Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine
Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00597/full |
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| author | Marsha S. Russell Marybeth Creskey Abenaya Muralidharan Abenaya Muralidharan Changgui Li Jun Gao Wangxue Chen Louise Larocque Jessie R. Lavoie Aaron Farnsworth Michael Rosu-Myles Michael Rosu-Myles Anwar M. Hashem Carole L. Yauk Jingxin Cao Gary Van Domselaar Terry Cyr Xuguang Li Xuguang Li |
| author_facet | Marsha S. Russell Marybeth Creskey Abenaya Muralidharan Abenaya Muralidharan Changgui Li Jun Gao Wangxue Chen Louise Larocque Jessie R. Lavoie Aaron Farnsworth Michael Rosu-Myles Michael Rosu-Myles Anwar M. Hashem Carole L. Yauk Jingxin Cao Gary Van Domselaar Terry Cyr Xuguang Li Xuguang Li |
| author_sort | Marsha S. Russell |
| collection | DOAJ |
| description | Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions. |
| first_indexed | 2024-12-11T01:27:12Z |
| format | Article |
| id | doaj.art-184618002a8343b39ce466d49b1559bc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T01:27:12Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-184618002a8343b39ce466d49b1559bc2022-12-22T01:25:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00597424625Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral VaccineMarsha S. Russell0Marybeth Creskey1Abenaya Muralidharan2Abenaya Muralidharan3Changgui Li4Jun Gao5Wangxue Chen6Louise Larocque7Jessie R. Lavoie8Aaron Farnsworth9Michael Rosu-Myles10Michael Rosu-Myles11Anwar M. Hashem12Carole L. Yauk13Jingxin Cao14Gary Van Domselaar15Terry Cyr16Xuguang Li17Xuguang Li18Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, CanadaNational Institutes for Food and Drug Control, WHO Collaborating Center for Standardization and Evaluation of Biologicals, Beijing, ChinaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaHuman Health Therapeutics Research Centre, National Research Council Canada, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, CanadaImmunotherapy Unit, Department of Medical Microbiology and Parasitology, Faculty of Medicine and Vaccines, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi ArabiaMechanistic Studies Division, Environmental and Radiation Health Sciences Directorate, Healthy Environments and Consumer Safety Branch (HECSB), Health Canada, Ottawa, ON, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaCentre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, CanadaDepartment of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, CanadaRespiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.https://www.frontiersin.org/article/10.3389/fimmu.2019.00597/fullRSV vaccinesRSV vaccine-enhanced diseaseproteomicssystems biologyhypercoagulationcytokine |
| spellingShingle | Marsha S. Russell Marybeth Creskey Abenaya Muralidharan Abenaya Muralidharan Changgui Li Jun Gao Wangxue Chen Louise Larocque Jessie R. Lavoie Aaron Farnsworth Michael Rosu-Myles Michael Rosu-Myles Anwar M. Hashem Carole L. Yauk Jingxin Cao Gary Van Domselaar Terry Cyr Xuguang Li Xuguang Li Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine Frontiers in Immunology RSV vaccines RSV vaccine-enhanced disease proteomics systems biology hypercoagulation cytokine |
| title | Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine |
| title_full | Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine |
| title_fullStr | Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine |
| title_full_unstemmed | Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine |
| title_short | Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine |
| title_sort | unveiling integrated functional pathways leading to enhanced respiratory disease associated with inactivated respiratory syncytial viral vaccine |
| topic | RSV vaccines RSV vaccine-enhanced disease proteomics systems biology hypercoagulation cytokine |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00597/full |
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