Immune homeostasis during Borrelia burgdorferi infection

About This Grant

SUMMARY Infections can have a significant negative impact on a person’s health even long after the pathogen is cleared from the host. Borrelia burgdorferi (Bb) the causative agent of Lyme disease causes persistent, non-resolving infections in laboratory mice. Previous work has identified significant immune suppression in infected mice, explaining the lack of bacterial clearance. This study is to explore our unexpected finding that Bb infection of mice causes a “leaky gut syndrome”, including endotoxemia, changes to the gut microbiome and fecal short- chain fatty acids. The mice demonstrate extensive hyper-gammaglobulinemia, including increased autoreactive IgG that appear resistant to antibiotic treatment and they lack the ability to generate robust T-dependent antibody responses, suggesting significant long-term effects on humoral immunity that may not resolve with the removal of the pathogen. The objective of this proposal is to define the impact of Bb infection-induced changes in gastrointestinal barrier function and microbiota on immune system health. Specifically, we will test our hypothesis that Bb infection-induced gut barrier dysfunction, dysbiosis, and endotoxemia result in prolonged immune dysfunction, affecting immune system health and the induction of protective immunity. Specific Aim 1 is to define the impact of Bb infection-induced gut barrier disruption on immune system health, testing the extent to which Bb infection-induced changes to the gut barrier alone contribute to Bb infection-induced alterations in immune homeostasis and its impact on Bb growth. Specific Aim 2: will determine the effects of Bb infection-induced changes to the gastrointestinal microbiome on host immune function. To separate effects of Bb infection from those of Bb-induced alterations to the microbiome, we will conduct fecal matter transfer experiments to assess effects on endotoxemia, gut permeability, hyper-IgG induction, T-dependent humoral immunity, and the ability to control early Bb dissemination. In Specific Aim 3 we aim to explore the impact of Bb infection on the host metabolome and how this in turn affect immune system health. This will be done by comprehensively measuring Bb-induced changes to the metabolome and assess these changes for their impact on immune homeostasis and immune system health. Thus, the study aims to pursue an innovative new concept of what may underlie the ineffective immune responses to Bb. Expected results would provide significant mechanistic insights and data in support of future human clinical studies and the development of therapeutic approaches that could reduce the effects of infection on short and long-term health.