Attenuated FNR Deficient Enterobacteria

Abstract

The invention provides an attenuated enterobacterium comprising an attenuating mutation in the fnr gene, and optionally further comprising a heterologous nucleic acid encoding a foreign antigen. Also provided are pharmaceutical formulations comprising the attenuated enterobacteria of the invention. Further disclosed are methods of inducing an immune response in a subject by administration of an immunogenically effective amount of an attenuated enterobacterium or pharmaceutical formulation of the invention.

1 . A pharmaceutical composition comprising an attenuated enterobacterium comprising an attenuating mutation in the fnr gene in a pharmaceutically acceptable carrier.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the attenuating mutation is an attenuating deletion mutation.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the attenuated enterobacterium is an attenuated  Salmonella.    
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the attenuated  Salmonella  is an attenuated  S. enterica  serovar  Typhimurium.    
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the attenuated enterobacterium is an attenuated  Shigella.    
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the attenuated enterobacterium is an attenuated  Escherichia coli.    
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the attenuated  E. coli  is an attenuated  E. coli  strain O157:H7.  
     
     
         8 . An attenuated enterobacterium comprising an attenuating mutation in the fnr gene and a heterologous nucleic acid sequence encoding a foreign antigen.  
     
     
         9 . The attenuated enterobacterium of  claim 8 , wherein the attenuating mutation is an attenuating deletion mutation.  
     
     
         10 . The attenuated enterobacterium of  claim 8 , wherein the attenuated enterobacterium is an attenuated  Salmonella.    
     
     
         11 . The attenuated enterobacterium of  claim 10 , wherein the attenuated  Salmonella  is an attenuated  S. enterica  serovar  Typhimurium.    
     
     
         12 . The attenuated enterobacterium of  claim 8 , wherein the attenuated enterobacterium is an attenuated  Shigella.    
     
     
         13 . The attenuated enterobacterium of  claim 8 , wherein the attenuated enterobacterium is an attenuated  Escherichia coli.    
     
     
         14 . The attenuated enterobacterium of  claim 13 , wherein the attenuated  E. coli  is an attenuated  E. coli  strain O157:H7.  
     
     
         15 . The attenuated enterobacterium of  claim 8 , wherein the heterologous nucleic acid sequence is incorporated into the bacterial genomic nucleic acid.  
     
     
         16 . The attenuated enterobacterium of  claim 9 , wherein the heterologous nucleic acid sequence is incorporated into the deleted FNR region.  
     
     
         17 . The attenuated enterobacterium of  claim 8 , wherein the heterologous nucleic acid sequence is incorporated into a plasmid.  
     
     
         18 . A pharmaceutical composition comprising the attenuated enterobacterium of  claim 8  in a pharmaceutically acceptable carrier.  
     
     
         19 . A method of inducing an immune response in a subject comprising administering to the subject an immunogenically effective amount of the pharmaceutical composition of  claim 1 .  
     
     
         20 . The method of  claim 19 , wherein an immune response is induced against one or more  Salmonella  spp.  
     
     
         21 . The method of  claim 20 , wherein an immune response is induced against  S. enterica  serovar  Typhimurium.    
     
     
         22 . The method of  claim 19 , wherein an immune response is induced against one or more  Shigella  spp.  
     
     
         23 . The method of  claim 19 , wherein an immune response is induced against one or more  E. coli  spp.  
     
     
         24 . The method of  claim 23 , wherein an immune response is induced against  E. coli  strain O157:H7.  
     
     
         25 . A method of inducing an immune response in a subject comprising administering to the subject an immunogenically effective amount of the attenuated enterobacterium of  claim 8 .  
     
     
         26 . The method of  claim 25 , wherein the immune response is induced against the foreign antigen and the enterobacterium.  
     
     
         27 . The method of  claim 26 , wherein an immune response is induced against one or more  Salmonella  spp.  
     
     
         28 . The method of  claim 27 , wherein an immune response is induced against  S. enterica  serovar  Typhimurium.    
     
     
         29 . The method of  claim 26 , wherein an immune response is induced against one or more  Shigella  spp.  
     
     
         30 . The method of  claim 26 , wherein an immune response is induced against one or more  E. coli  spp.  
     
     
         31 . The method of  claim 30 , wherein an immune response is induced against  E. coli  strain O157:H7.