Compositions and methods for preventing and treating infection
The present invention encompasses compositions and methods useful to treat or prevent Clostridium difficile antibiotic-associated colitis through administration of IL-25 and/or downstream cytokines IL-13, IL-4, and IL-5. It is disclosed herein that IL-25 expression is decreased during antibiotic treatment and during bacterial infection and that treatment with IL-25 protein is protective during infection. It is further disclosed herein the unexpected result that IL-25 treatment protects against C. difficile -associated mortality and morbidity. The present application further describes an unexpected result regarding eosinophils and their role in combating infection and their relationship to the effectiveness of IL-25.
1. A method for treating a Clostridium difficile ( C. difficile ) infection in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically-acceptable carrier, an effective amount of IL-25 and optionally an additional therapeutic agent, thereby treating said C. difficile infection.
2. The method of claim 1 , wherein said IL-25 is recombinant IL-25.
3. The method of claim 1 , wherein said method increases survival of said subject.
4. The method of claim 3 , wherein said method increases survival of said subject by about 10% to about 68% compared to a subject not receiving said treatment.
5. The method of claim 4 , wherein said method increases survival of said subject by about 45% compared to a subject not receiving said treatment.
6. The method of claim 1 , wherein said method stimulates eosinophil recruitment to lamina propria of the intestine.
7. The method of claim 6 , wherein said method induces IL-4 synthesis in said eosinophils.
8. The method of claim 1 , wherein said method stimulates eosinophil recruitment or levels in the colon.
9. The method of claim 1 , wherein said method stimulates mucin expression.
10. The method of claim 9 , wherein said mucin expression increases in lamina propria.
11. The method of claim 1 , wherein said method stimulates IL-10 expression.
12. The method of claim 1 , wherein said subject is susceptible to a C. difficile infection.
13. The method of claim 12 , wherein said subject is pretreated to reduce the severity of a C. difficile infection if said infection occurs in the subject.
14. The method of claim 13 , wherein when said subject is pretreated and said subject becomes infected with C. difficile , said method reduces morbidity and mortality.
15. The method of claim 13 , wherein said method increases survival of said subject by about 10% to about 68% compared to a subject not receiving said treatment.
16. The method of claim 15 , wherein said method increases survival of said subject by about 45% compared to a subject not receiving said treatment.
17. The method of claim 1 , wherein said method inhibits epithelial disruption by C. difficile in the colon.
18. The method of claim 17 , wherein said method does not alter the C. difficile burden.
19. The method of claim 17 , wherein said method does not stimulate neutrophil recruitment.
20. The method of claim 1 , wherein said method decreases IL-23 expression or levels.
21. The method of claim 1 , wherein said IL 25 is administered at a dose of about 1.0 μg IL-25/kilogram (kg) body weight to about 2500 μg IL-25/kg body weight.
22. The method of claim 21 , wherein said IL 25 is administered at a dose of about 10 μg IL-25/kg body weight to about 1500 μg IL-25/kg body weight.
23. The method of claim 22 , wherein said IL 25 is administered at a dose of about 25 μg IL-25/kg body weight to about 500 μg IL-25/kg body weight.
24. The method of claim 1 , wherein said IL 25 is administered at a dose of about 25 μg IL-25/kg body or about 62.5 μg IL-25/kg body weight.
25. The method of claim 1 , wherein said method reduces recurrent C. difficile infection in a subject susceptible to recurrent infection.
26. The method of claim 1 , wherein said method reduces C. difficile infection in a subject susceptible to said infection following prior antibiotic therapy.
27. The method of claim 1 , wherein said method reduces C. difficile infection in a subject susceptible to said infection following H-2 blocker therapy or stem cell transplant.
28. The method of claim 1 , wherein said method reduces C. difficile associated colitis.
29. The method of claim 28 , wherein said subject received prior antibiotic therapy.
30. The method of claim 29 , wherein said subject is infected with C. difficile.
31. A method for treating a C. difficile infection in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically-acceptable carrier, an effective amount of a stimulator of eosinophil recruitment in the gut or an effective amount of an inducer of IL-4 production by eosinophils in the intestine, wherein the stimulator of eosinophil recruitment in the gut or the inducer of IL-4 production is IL-25 and optionally an additionally therapeutic agent, thereby treating said C. difficile infection.