Cyclic di-AMP induction of type I interferon
View Patent ↗Methods of modulating type-I interferon production in a cell are provided. Aspects of the methods include modulating cytosolic cyclic di-adenosine monophosphate (c-di-AMP) activity in the cell in a manner sufficient to modulate type-I interferon production in the cell. Additional aspects of the invention include c-di-AMP activity modulatory compositions, e.g., c-di-AMP, mutant Listeria bacteria, cyclase and/or phosphodiesterase nucleic acid or protein compositions, etc. The subject methods and compositions find use in a variety of applications, including therapeutic applications.
1. A method of modulating type-I interferon production in a eukaryotic cell, the method comprising:
introducing into the cell a bacterium that increases cytosolic cyclic di-adenosine monophosphate (c-di-AMP) activity in the eukaryotic cell in a manner sufficient to increase type-I interferon production in the cell,
wherein the bacterium is a mutant that has, as compared to its corresponding wild-type bacterium, at least one of:
(i) enhanced di-adenylate cyclase activity;
(ii) enhanced secretion of di-adenylate cyclase; and
(iii) reduced c-di-AMP phosphodiesterase activity.
2. The method according to claim 1 , wherein the bacterium is a Listeria bacterium.
3. The method according to claim 2 , wherein the Listeria bacterium is a mutant that secretes enhanced amounts of c-di-AMP as compared to its corresponding wild-type bacterium.
4. The method according to claim 3 , wherein the Listeria bacterium is a mutant that has enhanced di-adenylate cyclase activity as compared to its corresponding wild-type bacterium.
5. The method according to claim 4 , wherein the Listeria bacterium overexpresses Imo2120 or a mutant thereof.
6. The method according to claim 3 , wherein the Listeria bacterium is a mutant that has reduced c-di-AMP phosphodiesterase activity as compared to its corresponding wild-type bacterium.
7. The method according to claim 6 , wherein the Listeria bacterium comprises an Imo0052 mutation.
8. The method according to claim 2 , wherein the bacterium is a mutant with enhanced secretion of di-adenylate cyclase as compared to its corresponding wild-type bacterium.
9. The method according to claim 8 , wherein the di-adenylate cyclase is Imo2120 or a mutant thereof.
10. The method according to claim 1 , wherein the method comprises enhancing cytosolic di-adenylate cyclase activity in the cell.
11. The method according to claim 10 , wherein the method comprises overexpressing a polypeptide having di-adenylate cyclase activity.
12. The method according to claim 1 , wherein the cell is a macrophage.
13. The method according to claim 1 , wherein the type-I interferon is interferon-β.
14. The method according to claim 1 , wherein the cell is in vitro.
15. A mutant Listeria bacterium comprising a mutation which enhances secretion of a compound selected from the group consisting of: cytosolic di-adenylate cyclase or c-di-AMP phosphodiesterase and combinations thereof; as compared to its corresponding wild-type control.
16. A method for modulating interferon-β production in a mammalian subject, the method comprising: administering to the mammalian subject an effective amount of a Listeria bacterium according to claim 15 .
17. The Listeria bacterium according to claim 15 , wherein the mutation enhances di-adenylate cyclase activity in the bacterium.
18. The Listeria bacterium according to claim 17 , wherein the mutation is an Imo2120 mutation that enhances the expression of Imo2120.
19. The Listeria bacterium according to claim 15 , wherein the mutation enhances secretion of cytosolic di-adenylate cyclase.
20. The Listeria bacterium according to claim 19 , wherein the bacteria overexpresses Imo2120 or a mutant thereof.
21. The Listeria bacterium according to claim 15 , wherein the Listeria bacterium is Listeria monocytogenes.
22. The Listeria bacterium according to claim 15 , wherein the Listeria bacterium is attenuated.
23. The Listeria bacterium according to claim 17 , wherein the Listeria bacterium increases interferon-β production in macrophages as compared to its corresponding wild-type control.
24. The Listeria bacterium according to claim 15 , wherein the bacterium comprises a heterologous nucleic acid.
25. The Listeria bacterium according to claim 24 , wherein the heterologous nucleic acid is integrated.
26. The Listeria bacterium according to claim 24 , wherein the heterologous nucleic acid encodes at least one product.
27. The Listeria bacterium according to claim 26 , wherein the at least one product is an antigen.