Oral Presentation Melbourne Immunotherapy Network Winter Symposium 2021

Treatment with recombinant interleukin-22 protects against uropathogenic Escherichia coli-induced pyelonephritis in mice  (#18)

Guy Cameron 1 , Ben Lawrence 1 , Nirmal Bhatt 2 , Bernadette Jones-Freeman 2 , Aniruddh Deshpande 3 , Malcolm R Starkey 2
  1. School of Biomedical Sciences and Pharmacy, The Univesrity of Newcastle, Newcastle, NSW, Australia
  2. Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
  3. Pediatric Urology, Westmead Childrens Hospital, Sydney, NSW, Australia

Urinary tract infections (UTI) are one of the commonest bacterial infections in humans, particularly in the paediatric population. Pyelonephritis (kidney infection) is a common and serious consequence of UTI in children, which can cause sepsis, renal scarring and life-long kidney function impairment. Reinfection with the same uropathogen is common, indicating a lack of an appropriate immune response in the urinary tract. Additionally, antibiotic resistance in uropathogens is increasing globally. Therefore, it is critical to know when to use antibiotics appropriately and the value of combining these with new immunotherapies. We have identified interleukin (IL)-22 as a new factor driving susceptibility to pyelonephritis and impaired kidney function.

We show that IL-22 is increased in the serum and bladder of infected female C57BL/6 mice compared to sham-inoculated controls. Circadian rhythms impact IL-22 levels in female kidneys, with decreased IL-22 levels observed at night, suggesting the best time to treat with IL-22 immunotherapy is at night. IL-22 protein levels are significantly reduced in infected Rag2-/-gc-/- mice compared to infected wildtype mice, supporting the idea that the major sources of IL-22 are likely ILC3 and Th22 cells. IL-22 receptor is expressed in epithelial cells in the mouse bladder and kidney. Mice with pyelonephritis had significantly reduced IL-22 protein levels in kidney homogenates, correlating with increased bacterial load and weight loss. Infected mice with pyelonephritis had increased blood urea nitrogen (BUN) and decreased glomerular filtration rate (GFR), which are indicators of impaired kidney function, compared to infected mice without pyelonephritis. Intraperitoneal administration of recombinant mouse (rm) IL-22 after infection prevented the development of pyelonephritis. Treatment with rmIL-22 increased both total IL-22 protein and pSTAT3 levels in the mouse kidney, indicating increased IL-22 activity.  

This early preliminary data supports the idea that IL-22 may be suitable as a novel therapy for the treatment of pyelonephritis.