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1
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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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2
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Rajput C, Han M, Ishikawa T, Lei J, Goldsmith AM, Jazaeri S, Stroupe CC, Bentley JK, Hershenson MB. Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation. Front Immunol 2021; 12:649520. [PMID: 33968043 PMCID: PMC8100319 DOI: 10.3389/fimmu.2021.649520] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/07/2021] [Indexed: 12/21/2022] Open
Abstract
Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, β, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Marc B. Hershenson
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, United States
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3
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Dastghaib S, Kumar PS, Aftabi S, Damera G, Dalvand A, Sepanjnia A, Kiumarsi M, Aghanoori MR, Sohal SS, Ande SR, Alizadeh J, Mokarram P, Ghavami S, Sharma P, Zeki AA. Mechanisms Targeting the Unfolded Protein Response in Asthma. Am J Respir Cell Mol Biol 2021; 64:29-38. [PMID: 32915643 DOI: 10.1165/rcmb.2019-0235tr] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 09/11/2020] [Indexed: 12/16/2022] Open
Abstract
Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell types to meet these increasing functional needs. Dysregulation of the UPR leads to the development of the disease. The UPR and ER stress are involved in several human conditions, such as chronic inflammation, neurodegeneration, metabolic syndrome, and cancer. Furthermore, potent and specific compounds that target the UPR pathway are under development as future therapies. The focus of this review is to thoroughly describe the effects of both internal and external stressors on the ER in asthma. Furthermore, we discuss how the UPR signaling pathway is activated in the lungs to overcome cellular damage. We also present an overview of the pathogenic mechanisms, with a brief focus on potential strategies for pharmacological interventions.
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Affiliation(s)
- Sanaz Dastghaib
- Department of Clinical Biochemistry and
- Autophagy Research Center, Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - P Sravan Kumar
- National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Sajjad Aftabi
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine
- Medical Physics Department and
| | - Gautam Damera
- Personalized and Predictive Medicine (Respiratory), Global Research and Development, Teva Pharmaceuticals, Malvern, Pennsylvania
| | - Azadeh Dalvand
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine
| | - Adel Sepanjnia
- Department of Immunology, School of Medicine, Jiroft University of Medical Science, Jiroft, Iran
| | - Mohammad Kiumarsi
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine
| | - Mohamad-Reza Aghanoori
- Department of Human Genetics, School of Medicine, and
- Department of Pharmacology and Therapeutics
- Division of Neurodegenerative Disorders, Albrechtsen Research Centre, St. Boniface Hospital, Winnipeg, Manitoba, Canada
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, College of Health and Medicine, University of Tasmania, Launceston, Tasmania, Australia
| | | | - Javad Alizadeh
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine
- Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, Manitoba, Canada
| | - Pooneh Mokarram
- Department of Clinical Biochemistry and
- Autophagy Research Center, Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Ghavami
- Autophagy Research Center, Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine
- Department of Internal Medicine, and
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Pawan Sharma
- Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Amir A Zeki
- Lung Center, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, School of Medicine, University of California, Davis, Davis, California; and
- Veterans Affairs Medical Center, Mather, California
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4
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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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5
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Han M, Rajput C, Hershenson MB. Rhinovirus Attributes that Contribute to Asthma Development. Immunol Allergy Clin North Am 2019; 39:345-359. [PMID: 31284925 PMCID: PMC6624084 DOI: 10.1016/j.iac.2019.03.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Early-life wheezing-associated infections with human rhinovirus (HRV) are strongly associated with the inception of asthma. The immune system of immature mice and humans is skewed toward a type 2 cytokine response. Thus, HRV-infected 6-day-old mice but not adult mice develop augmented type 2 cytokine expression, eosinophilic inflammation, mucous metaplasia, and airway hyperresponsiveness. This asthma phenotype depends on interleukin (IL)-13-producing type 2 innate lymphoid cells, the expansion of which in turn depends on release of the innate cytokines IL-25, IL-33, and thymic stromal lymphopoietin from the airway epithelium. In humans, certain genetic variants may predispose to HRV-induced childhood asthma.
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Affiliation(s)
- Mingyuan Han
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Medical Sciences Research Building II, 1150 West Medical Center Drive, Ann Arbor, MI, USA
| | - Charu Rajput
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Medical Sciences Research Building II, 1150 West Medical Center Drive, Ann Arbor, MI, USA
| | - Marc B Hershenson
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Medical Sciences Research Building II, 1150 West Medical Center Drive, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Medical Sciences Research Building II, 1150 West Medical Center Drive, Ann Arbor, MI, USA.
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6
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Wang H, Liu Y, Shi J, Cheng Z. ORMDL3 knockdown in the lungs alleviates airway inflammation and airway remodeling in asthmatic mice via JNK1/2-MMP-9 pathway. Biochem Biophys Res Commun 2019; 516:739-746. [PMID: 31255288 DOI: 10.1016/j.bbrc.2019.06.122] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 06/21/2019] [Indexed: 12/27/2022]
Abstract
Orosomucoid-like protein 3 (ORMDL3) is a common mutation in many asthma patients and its effects on the specific pathogenesis of asthma are still unclear. Therefore, in this study, we used a mouse that specifically knockout the mouse ORDML3 gene to further study the mechanism. We used ovalbumin (OVA) to induce asthma in wild-type mice and ORMDL3 knockout mice. Lung ventilation resistance, airway inflammation, mucus hypersecretion, collagen deposition, the levels of inflammatory factors and the expression of ORDML3 and JNK1/2-MMP-9 pathway were detected. The results showed that ORMDL3 gene was highly expressed in clinical asthmatic children and mouse asthma model. Knocking down the ORMDL3 gene in the lung tissue of asthmatic mice can reduce airway hyperresponsiveness, airway inflammation, mucus secretion, and collagen deposition around the airway. After knocking down the lung tissue of mice, the IL-4, IL-5 and IL-13 concentrations in broncho alveolar lavage fluid of asthmatic mice were significantly decreased, and the activation of JNK1/2-MMP-9 pathway was inhibited in mouse lung tissue. Collectively, our results demonstrate that the ORMDL3 gene may aggravate asthma symptoms by activating the JNK1/2-MMP-9 pathway, which indicates that the ORMDL3 gene may be the key molecule for the next step of asthma targeted therapy.
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Affiliation(s)
- Huan Wang
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Ying Liu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jiang Shi
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhe Cheng
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
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7
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Willis-Owen SAG, Cookson WOC, Moffatt MF. The Genetics and Genomics of Asthma. Annu Rev Genomics Hum Genet 2019; 19:223-246. [PMID: 30169121 DOI: 10.1146/annurev-genom-083117-021651] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Asthma is a common, clinically heterogeneous disease with strong evidence of heritability. Progress in defining the genetic underpinnings of asthma, however, has been slow and hampered by issues of inconsistency. Recent advances in the tools available for analysis-assaying transcription, sequence variation, and epigenetic marks on a genome-wide scale-have substantially altered this landscape. Applications of such approaches are consistent with heterogeneity at the level of causation and specify patterns of commonality with a wide range of alternative disease traits. Looking beyond the individual as the unit of study, advances in technology have also fostered comprehensive analysis of the human microbiome and its varied roles in health and disease. In this article, we consider the implications of these technological advances for our current understanding of the genetics and genomics of asthma.
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Affiliation(s)
- Saffron A G Willis-Owen
- National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom; , ,
| | - William O C Cookson
- National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom; , ,
| | - Miriam F Moffatt
- National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom; , ,
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8
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Ma X, Long F, Yun Y, Dang J, Wei S, Zhang Q, Li J, Zhang H, Zhang W, Wang Z, Liu Q, Zou C. ORMDL3 and its implication in inflammatory disorders. Int J Rheum Dis 2018; 21:1154-1162. [PMID: 29879314 DOI: 10.1111/1756-185x.13324] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
A growing body of evidence has suggested the genetic association of ORMDL3 gene (ORMDL Sphingolipid Biosynthesis Regulator 3) polymorphisms with a diverse set of inflammatory disorders that include bronchial asthma, inflammatory bowel disease, ankylosing spondylitis and atherosclerosis. Gene functional investigations have revealed the particular relevance of ORMDL3 in endoplasmic reticulum stress, lipid metabolism and inflammatory reactions. Additionally, several reports have recently added a new dimension to our understanding of the modulation of ORMDL3 gene expression in inflammation. This mini-review summarizes the pertinent publications regarding the genetic association studies and mechanistic exploration of ORMDL3 in common inflammatory disorders.
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Affiliation(s)
- Xiaochun Ma
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.,Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Jinan, China
| | - Feng Long
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Jinan, China
| | - Yan Yun
- Brain Research Institute, Qilu Hospital of Shandong University, Jinan, China
| | - Jie Dang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Jinan, China.,Department of Medical Genetics and Cell Biology, Ningxia Medical University, Yinchuan, China
| | - Shijun Wei
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Jinan, China
| | - Qian Zhang
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Jinzhang Li
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Haizhou Zhang
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Wenlong Zhang
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Zhengjun Wang
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Qiji Liu
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Jinan, China
| | - Chengwei Zou
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
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9
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Lauzon-Joset JF, Jones AC, Mincham KT, Thomas JA, Rosenthal LA, Bosco A, Holt PG, Strickland DH. Atopy-Dependent and Independent Immune Responses in the Heightened Severity of Atopics to Respiratory Viral Infections: Rat Model Studies. Front Immunol 2018; 9:1805. [PMID: 30150981 PMCID: PMC6099265 DOI: 10.3389/fimmu.2018.01805] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 07/23/2018] [Indexed: 12/04/2022] Open
Abstract
Allergic (Th2high immunophenotype) asthmatics have a heightened susceptibility to common respiratory viral infections such as human rhinovirus. Evidence suggests that the innate interferon response is deficient in asthmatic/atopic individuals, while other studies show no differences in antiviral response pathways. Unsensitized and OVA-sensitized/challenged Th2high (BN rats) and Th2low immunophenotype (PVG rats) animals were inoculated intranasally with attenuated mengovirus (vMC0). Sensitized animals were exposed/unexposed during the acute viral response phase. Cellular and transcriptomic profiling was performed on bronchoalveolar lavage cells. In unsensitized PVG rats, vMC0 elicits a prototypical antiviral response (neutrophilic airways inflammation, upregulation of Th1/type I interferon-related pathways). In contrast, response to infection in the Th2high BN rats was associated with a radically altered intrinsic host response to respiratory viral infection, characterized by macrophage influx/Th2-associated pathways. In sensitized animals, response to virus infection alone was not altered compared to unsensitized animals. However, allergen exposure of sensitized animals during viral infection unleashes a notably exaggerated airways inflammatory response profile orders of magnitude higher in BN versus PVG rats despite similar viral loads. The co-exposure responses in the Th2high BN incorporated type I interferon/Th1, alternative macrophage activation/Th2 and Th17 signatures. Similar factors may underlie the hyper-susceptibility to infection-associated airways inflammation characteristic of the human Th2high immunophenotype.
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Affiliation(s)
| | - Anya C Jones
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.,School of Medicine, University of Western Australia, Perth, WA, Australia
| | - Kyle T Mincham
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.,School of Medicine, University of Western Australia, Perth, WA, Australia
| | - Jenny A Thomas
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia
| | - Louis A Rosenthal
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Anthony Bosco
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia
| | - Patrick G Holt
- Telethon Kids Institute, University of Western Australia, Perth, WA, Australia
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10
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Veerapandian R, Snyder JD, Samarasinghe AE. Influenza in Asthmatics: For Better or for Worse? Front Immunol 2018; 9:1843. [PMID: 30147697 PMCID: PMC6095982 DOI: 10.3389/fimmu.2018.01843] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/26/2018] [Indexed: 12/17/2022] Open
Abstract
Asthma and influenza are two pathologic conditions of the respiratory tract that affect millions worldwide. Influenza virus of the 2009 pandemic was highly transmissible and caused severe respiratory disease in young and middle-aged individuals. Asthma was discovered to be an underlying co-morbidity that led to hospitalizations during this influenza pandemic albeit with less severe outcomes. However, animal studies that investigated the relationship between allergic inflammation and pandemic (p)H1N1 infection, showed that while characteristics of allergic airways disease were exacerbated by this virus, governing immune responses that cause exacerbations may actually protect the host from severe outcomes associated with influenza. To better understand the relationship between asthma and severe influenza during the last pandemic, we conducted a systematic literature review of reports on hospitalized patients with asthma as a co-morbid condition during the pH1N1 season. Herein, we report that numerous other underlying conditions, such as cardiovascular, neurologic, and metabolic diseases may have been underplayed as major drivers of severe influenza during the 2009 pandemic. This review synopses, (1) asthma and influenza independently, (2) epidemiologic data surrounding asthma during the 2009 influenza pandemic, and (3) recent advances in our understanding of allergic host–pathogen interactions in the context of allergic airways disease and influenza in mouse models. Our goal is to showcase possible immunological benefits of allergic airways inflammation as countermeasures for influenza virus infections as a learning tool to discover novel pathways that can enhance our ability to hinder influenza virus replication and host pathology induced thereof.
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Affiliation(s)
- Raja Veerapandian
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States.,Children's Foundation Research Institute, University of Tennessee Health Science Center, Memphis, TN, United States
| | - John D Snyder
- Children's Foundation Research Institute, University of Tennessee Health Science Center, Memphis, TN, United States.,College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Amali E Samarasinghe
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States.,Children's Foundation Research Institute, University of Tennessee Health Science Center, Memphis, TN, United States
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11
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Mehta AK, Doherty T, Broide D, Croft M. Tumor necrosis factor family member LIGHT acts with IL-1β and TGF-β to promote airway remodeling during rhinovirus infection. Allergy 2018; 73:1415-1424. [PMID: 29315623 DOI: 10.1111/all.13390] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND Rhinovirus (RV) can exacerbate allergen-driven asthma. However, it has been suggested that serial infections with RV may also lead to asthma-like features in childhood without prior allergen exposure. AIM We sought to test the effects of RV infection in the absence of allergen challenge on lung tissue remodeling and to understand whether RV induced factors in common with allergen that promote remodeling. METHODS We infected C57BL/6 mice multiple times with RV in the absence or presence of allergen to assess airway remodeling. We used knockout mice and blocking reagents to determine the participation of LIGHT (TNFSF14), as well as IL-1β and TGF-β, each previously shown to contribute to lung remodeling driven by allergen. RESULTS Recurrent RV infection without allergen challenge induced an increase in peribronchial smooth muscle mass and subepithelial fibrosis. Rhinovirus (RV) induced LIGHT expression in mouse lungs after infection, and alveolar epithelial cells and neutrophils were found to be potential sources of LIGHT. Accordingly, LIGHT-deficient mice, or mice where LIGHT was neutralized, displayed reduced smooth muscle mass and lung fibrosis. Recurrent RV infection also exacerbated the airway remodeling response to house dust mite allergen, and this was significantly reduced in LIGHT-deficient mice. Furthermore, neutralizing IL-1β or TGF-β also limited subepithelial fibrosis and/or smooth muscle thickness induced by RV. CONCLUSION Rhinovirus can promote airway remodeling in the absence of allergen through upregulating common factors that also contribute to allergen-associated airway remodeling.
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Affiliation(s)
- A. K. Mehta
- Division of Immune Regulation; La Jolla Institute for Allergy and Immunology; La Jolla CA USA
| | - T. Doherty
- Department of Medicine; University of California San Diego; La Jolla CA USA
| | - D. Broide
- Department of Medicine; University of California San Diego; La Jolla CA USA
| | - M. Croft
- Division of Immune Regulation; La Jolla Institute for Allergy and Immunology; La Jolla CA USA
- Department of Medicine; University of California San Diego; La Jolla CA USA
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12
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Wu Q, Jiang D, Schaefer NR, Harmacek L, O'Connor BP, Eling TE, Eickelberg O, Chu HW. Overproduction of growth differentiation factor 15 promotes human rhinovirus infection and virus-induced inflammation in the lung. Am J Physiol Lung Cell Mol Physiol 2017; 314:L514-L527. [PMID: 29192094 DOI: 10.1152/ajplung.00324.2017] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Human rhinovirus (HRV) is the most common virus contributing to acute exacerbations of chronic obstructive pulmonary disease (COPD) nearly year round, but the mechanisms have not been well elucidated. Recent clinical studies suggest that high levels of growth differentiation factor 15 (GDF15) protein in the blood are associated with an increased yearly rate of all-cause COPD exacerbations. Therefore, in the current study, we investigated whether GDF15 promotes HRV infection and virus-induced lung inflammation. We first examined the role of GDF15 in regulating host defense and HRV-induced inflammation using human GDF15 transgenic mice and cultured human GDF15 transgenic mouse tracheal epithelial cells. Next, we determined the effect of GDF15 on viral replication, antiviral responses, and inflammation in human airway epithelial cells with GDF15 knockdown and HRV infection. Finally, we explored the signaling pathways involved in airway epithelial responses to HRV infection in the context of GDF15. Human GDF15 protein overexpression in mice led to exaggerated inflammatory responses to HRV, increased infectious particle release, and decreased IFN-λ2/3 (IL-28A/B) mRNA expression in the lung. Moreover, GDF15 facilitated HRV replication and inflammation via inhibiting IFN-λ1/IL-29 protein production in human airway epithelial cells. Lastly, Smad1 cooperated with interferon regulatory factor 7 (IRF7) to regulate airway epithelial responses to HRV infection partly via GDF15 signaling. Our results reveal a novel function of GDF15 in promoting lung HRV infection and virus-induced inflammation, which may be a new mechanism for the increased susceptibility and severity of respiratory viral (i.e., HRV) infection in cigarette smoke-exposed airways with GDF15 overproduction.
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Affiliation(s)
- Qun Wu
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, Colorado.,Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health , Denver, Colorado
| | - Di Jiang
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health , Denver, Colorado
| | - Niccolette R Schaefer
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health , Denver, Colorado
| | - Laura Harmacek
- Center for Genes, Environment, and Health, National Jewish Health , Denver, Colorado
| | - Brian P O'Connor
- Center for Genes, Environment, and Health, National Jewish Health , Denver, Colorado
| | - Thomas E Eling
- The Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, North Carolina
| | - Oliver Eickelberg
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus , Aurora, Colorado
| | - Hong Wei Chu
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health , Denver, Colorado
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