovirus Biology, Antigenic Diversity, and Advancements in the Design of a Human Rhinovirus Vaccine. Front Microbiol 2017; 8:2412. [PMID: 29259600 PMCID: PMC5723287 DOI: 10.3389/fmicb.2017.02412] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/21/2017] [Indexed: 01/06/2023] Open
Abstract
Human rhinovirus (HRV) remains a leading cause of several human diseases including the common cold. Despite considerable research over the last 60 years, development of an effective vaccine to HRV has been viewed by many as unfeasible due, in part, to the antigenic diversity of circulating HRVs in nature. Over 150 antigenically distinct types of HRV are currently known which span three species: HRV A, HRV B, and HRV C. Early attempts to develop a rhinovirus vaccine have shown that inactivated HRV is capable of serving as a strong immunogen and inducing neutralizing antibodies. Yet, limitations to virus preparation and recovery, continued identification of antigenic variants of HRV, and logistical challenges pertaining to preparing a polyvalent preparation of the magnitude required for true efficacy against circulating rhinoviruses continue to prove a daunting challenge. In this review, we describe HRV biology, antigenic diversity, and past and present advances in HRV vaccine design.
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Affiliation(s)
- Christopher C Stobart
- Department of Biological Sciences, Butler University, Indianapolis, IN, United States
| | - Jenna M Nosek
- Department of Biological Sciences, Butler University, Indianapolis, IN, United States
| | - Martin L Moore
- Department of Pediatrics, Emory University, Atlanta, GA, United States.,Children's Healthcare of Atlanta, Atlanta, GA, United States
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Abstract
Infected cells can undergo apoptosis as a protective response to viral infection, thereby limiting viral infection. As viruses require a viable cell for replication, the death of the cell limits cellular functions that are required for virus replication and propagation. Picornaviruses are single-stranded RNA viruses that modify the host cell apoptotic response, probably in order to promote viral replication, largely as a function of the viral proteases 2A, 3C, and 3CD. These proteases are essential for viral polyprotein processing and also cleave cellular proteins. Picornavirus proteases cleave proapoptotic adaptor proteins, resulting in downregulation of apoptosis. Picornavirus proteases also cleave nucleoporins, disrupting the orchestrated manner in which signaling pathways use active nucleocytoplasmic trafficking, including those involved in apoptosis. In addition to viral proteases, the transmembrane 2B protein alters intracellular ion signaling, which may also modulate apoptosis. Overall, picornaviruses, via the action of virally encoded proteins, exercise intricate control over and subvert cell death pathways, specifically apoptosis, thereby allowing viral replication to continue.
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48
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Stenberg-Hammar K, Hedlin G, Söderhäll C. Rhinovirus and preschool wheeze. Pediatr Allergy Immunol 2017; 28:513-520. [PMID: 28599066 DOI: 10.1111/pai.12740] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/25/2017] [Indexed: 12/16/2022]
Abstract
Rhinovirus (RV) known as the common cold virus generally only causes a mild upper respiratory infection, but severe lower respiratory symptoms have been associated with RV infections especially in asthmatic individuals. Wheezing is a symptom of airway obstruction, and preschool children wheezing with RV have been associated with increased risk of asthma at school age. There are, however, conflicting opinions as to whether there are differences in response to RV infection or whether wheezing with RV reveals a preexisting impairment that promotes asthma mainly in predisposed children. The advent of molecular diagnostics to detect respiratory viruses has led to new insights into the role of RV infections. This review will discuss recent information concerning the role of RV as an important respiratory pathogen related to early onset wheeze and exacerbation of established asthma in preschool children.
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Affiliation(s)
- Katarina Stenberg-Hammar
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.,Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden
| | - Gunilla Hedlin
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.,Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden
| | - Cilla Söderhäll
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Centre of Allergy Research, Karolinska Institutet, Stockholm, Sweden.,Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
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49
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Dong Y, Liu Y, Jiang W, Smith TJ, Xu Z, Rossmann MG. Antibody-induced uncoating of human rhinovirus B14. Proc Natl Acad Sci U S A 2017; 114:8017-8022. [PMID: 28696310 PMCID: PMC5544331 DOI: 10.1073/pnas.1707369114] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Rhinoviruses (RVs) are the major causes of common colds in humans. They have a nonenveloped, icosahedral capsid surrounding a positive-strand RNA genome. Here we report that the antigen-binding (Fab) fragment of a neutralizing antibody (C5) can trigger genome release from RV-B14 to form emptied particles and neutralize virus infection. Using cryo-electron microscopy, structures of the C5 Fab in complex with the full and emptied particles have been determined at 2.3 Å and 3.0 Å resolution, respectively. Each of the 60 Fab molecules binds primarily to a region on viral protein 3 (VP3). Binding of the C5 Fabs to RV-B14 results in significant conformational changes around holes in the capsid through which the viral RNA might exit. These results are so far the highest resolution view of an antibody-virus complex and elucidate a mechanism whereby antibodies neutralize RVs and related viruses by inducing virus uncoating.
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Affiliation(s)
- Yangchao Dong
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907
- Department of Microbiology, Faculty of Preclinical Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Yue Liu
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907
| | - Wen Jiang
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907
| | - Thomas J Smith
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555
| | - Zhikai Xu
- Department of Microbiology, Faculty of Preclinical Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Michael G Rossmann
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907;
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50
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Rhinovirus C, Asthma, and Cell Surface Expression of Virus Receptor CDHR3. J Virol 2017; 91:JVI.00072-17. [PMID: 28100615 DOI: 10.1128/jvi.00072-17] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Human rhinoviruses (RVs) of the A, B, and C species are defined agents of the common cold. But more than that, RV-A and RV-C are the dominant causes of hospitalization category infections in young children, especially those with asthma. The use of cadherin-related family member 3 (CDHR3) by RV-C as its cellular receptor creates a direct phenotypic link between human genetics (G versus A alleles cause Cys529 versus Tyr529 protein variants) and the efficiency with which RV-C can infect cells. With a lower cell surface display density, the human-specific Cys529 variant apparently confers partial protection from the severest virus-induced asthma episodes. Selective pressure favoring the Cys529 codon may have coemerged with the evolution of RV-C and helped shape modern human genomes against the virus-susceptible, albeit ancestral Tyr529.
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