In Vivo Characterization of the Immune Response Towards the Pathogenic Escherichia coli antigen SslE and Modulation of the Intestinal Microbiota
Résumé
Pathogenic E. coli, both intestinal (InPEC) and extraintestinal (ExPEC), account for a wide range of diseases, which can be fatal, across developing and developed countries. The vast array of virulence factors they can acquire may dramatically increase the severity of the infection. Emergence of resistant strains often renders antibiotics inefficient; in the case of Shiga toxin-producing E. coli, antibiotics can even be detrimental. Hence, a broad spectrum E. colivaccine could be a promising alternative to prevent the spread of such diseases, while offering the potential forcovering against several InPEC and ExPEC at once.Using the «reverse vaccinology» approach on an ExPEC strain, nine antigens were identified as protective against a mouse sepsis model. With 82% protective efficacy, SslE (Secreted and Surface-associated Lipoprotein of E. coli) was the most potent candidate; additional models demonstrated that SslE was also cross-protective against other ExPEC strains. Functional assays have demonstrated in vitro and in vivo that SslE is a mucinase which plays an important role for colonization and virulence of E. coli.To better understand the mechanism behind such protection, particularly at the mucosa, we are investigating the intestinal immune response obtained after immunizations with SslE using different routes of injection. In-depth analysis of each regimen will allow us to determine the most efficient method of immunization and adjuvant choice for SslE to be protective. Further, using this model of immunization, we will evaluate the potential perturbation caused by SslE on a human intestinal microbiota. These findings will be important to help us optimize the development of a potential broad spectrum vaccine
Pathogenic E. coli, both intestinal (InPEC) and extraintestinal (ExPEC), account for a wide range of diseases, which can be fatal, across developing and developed countries. The vast array of virulence factors they can acquire may dramatically increase the severity of the infection. Emergence of resistant strains often renders antibiotics inefficient; in the case of Shiga toxin-producing E. coli, antibiotics can even be detrimental. Hence, a broad spectrum E. colivaccine could be a promising alternative to prevent the spread of such diseases, while offering the potential forcovering against several InPEC and ExPEC at once.Using the «reverse vaccinology» approach on an ExPEC strain, nine antigens were identified as protective against a mouse sepsis model. With 82% protective efficacy, SslE (Secreted and Surface-associated Lipoprotein of E. coli) was the most potent candidate; additional models demonstrated that SslE was also cross-protective against other ExPEC strains. Functional assays have demonstrated in vitro and in vivo that SslE is a mucinase which plays an important role for colonization and virulence of E. coli.To better understand the mechanism behind such protection, particularly at the mucosa, we are investigating the intestinal immune response obtained after immunizations with SslE using different routes of injection. In-depth analysis of each regimen will allow us to determine the most efficient method of immunization and adjuvant choice for SslE to be protective. Further, using this model of immunization, we will evaluate the potential perturbation caused by SslE on a human intestinal microbiota. These findings will be important to help us optimize the development of a potential broad spectrum vaccine