METHODS FOR TREATING INFLAMMATORY BOWEL DISEASE BASED ON HOST-MYCOBIOTA INTERACTIONS

Abstract

Disclosed herein are methods for selecting a patient suffering from fungal-associated intestinal inflammation for treatment with an IL-1 pathway inhibitor, including inflammasome-blocking drugs based on the presence of candidalysin-secreting C. albicans strains in gut tissue.

Description

Claims

1. A method for treating a patient suffering from a fungal-associated intestinal inflammatory disorder comprising administering to the patient an effective amount of an IL-1 pathway inhibitor, wherein gut tissue of the patient comprises a population of candidalysin-secreting C. albicans.

2. A method for selecting a patient suffering from a fungal-associated intestinal inflammatory disorder for treatment with an IL-1 pathway inhibitor comprising (a) detecting the presence of candidalysin-secreting C. albicans in a biological sample obtained from the patient; and(b) administering to the patient an effective amount of an IL-1 pathway inhibitor.

3. The method of claim 2, wherein the biological sample is a colonic mucosa-enriched lavage sample, a fecal sample, a rectal swab, or an intestinal sample.

4. The method of claim 1, wherein the fungal-associated intestinal inflammatory disorder is inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC).

5. The method of claim 1, wherein the IL-1 pathway inhibitor is an inflammasome-blocking drug, an anti-IL-1R1 antibody or antigen binding fragment, Anakinra, Rilonacept, Canakinumab, Gevokizumab, LY2189102, MABp1, MEDI-8968, CYT013, sIL-1RI, sIL-1RII, EBI-005, CMPX-1023, MCC950, Inzomelid, Somalix, NT-0167, IFM-2427 (DFV890), Dapansutrile (OLT1177), glyburide, 16673-34-0, JC124, FC11A-2, parthenolide, Bay 11-7082, BHB, MNS, CY-09, tranilast, oridonin, VX-740, or VX-765.

6. The method of claim 1, wherein the candidalysin-secreting C. albicans expresses elevated enhanced filamentous growth protein 1 (EFG1) expression compared to a reference non-filamentous C. albicans strain or a predetermined threshold.

7. The method of claim 1, wherein the candidalysin-secreting C. albicans expresses increased hyphae production relative to a reference non-filamentous C. albicans strain.

8. The method of claim 1, wherein the candidalysin-secreting C. albicans expresses elevated expression levels of at least one protease selected from among SAP6, SAP5, or SAP2 compared to a reference non-filamentous C. albicans strain or a predetermined threshold.

9. The method of claim 1, wherein the candidalysin-secreting C. albicans expresses elevated expression levels of ALS3 or ALS1 compared to a reference non-filamentous C. albicans strain or a predetermined threshold.

10. The method of claim 6, wherein the reference non-filamentous C. albicans strain is an efg1Δ/Δ C. albicans mutant strain.

11. The method of claim 1, wherein the candidalysin-secreting C. albicans induces an in vivo proinflammatory response in host cells.

12. The method of claim 11, wherein the in vivo proinflammatory responses comprises neutrophil infiltration and/or Th17 responses in the colon of the patient.

13. A kit comprising (a) an expression vector comprising a nucleic acid sequence encoding a Candida-compatible Cas9 nuclease and a nucleic acid sequence encoding a synthetic guide RNA (sgRNA) that is configured to cleave a region in a target gene of at least one C. albicans strain that resides in human gut tissue, wherein the target gene is associated with high immune cell-damaging capacity and wherein the at least one C. albicans strain induces proinflammatory immunity in a human subject; and(b) a heterologous repair template nucleic acid sequence comprising (i) a 5′ region that is homologous to a C. albicans nucleic acid sequence that is upstream or downstream from the region in the target gene that is cleaved by the sgRNA and (ii) a 3′ region comprising an open reading frame (ORF) deletion of the target gene.

14. The kit of claim 13, wherein the 5′ region of the heterologous repair template nucleic acid sequence is about 60 base pairs in length.

15. The kit of claim 13, wherein the 3′ region of the heterologous repair template nucleic acid sequence is about 20 base pairs in length.

16. The kit of claim 13, wherein the human subject is suffering from inflammatory bowel disease.