Targeting the histone code as a bacterial strategy for selectively modulating gene expression

Abstract

The ospF gene of Shigella flexneri encodes a phosphatase, which is a member of a new class of phosphatases. The OspF phosphatase inhibits the activity of several proteins either by direct protein modification or transcription downregulation. These proteins include MAP kinase, IL-8, CCL20, IL-12, AP1, CREB, RPA p32, and BCL2 related proteins. Methods for treating diseases using OspF phosphatase, methods for identifying agents that modulate OspF phosphatase's activity, methods for identifying agents that mimic OspF phosphatase's activity, and immunogenic compositions comprising OspF phosphatase are provided. A strain of Shigella flexneri containing an inactivated ospF gene is also provided.

1 . A method for treating or preventing cancer in a mammal, comprising administering to the mammal a composition comprising OspF or a substance that mimics OspF activity. 
     
     
         2 . The method of  claim 1 , wherein the cancer is chosen from colonic cancer and pancreatic cancer. 
     
     
         3 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         4 . An anticancer treatment comprising a pharmaceutical composition comprising OspF or a substance that mimics OspF activity. 
     
     
         5 . A method of screening for compounds that modulate OspF activity in a cell, comprising:
 (A) adding a compound to a cultured cell;   (B) incubating the cell;   (C) detecting one or more OspF protein regulation activities in the cell;   (D) determining which compounds alter the one or more OspF protein regulation activities in the cell; and   (E) selecting the compounds that modulate OspF activity.   
     
     
         6 . The method as claimed in  claim 5 , wherein the protein regulation activity is chosen from regulation of the protein expression and/or activities of AP-1, CREB, RPA p32 (STAT activator), antiapoptotic proteins related to BCL2, and major proinflammatory genes like CCL20, IL-8, and IL-12. 
     
     
         7 . The method of  claim 5 , wherein the cell is a HeLa cell, a Caco 2 cell, or a cell of the immune system. 
     
     
         8 . A method of screening for compounds that mimic OspF activity comprising:
 (A) adding a compound to a cultured cell;   (B) incubating the cell;   (C) detecting one or more OspF protein regulation activities in the cell;   (D) comparing the protein regulation activities of the compound with the protein regulation activities of OspF; and   (E) identifying a compound that mimics OspF activity.   
     
     
         9 . The method as claimed in  claim 8 , wherein the protein regulation activity is chosen from regulation of the protein expression and/or activities of AP-1, CREB, RPA p32 (STAT activator), antiapoptotic proteins related to BCL2, and major proinflammatory genes like CCL20, IL-8, and IL-12. 
     
     
         10 . The method of  claim 8 , wherein the cell is a HeLa cell, a Caco 2 cell, or a cell of the immune system. 
     
     
         11 . A method for treating or preventing an inflammatory disease in a mammal comprising administering to the mammal a composition comprising OspF or a substance that mimics OspF activity. 
     
     
         12 . The method of  claim 11 , wherein the mammal is human. 
     
     
         13 . A method for treating or preventing disorders associated with transplantation in a mammal comprising administering to the mammal a composition comprising OspF or a substance that mimics OspF activity. 
     
     
         14 . The method of  claim 13 , wherein the mammal is human. 
     
     
         15 . A pharmaceutical composition comprising OspF or a substance that mimics OspF activity. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the composition is an adjuvant. 
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein the composition further comprises a compound that increases OspF activity. 
     
     
         18 . A method of regulating an immune response comprising administering an effective dose of the pharmaceutical composition of  claim 15  to a subject in need thereof. 
     
     
         19 . A strain of  Shigella flexneri , wherein the ospF gene is inactivated. 
     
     
         20 . The strain of  claim 19 , wherein the strain is deposited at the CNCM under Accession Number CNCM I-3480. 
     
     
         21 . A plasmid that expresses OspF with a myc label, wherein the plasmid is deposited at the CNCM under Accession Number CNCM I-3496. 
     
     
         22 . A vaccine comprising the strain of  claim 19  and a pharmaceutically acceptable carrier. 
     
     
         23 . A method of treating or preventing dysentery caused by  Shigella  infection comprising vaccinating a patient in need thereof with the strain of  claim 19 . 
     
     
         24 . The method of  claim 23 , wherein the  Shigella flexneri  is the strain deposited at the CNCM under Accession Number CNCM I-3480. 
     
     
         25 . A method of treating or preventing a  Shigella  infection comprising administering a compound that decreases OspF activity to a patient in need thereof. 
     
     
         26 . A substance that mimics the protein regulation activity of OspF, wherein the protein regulation activity is chosen from regulation of the protein expression and/or activities of AP-1, CREB, RPA p32 (STAT activator), antiapoptotic proteins related to BCL2, and major proinflammatory genes like CCL20, IL-8, and IL-12. 
     
     
         27 . The substance of  claim 26 , wherein the substance is a protein. 
     
     
         28 . The substance of  claim 26 , wherein the substance is a chemical. 
     
     
         29 . The method according to  claim 11 ,  13 , or  18 , wherein the pharmaceutical composition further comprises a compound that increases OspF activity.