Doctoral thesis
Open access

Influenza A Virus: From Infection to Prevention. Long-term Effects of an Early Life IAV Infection in vivo and Optimization of the Live Attenuated Influenza A Vaccine Backbone Using Mouse Models

Number of pages207
Imprimatur date2022-12-12
Defense date2022-12-12

Influenza A virus (IAV) is one of the major causative agents of acute respiratory infections in humans. Influenza disease causes up to 650,000 deaths every year with its burden highest among high-risk populations. A major complication during IAV infections is the increased susceptibility to bacterial secondary infections, however the impact on the commensal bacterial community is still poorly understood. This is particularly important during childhood, when IAV infections are frequent and the microbiota community is still developing. Vaccination is the best way to prevent influenza disease. The live attenuated influenza vaccine (LAIV) provides good protection and induces mucosal responses important in blocking transmission. However, due to safety concerns, key target populations that could benefit from the advantages of this vaccine, are left out. The aim of this thesis was two-fold. To optimize the current LAIV backbone and increase its safety profile and to explore the effects of a childhood IAV infection on the development of the host microbiota and their impact in adult life using a mouse model. To address the first aim, we performed targeted mutagenesis on the backbone of the LAIV and rescued an optimized LAIV (optiLAIV) with a higher attenuation degree. We characterized optiLAIV in two mouse models representing infants under 2-years old and highly susceptible populations to viral infections. In neonatal mice, we showed that optiLAIV is cleared faster from the upper respiratory tract (URT) while still maintaining its protective ability against two challenge models. Additionally, we showed that in adult mice lacking a key player of the interferon signaling response, optiLAIV presented reduced replication in the lower respiratory tract (LRT) and caused no signs of morbidity compared to a 50% mortality rate observed in animals vaccinated with LAIV. OptiLAIV induced UPR-related genes in a human nasal epithelial tissue model suggesting this pathway as a potential mechanism of attenuation. Our results present an optimized LAIV candidate that could be explored as a safer alternative to the licensed LAIV in high-risk patient groups. To address the second aim, we used a neonatal mouse model, in which we report that a single subclinical IAV infection leads to a significant decrease in the bacterial abundance of the small intestine in adulthood. This observation was accompanied by an enrichment of Enterobacteriales and a reduction of Clostridiales. Furthermore, IAV-imprinted male animals had an increased body weight and lower energy expenditure compared to mock imprinted animals. Cohousing experiments abrogated the body weight differences observed while a highfat-high-sucrose diet enhanced the phenotype, suggesting a microbiota-dependent effect. Our results show that an acute respiratory infection during childhood induces long-term dysbiosis with possible consequences on host metabolic processes. Together, our findings highlight the importance of preventing IAV infections during childhood and propose an alternative strategy to do so.

Citation (ISO format)
PEREIRA BONIFACIO LOPES, Joao Pedro. Influenza A Virus: From Infection to Prevention. Long-term Effects of an Early Life IAV Infection in vivo and Optimization of the Live Attenuated Influenza A Vaccine Backbone Using Mouse Models. 2022. doi: 10.13097/archive-ouverte/unige:166495
Main files (2)

Technical informations

Creation01/27/2023 2:48:00 PM
First validation01/27/2023 2:48:00 PM
Update time03/16/2023 10:31:34 AM
Status update03/16/2023 10:31:32 AM
Last indexation09/18/2023 9:43:14 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack