Targeting immunological functions to the site of bacterial infections using cell wall targeting domains of bacteriolysins
This disclosure provides a comprehensive approach to specifically target various immune functions to the site of infection by a variety of fusion proteins that consist of a bacteriolysin cell wall targeting domain (CWT) and an immune function mediating component (IFMC). The CWT targets the fusion protein to the bacterial surface leading to accumulation at the site of infection. The IFMC mediates various immune functions such as toxin neutralization or recruitment of immune cells that can clear the bacteria.
1. A method for treating a bacterial infection, disease, or disorder, comprising administering to a subject in need of treatment an effective amount of a therapeutic polypeptide comprising a cell wall targeting (CWT) domain of a bacteriolysin fused to an immune function mediating component (IFMC) through a peptide linker:
wherein the bacteriolysin is a bacteriocin selected from the group consisting of: Lysostaphin, Bacteriocin AS-48, Bacteriocin ColE9, adherence binding domain DSL peptides of the pilin protein, an E-colicin, Autolysin, and the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme, or
wherein the bacteriolysin is a phage encoded lysin selected from the group consisting of: Phage phiKZ gp144 lysin, ϕNM3 lysin, ϕ11 lysin, ϕ68 P17 lysin, ϕB30 lysin, OK LysK lysin, ϕ MR11 MV-L lysin, ϕSs2 PlySs2bacteriophage lysin, OBPgp279 endolysin, PVP-SE1gp146 lysin, E201φ2-1gp229 lysin, Endolysin PlyL, Endolysin PlyG, LambdaSa2 cpl-7 lysin, bacteriophage SM1 lysin, Endolysin CD27L, and mycobacteriophage Ms6 lysin,
wherein the IFMC comprises an antibody or antigen binding fragment thereof to a bacterial toxin or toxoid, or a fragment thereof, wherein the antibody or antigen binding fragment thereof lacks the ability to recognize a bacterial cell wall, and wherein the CWT domain of the therapeutic polypeptide can target the IFMC to a bacterial target.
2. The method of claim 1 , wherein the disease is a respiratory disease.
3. The method of claim 2 , wherein the respiratory disease is pneumonia.
4. The method of claim 1 , wherein the disease is sepsis.
5. The method of claim 1 , wherein the subject is a human.
6. The method of claim 1 , wherein the therapeutic polypeptide or composition is administered via intramuscular injection, intradermal injection, intraperitoneal injection, subcutaneous injection, intravenous injection, oral administration, mucosal administration, intranasal administration, or pulmonary administration.
7. The method of claim 1 , wherein the bacterial toxin or toxoid comprises a Staphylococcus aureus toxin, a Clostridium difficile toxin A (TcdA), a Clostridium difficile toxin B (TcdB), a Clostridium perfringens toxin, a Bacillus anthracis toxin, a Clostridium diphtheria toxin, an E. coli toxin, a Pseudomonas exoprotein A (EPA) or other Pseudomonas aeruginosa toxin, a Vibrio cholerae toxin, a Klebsiella pneumoniae toxin, a pneumolysin or other Streptococcus pneumoniae toxin, a streptolysin, an Enterococcus faecalis toxin, a tetanus toxoid, a pertussis toxoid, a diphtheria toxoid, or a fragment thereof.
8. The method of claim 7 , wherein the Staphylococcus aureus toxin comprises a superantigen, a staphylococcal enterotoxin, a toxic shock syndrome toxin 1 (TSST-1), an alpha hemolysin, a gamma hemolysin, a leukocidin, or any fragment thereof.
9. The method of claim 1 wherein the therapeutic peptide further comprises a heterologous amino acid sequence.
10. The method of claim 9 , wherein the heterologous amino acid sequence encodes an immunogen, a T-cell epitope, a B-cell epitope, a fragment of any of said heterologous peptides, and a combination of two or more of said heterologous peptides.
11. The method of claim 1 , comprising administering the therapeutic polypeptide and a carrier.
12. The method of claim 1 , wherein the bacteriolysin is the bacteriocin Lysostaphin and the bacterial toxin is a Staphylococcus aureus alpha hemolysin toxin, or a toxoid and/or fragment thereof.
13. The method of claim 1 , wherein the bacteriolysin is the phage encoded lysin Endolysin PlyL and the bacterial toxin is a Bacillus anthracis toxin, or a toxoid and/or fragment thereof.
14. The method of claim 1 , wherein the bacteriolysin is the phage encoded Endolysin CD27L and the bacterial toxin is a Clostridium difficile toxin A (TcdA), or a toxoid and/or fragment of TcdA.
15. The method of claim 1 , wherein the bacteriolysin is the phage encoded lysin Endolysin PlyG and the bacterial toxin is a Bacillus anthracis toxin, or a toxoid and/or fragment thereof.
16. The method of claim 1 , wherein the bacteriolysin is the phage encoded Endolysin CD27L and the bacterial toxin is a Clostridium difficile toxin B (TcdB), or a toxoid and/or fragment of TcdB.
17. The method of claim 1 , wherein the bacteriolysin is the phage encoded ϕSs2 PlySs2bacteriophage lysin, and the bacterial toxin is a pneumolysin, or a toxoid and/or fragment thereof.
18. The method of claim 1 , wherein the bacteriolysin is the phage encoded bacteriophage SM1 lysin, and the bacterial toxin is a pneumolysin, or a toxoid and/or fragment thereof.
19. The method of claim 1 , wherein the bacteriolysin is the phage encoded ϕSs2 PlySs2bacteriophage lysin, and the bacterial toxin is a Streptococcus pneumoniae toxin other than a pneumolysin, or a toxoid and/or fragment thereof.
20. The method of claim 1 , wherein the bacteriolysin is the phage encoded bacteriophage SM1 lysin, and the bacterial toxin is a Streptococcus pneumoniae toxin other than a pneumolysin, or a toxoid and/or fragment thereof.