CD4 + T Cells Drive Lung Disease Enhancement Induced by Immunization with Suboptimal Doses of Respiratory Syncytial Virus Fusion Protein in the Mouse Model
العنوان: | CD4 + T Cells Drive Lung Disease Enhancement Induced by Immunization with Suboptimal Doses of Respiratory Syncytial Virus Fusion Protein in the Mouse Model |
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المؤلفون: | Gaurav Manohar Rajani, Terrence O'Day, Sean K. Maynard, Lily Cheng, Angie Snell Bennett, Michelle Lazzaro, Corinne Cayatte, Kirsten Schneider-Ohrum, Leigh Hostetler |
المصدر: | Journal of Virology. 93 |
بيانات النشر: | American Society for Microbiology, 2019. |
سنة النشر: | 2019 |
مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Lung Diseases, medicine.medical_treatment, Immunology, Respiratory Syncytial Virus Infections, Microbiology, Virus, Proinflammatory cytokine, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Adjuvants, Immunologic, Antigen, Virology, Vaccines and Antiviral Agents, Respiratory Syncytial Virus Vaccines, medicine, Animals, Cotton rat, Lung, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, biology, Respiratory disease, respiratory system, biology.organism_classification, medicine.disease, Vaccination, Disease Models, Animal, Insect Science, Vaccines, Subunit, Immunization, Viral Fusion Proteins, Adjuvant, 030215 immunology |
الوصف: | Respiratory syncytial virus (RSV) infection of seronegative children previously immunized with formalin-inactivated (FI) RSV has been associated with serious enhanced respiratory disease (ERD). The phenomenon was reproduced in the cotton rat and the mouse, and both preclinical models have been routinely used to evaluate the safety of new RSV vaccine candidates. More recently, we demonstrated that immunizations with suboptimal doses of the RSV fusion (F) antigen, in its post- or prefusion conformation, and in the presence of a Th1-biasing adjuvant, unexpectedly led to ERD in the cotton rat model. To assess if those observations are specific to the cotton rat and to elucidate the mechanism by which vaccination with low antigen doses can drive ERD post-RSV challenge, we evaluated RSV post-F antigen dose de-escalation in BALB/c mice in the presence of a Th1-biasing adjuvant. While decreasing antigen doses, we observed an increase in lung inflammation associated with an upregulation of proinflammatory cytokines. The amplitude of the lung histopathology was comparable to that of FI-RSV-induced ERD, confirming the observations made in the cotton rat. Importantly, depletion of CD4(+) T cells prior to viral challenge completely abrogated ERD, preventing proinflammatory cytokine upregulation and the infiltration of T cells, neutrophils, eosinophils, and macrophages into the lung. Overall, low-antigen-dose-induced ERD resembles FI-RSV-induced ERD, except that the former appears in the absence of detectable levels of viral replication and in the context of a Th1-biased immune response. Taken together, our observations reinforce the recent concept that vaccines developed for RSV-naïve individuals should be systematically tested under suboptimal dosing conditions. IMPORTANCE RSV poses a significant health care burden and is the leading cause of serious lower-respiratory-tract infections in young children. A formalin-inactivated RSV vaccine developed in the 1960s not only showed a complete lack of efficacy against RSV infection but also induced severe lung disease enhancement in vaccinated children. Since then, establishing safety in preclinical models has been one of the major challenges to RSV vaccine development. We recently observed in the cotton rat model that suboptimal immunizations with RSV fusion protein could induce lung disease enhancement. In the present study, we extended suboptimal dosing evaluation to the mouse model. We confirmed the induction of lung disease enhancement by vaccinations with low antigen doses and dissected the associated immune mechanisms. Our results stress the need to evaluate suboptimal dosing for any new RSV vaccine candidate developed for seronegative infants. |
تدمد: | 1098-5514 0022-538X |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7cce63f955999ded4f66a1a89f86026b https://doi.org/10.1128/jvi.00695-19 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....7cce63f955999ded4f66a1a89f86026b |
قاعدة البيانات: | OpenAIRE |
تدمد: | 10985514 0022538X |
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