Abstract: TH-PO278

Sensing of Bacterial Infection by Nerves and the Induction of Inter-Organ Communication during the First Hours of Pyelonephritis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Steiner, Svava E, Karolinska Institutet, Stockholm, Sweden
  • Choong, Ferdinand X, Karolinska Institutet, Stockholm, Sweden
  • Schulz, Anette, Karolinska Institutet, Stockholm, Sweden
  • Melican, Keira, Karolinska Institutet, Stockholm, Sweden
  • Svensson, Camilla, Karolinska Institutet, Stockholm, Sweden
  • Richter-Dahlfors, Agneta, Karolinska Institutet, Stockholm, Sweden
Background

Tissue microbiological studies have revealed that inter-organ communication occurs within the first hours of pyelonephritis. IFN-γ released from the spleen is known to modulate the host responses at the site of renal infection within 8 h. We hypothesize that this rapid inter-organ signaling is, at least in part, mediated by the nervous system. Here we investigate nervous sensing of the bacterial infection and implicate nervous signals as mediators of the inter-organ communication between infected kidney and the responding spleen.

Methods

GFP+-expressing uropathogenic Escherichia coli (UPEC) were microinfused into single proximal tubules in exposed kidneys of anesthetized rats. After 4 h the infection site was examined by ex vivo immunofluorescence (IF) analysis. Nervous projections in the renal cortex were identified through IF analysis of fixed, uninfected rat renal tissue. Splenic Ifng mRNA expression was determined by qPCR on splenic tissue. Cytokine and ATP release of UPEC infected renal epithelial cells (A498) were investigated in cell culture in vitro. Primary sensory nerve cells from mice were used to determine immune and nervous responses to UPEC infection.

Results

Despite the very localized nature of the infection, splenic Ifng expression was found to be upregulated already within 4 h of kidney infection. We found that sensory nerves are present in the basement membrane of proximal tubules, where they can come into close contact with infection related products. In vitro we found that primary mouse sensory nerves can detect pathogen-associated molecular patterns and damage-associated molecular patterns during infection and have both immunological IL-6, and nervous CGRP, responses. In cell culture, nervous responses were found to only occur during infection with bacteria that produce the toxin α-haemolysin. Translating this finding in vivo, we found that inter-organ communication was abrogated in animals infected with a UPEC strain that does not produce α-haemolysin.

Conclusion

Our work shows the role of the sensory nervous system in sensing a local infection in the kidney and alerting distal organs to alter the systemic host response. Bacterial production of the α-haemolysin toxin plays an important role in initiating such an alerting signal.

Funding

  • Government Support - Non-U.S.