Staphylococcus aureus leukocidins, therapeutic compositions, and uses thereof

Abstract

Disclosed herein are isolated and purified Staphylococcus aureus bi-component leukocidin, referred to herein as LukAB, and its components LukA and LukB, antibodies specific to LukA, antibodies specific to LukB, therapeutic compositions containing LukA and/or LukB, or anti-LukA and/or anti-LukB antibodies, uses of the compositions to treat acute inflammatory conditions or S. aureus infection, methods for identifying inhibitors of LukAB-mediated cytotoxicity of human phagocytes, and methods for using LukAB as a marker to predict severity of S. aureus infection.

1 . (canceled) 
     
     
         2 . A pharmaceutical composition comprising:
 a leukocidin A (LukA) polypeptide, said polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of (i) amino acid residues 28-351 of any one of SEQ ID NOs: 1-3 and 7-14, or (ii) amino acid residues 28-350 of any one of SEQ ID NOs: 4-6.   
     
     
         3 . The composition of  claim 2 , wherein said composition comprises:
 the LukA polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of amino acid residues 28-351 of SEQ ID NO: 10.   
     
     
         4 . The composition of  claim 3 , wherein said LukA polypeptide does not comprise amino acid residues 342-351 of SEQ ID NO: 10. 
     
     
         5 . The composition of  claim 2 , wherein said composition comprises:
 the LukA polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of amino acid residues 28-351 of SEQ ID NO: 2.   
     
     
         6 . The composition of  claim 5 , wherein said LukA polypeptide does not comprise amino acid residues 342-351 of SEQ ID NO: 2. 
     
     
         7 . The composition of  claim 2 , wherein the LukA polypeptide has at least 90% sequence identity to the amino acid sequence of amino acid residues 28-351 of any one of SEQ ID NOs: 1-3 and 7-14 or amino acid residues 28-350 of any one of SEQ ID NOs: 4-6. 
     
     
         8 . The composition of  claim 2 , wherein the LukA polypeptide has at least 95% sequence identity to the amino acid sequence of amino acid residues 28-351 of any one of SEQ ID NOs: 1-3 and 7-14 or amino acid residues 28-350 of any one of SEQ ID NOs: 4-6. 
     
     
         9 . The composition of  claim 2  further comprising:
 a leukocidin B (LukB) polypeptide, said LukB polypeptide comprising an amino acid sequence having at least 85% sequence identity to the amino acid sequence of amino acid residues 30-338 of any one of SEQ ID NOs: 15, 18, 20, and 22-27 or amino acid residues 30-339 of any one of SEQ ID NOs: 16, 19, and 21. 
 
     
     
         10 . The composition of  claim 9 , wherein said composition comprises the LukB polypeptide having at least 85% sequence identity to the amino acid sequence of amino acid residues 30-339 of SEQ ID NO: 16. 
     
     
         11 . The composition of  claim 9 , wherein said composition comprises the LukB polypeptide having at least 85% sequence identity to the amino acid sequence of amino acid residues 30-338 of SEQ ID NO: 27. 
     
     
         12 . The composition of  claim 9 , wherein the LukB polypeptide has at least 90% sequence identity to the amino acid sequence of amino acid residues 30-338 of any one of SEQ ID NOs: 15, 18, 20, and 22-27 or amino acid residues 30-339 of any one of SEQ ID NOs: 16, 19, and 21. 
     
     
         13 . The composition of  claim 9 , wherein the LukB polypeptide has at least 95% sequence identity to the amino acid sequence of amino acid residues 30-338 of any one of SEQ ID NOs: 15, 18, 20, and 22-27 or amino acid residues 30-339 of any one of SEQ ID NOs: 16, 19, and 21. 
     
     
         14 . The composition of  claim 2  further comprising a pharmaceutically acceptable carrier. 
     
     
         15 . The composition of  claim 2  further comprising an adjuvant. 
     
     
         16 . A method of generating an antibody response in a mammalian subject, said method comprising:
 administering to a mammalian subject the composition of  claim 2  under conditions effective to induce an antibody response against the lukA polypeptide present in the composition.   
     
     
         17 . The method of  claim 16 , wherein the LukA polypeptide comprises a deletion of amino acid residues 342-351 of SEQ ID NO: 10. 
     
     
         18 . The method of  claim 16 , wherein said LukA polypeptide comprises a deletion of the amino acid residues 342-351 of SEQ ID NO: 2. 
     
     
         19 . The method of  claim 16 , wherein the subject has an infection and wherein the infection is an MRSA infection.