Targeting Poly-Gamma-Glutamic Acid to Treat Staphylococcus Epidermidis and Related Infections

Abstract

Immunogenic compositions and methods for eliciting an immune response against S. epidermidis and other related staphylococci are provided. The immunogenic compositions can include immunogenic conjugates of poly-γ-glutamic acid (such as γDLPGA) polypeptides of S. epidermidis , or related staphylococci that express a γPGA polypeptide. The γPGA conjugates elicit an effective immune response against S. epidermidis , or other staphylococci, in subjects to which the conjugates are administered. A method of treating an infection caused by a Staphylococcus organism that expresses cap genes is also disclosed. The method can include selecting a subject who is at risk of or has been diagnosed with the infection by the Staphylococcus organism which expresses γPGA from the cap genes. Further, the expression of a γPGA polypeptide by the organism can then be altered.

1 . An immunogenic conjugate comprising a  Staphylococcus  capsular poly-γ-glutamic acid (γPGA) polypeptide and an adjuvant, wherein the conjugate elicits an immune response in a subject. 
     
     
         2 . The immunogenic conjugate of  claim 1 , wherein the  Staphylococcus  capsular γPGA polypeptide is a  S. epidermidis  poly-γ-DL-glutamic acid (γDLPGA) polypeptide. 
     
     
         3 . The immunogenic conjugate of  claim 1 , wherein the immunogenic conjugate is covalently linked to a carrier. 
     
     
         4 . The immunogenic conjugate of  claim 3 , wherein the carrier is selected from the group consisting of: (a) bovine serum albumin, (b) recombinant  B. anthracis  protective antigen, (c) recombinant  P. aeruginosa  exotoxin A, (d) tetanus toxoid, (e) diphtheria toxoid, (f) pertussis toxoid, (g)  C. perfringens  toxoid, (h) hepatitis B surface antigen, (i) hepatitis B core antigen, (j) keyhole limpet hemocyanin, (k) horseshoe crab hemocyanin, (l) edestin, (m) mammalian serum albumin, (n) mammalian immunoglobulin, analog or mimetic of any one of (a)-(n), and combinations of two or more thereof. 
     
     
         5 . The immunogenic conjugate of  claim 3 , wherein the carrier is covalently linked to the amino terminus or carboxyl terminus of the  Staphylococcus  capsular γPGA polypeptide. 
     
     
         6 . The immunogenic conjugate of  claim 3 , wherein the immune response comprises opsonophagocytic activity. 
     
     
         7 . The immunogenic conjugate of  claim 3 , wherein the  Staphylococcus  capsular γPGA polypeptide is a  S. epidermidis  γPGA polypeptide. 
     
     
         8 . The immunogenic conjugate of  claim 1 , wherein the  Staphylococcus  capsular γPGA polypeptide includes poly-γ-D-glutamic acid (γDPGA) and poly-γ-L-glutamic acid (γLPGA). 
     
     
         9 . The immunogenic conjugate of  claim 8 , wherein the  Staphylococcus  capsular γPGA polypeptide includes γDPGA and γLPGA in substantially equivalent amounts. 
     
     
         10 . A composition comprising the immunogenic conjugate of  claim 1  and a pharmaceutically acceptable vehicle. 
     
     
         11 . The immunogenic conjugate of  claim 1 , wherein the  Staphylococcus  capsular γPGA polypeptide is  S. capitis  or  S. warneri  or  S. saccharolyticus  or  S. caprae  or  S. hominis  or  S. haemolyticus  or  S. lugdunensis  or  S. simulans  or  S. epidermidis.    
     
     
         12 . A method of treating a  Staphylococcus  infection in a subject, comprising:
 introducing into the subject the immunogenic composition of  claim 1 , thereby eliciting an immune response that treats the  Staphylococcus  infection in the subject.   
     
     
         13 . The method of  claim 12 , wherein the immune response is elicited against a  Staphylococcus  capsular poly-γ-glutamic acid (γPGA) polypeptide. 
     
     
         14 . The method of  claim 13 , wherein the  Staphylococcus  capsular poly-γ-glutamic acid (γPGA) polypeptide is a  S. epidermidis  capsular poly-γ-glutamic acid (γPGA) polypeptide. 
     
     
         15 . The method of  claim 12 , wherein the immune response is elicited against a poly-γ-D-L-glutamic acid (γDLPGA) polypeptide 
     
     
         16 . A method of eliciting an immune in a subject, comprising: introducing into the subject an immunogenic composition, the immunogenic composition comprising a  Staphylococcus  capsular poly-γ-glutamic acid (γPGA) polypeptide covalently linked to a carrier, thereby eliciting an immune response in the subject. 
     
     
         17 . The method of  claim 16 , wherein the immunogenic composition further comprises an adjuvant. 
     
     
         18 . The method of  claim 16 , wherein the  Staphylococcus  capsular γPGA polypeptide is from  S. epidermidis.    
     
     
         19 . The method of  claim 16 , wherein the carrier is selected from the group consisting of: (a) bovine serum albumin, (b) recombinant  B. anthracis  protective antigen, (c) recombinant  P. aeruginosa  exotoxin A, (d) tetanus toxoid, (e) diphtheria toxoid, (f) pertussis toxoid, (g)  C. perfringens  toxoid, (h) hepatitis B surface antigen, (i) hepatitis B core antigen, (j) keyhole limpet hemocyanin, (k) horseshoe crab hemocyanin, (l) edestin, (m) mammalian serum albumin, (n) mammalian immunoglobulin, analog or mimetic of any one of (a)-(n), and combinations of two or more thereof. 
     
     
         20 . The method of  claim 16 , wherein the carrier is covalently linked to the amino terminus or carboxyl terminus of the  Staphylococcus  capsular γPGA polypeptide. 
     
     
         21 . The method of  claim 16 , wherein the  Staphylococcus  capsular γPGA polypeptide includes poly-γ-D-L-glutamic acid (γDLPGA). 
     
     
         22 . The method of  claim 21 , wherein the poly-γ-D-L-glutamic acid (γDLPGA) includes poly-γ-D-glutamic acid and poly-γ-L-glutamic acid in substantially equal amounts. 
     
     
         23 . The method of  claim 16 , wherein the immune response comprises opsonophagocytic activity. 
     
     
         24 . The method of  claim 16 , wherein the immune conjugate is introduced into the subject to treat a  S. epidermidis  infection. 
     
     
         25 . The method of  claim 24 , wherein the  S. epidermidis  infection is on an in-dwelling medical device. 
     
     
         26 . The method of  claim 16 , wherein the immune conjugate is introduced into the subject to produce or artificially increase immunity to  S. epidermidis.    
     
     
         27 . A method of treating or inhibiting an  S. epidermidis  infection in a subject, comprising:
 enhancing an immune response against poly-γ-D-L-glutamic acid (γDLPGA).   
     
     
         28 . The method of  claim 27 , wherein enhancing the immune response comprises administrating to the subject an antiserum against poly-γ-D-L-glutamic acid. 
     
     
         29 . The method of  claim 28 , wherein the antiserum is administered to treat or inhibit a  S. epidermidis  infection on an in-dwelling medical device. 
     
     
         30 . The method of  claim 27 , wherein enhancing the immune response comprises administrating to the subject an immunogenic composition that stimulates an immune response against the poly-γ-D-L-glutamic acid (γDLPGA). 
     
     
         31 . A method of detecting an organism from a  Staphylococcus epidermidis  group in a subject, comprising:
 detecting the presence of poly-γ-DL-glutamic acid (γDLPGA) in a  Staphylococcus  obtained from the subject, wherein presence of γDLPGA indicates the organism is a member of the  Staphylococcus epidermidis  group.   
     
     
         32 . The method of  claim 31 , wherein the members of the  Staphylococcus epidermidis  group comprises:  S. capitis, S. warneri, S. saccharolyticus, S. caprae, S. hominis , and  S. haemolyticus.    
     
     
         33 . An isolated antibody that binds to a  Staphylococcus epidermidis  capsular poly-γ-glutamic acid (γPGA) polypeptide, wherein the antibody binds to an  S. epidermidis  capsular poly γ-D-L-glutamic acid (γDLPGA) polypeptide and inhibits an  S. epidermidis  infection. 
     
     
         34 . (canceled) 
     
     
         35 . A method of treating an infection caused by a  Staphylococcus  organism that secretes poly-γ-glutamic acid (γPGA), comprising:
 selecting a subject who is at risk of or has been diagnosed with the infection by the  Staphylococcus  organism which expresses poly-γ-glutamic acid (γPGA); and   interfering with secretion of a γPGA polypeptide by the organism.   
     
     
         36 . The method of  claim 35 , wherein interfering with the secretion of the γPGA comprises promoting an immune response against the γPGA of the organism, thereby promoting an effective immune response against the organism. 
     
     
         37 . The method of  claim 36 , wherein promoting the immune response against the γPGA comprises administering an effective amount of the conjugate of  claim 1 . 
     
     
         38 . The method of  claim 35 , wherein promoting the immune response against the γPGA comprises interfering with expression of the γPGA to increase immunodetection of the organism. 
     
     
         39 . The method of  claim 38 , wherein interfering with expression of the γPGA comprises inhibiting expression of the γPGA by cap genes. 
     
     
         40 . The method of  claim 36 , wherein promoting the immune response against the γPGA comprises administering an effective amount of anti-γPGA antibodies sufficient to enhance an immune response against the organism. 
     
     
         41 . The method of  claim 36 , wherein interfering with the secretion of the γPGA comprises promoting an immune response against poly-γ-D-L-glutamic acid (γDLPGA). 
     
     
         42 . The method of  claim 41 , wherein the γDLPGA includes γDPGA and γLPGA in substantially equivalent amounts. 
     
     
         43 . The method of  claim 35 , wherein interfering with the secretion of the γPGA avoids formation of a biofilm associated with the organism. 
     
     
         44 . The method of  claim 35 , wherein the organism is  S. capitis  or  S. warneri  or  S. saccharolyticus  or  S. caprae  or  S. hominis  or  S. haemolyticus  or  S. lugdunensis  or  S. simulans  or  S. epidermidis.    
     
     
         45 . The method of  claim 44 , where the organism is  S. epidermidis.    
     
     
         46 . The method of  claim 35 , wherein selecting the subject comprises selecting a subject who has an in-dwelling medical device.