PD32-07: Microbial Exposure Reduces Susceptibility to Uropathogenic E. Coli (UPEC)-Induced Urosepsis

Matthew Martin*, Whitney Swanson, Tamara Kucaba, Minneapolis, MN, Vladimir Badovinac, Iowa City, IA, Molly Ingersoll, Paris, France, Thomas Griffith, Minneapolis, MN

Introduction: Urinary tract infections (UTIs) are the most prevalent infectious disease of the bladder – affecting >130 million people worldwide annually. Uropathogenic E. coli (UPEC) causes most UTIs, starting with bladder colonization and then ascension to the kidneys. In severe cases of pyelonephritis, bacteria can enter the bloodstream, causing urosepsis. The immune system is involved in the development of these pathologies, but little is known about how the basal immune state influences the ability to respond to systemic UPEC infection (urosepsis). Most preclinical studies are conducted with specific pathogen-free (SPF) mice, which possess a largely naïve immune system like neonatal humans. Cohousing (CoH) SPF mice with microbially diverse pet store mice matures the immune system to resemble that of adult humans. Thus, the objective of these studies is to determine how prior microbial exposure affects the immune response to systemic UPEC infection modeling urosepsis.

Methods: For these studies, we infected SPF and CoH mice with UPEC strain UTI89 systemically via intravenous injection. Immune responses, bacterial clearance, and survival following infection was monitored.

Results: Interestingly, we found CoH were less susceptible  to mortality following systemic infection and cleared UPEC at a faster rate than SPF mice. Following infection, greater numbers of neutrophils, macrophages, CD4 T cells, and antigen-experienced CD8 T cells, and higher amounts of inflammatory cytokines including IFNg were found in the circulation of CoH mice vs. SPF mice. Upon immune cell subset depletion, macrophage-depleted CoH mice showed enhanced mortality to infection similar to SPF mice, and macrophage-depleted CoH mice cleared infection at a slower rate than intact CoH mice, suggesting macrophages are responsible for enhanced protection from systemic UPEC infection in CoH mice. RNA sequencing of macrophages from SPF and CoH mice revealed that microbial exposure alters the macrophage transcriptional profile and suggested cohousing results in a program of innate immunity training.

Conclusions: Our results have important implications in the study of urosepsis, as the data suggest a general history of microbial exposure dramatically alters innate immunity and reduces susceptibility to systemic UPEC infection. While these studies further our understanding of the immune response initiated after systemic UPEC infection, they also suggest mouse studies incorporating exposure to diverse infections may provide a more clinically relevant experimental urosepsis model.

Source of Funding: American Urological Association Research Scholar Award (MDM)

NIH R21 AI154527-01A1 (TSG)