The dynamics of intra- and inter-organ communication during an acute kidney infection

Abstract: This thesis focuses on the roles of neuro-immune communication and infection-mediated coagulation during bacterial kidney infections. We demonstrate dynamic intra- and inter-organ host responses, where the outcome of an infection depends on both bacterial and host factors. Our full understanding of these interactions will enable us to improve diagnostics and develop new treatments of bacterial infections to aid us as we face the increasing threat of antibiotic resistance. Urinary tract infections (UTIs) are very common and Uropathogenic Escherichia coli (UPEC) is the most common causative pathogen. If bacteria reach the kidneys, they can cause a more severe form of UTI – pyelonephritis. Untreated pyelonephritis can lead to acute complications, such as bacteremia or urosepsis, as well as chronic complications due to kidney injury, which might result in chronic renal scarring. UPEC kidney infection triggers a number of host responses that are both local (intra-organ) and systemic (inter-organ), but many of these responses are still poorly understood. Using both in vitro and in vivo techniques we have studied the initial stages of host-pathogen interaction and different aspects of intra- as well as inter-organ signaling during UPEC kidney infection. Stemming from our experimental findings we also conducted an epidemiological study investigating infection-medicated coagulation in patients with acute pyelonephritis. Paper I and II focus on how the nervous system can sense a UPEC kidney infection and give rise to neuro-immune reflexes. By inducing in vivo UPEC kidney infections with high spatio-temporal precision, in Paper I we were able to zoom in on extremely early events and show that the spleen is activated within 4 h. This rapid inter-organ communication triggered by infection is enabled by intact nerve signaling to the spleen, and dependent on bacterial expression of the toxin α-hemolysin. Sensory nerves can be activated by ether direct contact with α-hemolysin, or indirect contact with the toxin as renal epithelial cells infected with strains expressing α-hemolysin release ATP that in turn activates neural responses. The splenic activation results in systemic Interferon-γ (IFNγ) release, and is found to modulate the inflammatory signaling at the infection site in the kidney. In Paper II we continue to show that the bacterial endotoxin lipopolysaccharide (LPS) has a differential role as an activator of both inflammatory and neural signaling during UPEC kidney infection. In vivo, UPEC infection triggers a release of the neurotransmitter calcitonin gene-related peptide (CGRP) in the infected kidney tissue, independent of the presence of α-hemolysin. Together with in vitro data from cell culture models we suggest that LPS triggers this local neuro-immune reflex. Collectively Papers I and II demonstrate that nerves can sense a UPEC kidney infection and initiate both distant and local neuro-immune reflexes that can modulate the immune responses at the site of infection. In parallel to activating the nervous system, UPEC kidney infections also trigger activation of the coagulation system. This infection-mediated coagulation is the focus of Papers III and IV. We have previously shown that coagulation occurs in peritubular capillaries as a rapid response to in vivo UPEC kidney infection. In Paper III, we investigate potential signaling mechanisms responsible for this response. Again, we show that two UPEC virulence factors may be involved in the signaling mechanisms behind the initiation of infection-mediated coagulation. The kinetics of the activation of coagulation in vivo is altered by the acylation state of the lipid A of UPEC LPS. Further, CD147 is released by renal proximal epithelial cells infected with UPEC expressing α-hemolysin, and was found to be a potential host factor involved in infection-mediated coagulation. We found that CD147 can activate tissue factor on endothelial cells, which indicates that it may initiate the first steps of the coagulation cascade. The infection-mediated coagulation has earlier been found to result in local ischemia in the kidney, but it has also been found to protect the host from progressing from a localized infection in the kidney to systemic spread through the blood stream. The protective role of coagulation seen during UPEC kidney infection in rodents suggests that patients prescribed antithrombotic treatments could be at higher risk of developing bacteremia or urosepsis. On the other hand, infection-mediated coagulation could contribute to ischemia induced kidney injury. Since an increasing number of patients are prescribed antithrombotic treatments, and UTIs are so common, mapping potential harms or benefits of antithrombotic treatment during kidney infections is clinically important. In Paper IV we conducted a retrospective cohort study to investigate the association between antithrombotic treatment and bacteremia or acute kidney injury in patients with acute pyelonephritis. We did not find any association between antithrombotic treatment and increased risk of bacteremia during acute pyelonephritis. Rather, low-molecular-weight heparin (LMWH) at prophylactic doses was associated with both a lower risk of bacteremia and a lower risk of acute kidney injury, compared to no antithrombotic treatment. Thus, our results suggest that it is safe to continue antithrombotic treatment during acute pyelonephritis, with regards to bacteremia and acute kidney injury.