UPEC kidney infection triggers neuro-immune communication leading to modulation of local renal inflammation by splenic IFNγ.

Bacterial infection results in a veritable cascade of host responses, both local and systemic. To study the initial stages of host-pathogen interaction in living tissue we use spatially-temporally controlled in vivo models. Using this approach, we show here that within 4 h of a uropathogenic Escherichia coli (UPEC) infection in the kidney, an IFNγ response is triggered in the spleen. This rapid infection-mediated inter-organ communication was found to be transmitted via nerve signalling. Bacterial expression of the toxin α-hemolysin directly and indirectly activated sensory neurons, which were identified in the basement membrane of renal tubules. Nerve activation was transmitted via the splenic nerve, inducing upregulation of IFNγ in the marginal zones of the spleen that led to increasing concentrations of IFNγ in the circulation. We found that IFNγ modulated the inflammatory signalling generated by renal epithelia cells in response to UPEC infection. This demonstrates a new concept in the host response to kidney infection; the role of nerves in sensing infection and rapidly triggering a systemic response which can modulate inflammation at the site of infection. The interplay between the nervous and immune systems is an exciting, developing field with the appealing prospect of non-pharmaceutical interventions. Our study identifies an important role for systemic neuro-immune communication in modulating inflammation during the very first hours of a local bacterial infection in vivo. Author summary: Our understanding of how the host responds to bacterial infection is constantly evolving. Here we use complex animal and cell culture models to demonstrate how nerves can sense a bacterial infection in the kidney and transmit that information to the spleen within a few hours. We show that the bacterial toxin α-hemolysin is a trigger for the nervous reflex which leads to increased IFNγ production in the spleen, which can be detected in the blood. IFNγ, in turn, modulates how the kidney cells respond to bacterial infection. Our work identifies a new role for nerves in sensing a local bacterial infection and rapidly activating a modulating systemic immune response within the very first hours of infection. Nerve driven immunity during bacterial infection is an expanding field. Here we contribute by highlighting a potential for nerves in monitoring and modulating the immune response during the early hour of infection. Understanding all interplaying factors of infection is crucial as we search for alternative targets for diagnosis or treatment of infection in the face of a post-antibiotic era. [ABSTRACT FROM AUTHOR]