Identifying blood-based markers for predicting recurrent urinary tract infection and developing personalized preventive immunotherapies – PredictUTI

Urinary tract infections (UTIs) are among the most common of all infections, impacting more than 130 million people annually, worldwide. Nearly 50% of otherwise healthy adult women will have one UTI, and half of them will experience recurrent infection. Despite the extreme prevalence and economic burden on health care systems, treatment options for UTI are surprisingly limited. Antibiotics are the only first line treatment for UTI, however, antibiotic efficacy is threatened by the rapid global dissemination of multi-drug resistant uropathogens. We aim to elucidate and validate variation in the human immune response that predicts susceptibility to UTI. Based on previous work, we hypothesize that innate immunity shapes the development of the adaptive response to UTI, and that biomarkers of increased risk for recurrence can be used to stratify patient populations for differential clinical outcome. We hypothesize that novel immunotherapeutic strategies specifically targeting immunity will reduce recurrent UTI.

We will perform a systems biology analysis of host risk factors for susceptibility to recurrent UTI capitalizing upon a well-defined healthy human cohort study, the Milieu Intérieur (MI). The MI cohort aims to understand variance in healthy human immune responses and as such has developed novel immuno-monitoring and analytical tools, including standardized whole blood stimulation systems, called TruCulture tubes, and a single step RNA extraction protocol from stimulated whole blood, which, combined with a Nanostring hybridization array readout, enables characterization of the induced transcriptomic responses. These systems are robust and reproducible and permit the standardized analysis of complex molecular pathways in response to ex vivo stimulation and are ideal for application to disease-based studies such as UTI.

We will test whether our unique biomarker signature of risk of recurrent UTI elaborated from the MI cohort can reliably identify individuals at risk in a prospective clinical study. This study will be nested within the i-Share cohort. This cohort was established to analyze aspects of student health and better understand mechanisms contributing to the occurrence of common diseases representing an important public health burden among 30,000 students at the Universities of Bordeaux and Nice Sophia Antipolis. Registered volunteers will be invited to participate via a secure website, providing information on their UTI history and a blood sample. Within the context of this study, we will recruit individuals with differential UTI histories with the hypothesis that genetic factors such as SNPs in immune loci, which subsequently influence innate immune responses, will be specifically enriched in one population over the other.

In parallel, we will perform mechanistic studies aimed at augmenting immunity to UTI using immunomodulatory approaches. The key concept that an immunomodulatory approach can improve the host response to bladder disease is well established for bladder cancer, however, the novelty in our proposal rests upon the application of tumor immunotherapy approaches to treat an infectious disease. Our aim is to increase the efficacy of the innate response such that stronger adaptive immunity develops, leading to improved protection against recurrent UTI.

As well as the potential to reveal novel mechanistic information regarding how immunity develops in the bladder, we believe that findings from our project will help in the identification and application of efficient treatments. Our ambition is to identify patients most at risk for recurrent UTI, to minimize repeated antibiotic use, and to establish foundational evidence for non-antibiotic based strategies to prevent recurrent UTI and improve the adaptive immune response to uropathogens.