Genetic Control of the Variable Innate Immune Response to Asymptomatic Bacteriuria

Abstract

The severity of urinary tract infection (UTI) reflects the quality and magnitude of the host response. While strong local and systemic innate immune activation occurs in patients with acute pyelonephritis, the response to asymptomatic bacteriuria (ABU) is low. The immune response repertoire in ABU has not been characterized, due to the inherent problem to distinguish bacterial differences from host-determined variation. In this study, we investigated the host response to ABU and genetic variants affecting innate immune signaling and UTI susceptibility. Patients were subjected to therapeutic urinary tract inoculation with E. coli 83972 to ensure that they were exposed to the same E. coli strain. The innate immune response repertoire was characterized in urine samples, collected from each patient before and after inoculation with bacteria or PBS, if during the placebo arm of the study. Long-term E. coli 83972 ABU was established in 23 participants, who were followed for up to twelve months and the innate immune response was quantified in 233 urine samples. Neutrophil numbers increased in all but two patients and in an extended urine cytokine/chemokine analysis (31 proteins), the chemoattractants IL-8 and GRO-α, RANTES, Eotaxin-1 and MCP-1, the T cell chemoattractant and antibacterial peptide IP-10, inflammatory regulators IL-1-α and sIL-1RA and the T lymphocyte/dendritic cell product sIL-2Rα were detected and variably increased, compared to sterile samples. IL-6, which is associated with symptomatic UTI, remained low and numerous specific immune mediators were not detected. The patients were also genotyped for UTI-associated IRF3 and TLR4 promoter polymorphisms. Patients with ABU associated TLR4 polymorphisms had low neutrophil numbers, IL-6, IP-10, MCP-1 and sIL-2Rα concentrations. Patients with the ABU-associated IRF3 genotype had lower neutrophils, IL-6 and MCP-1 responses than the remaining group. The results suggest that the host-specific, low immune response to ABU mainly includes innate immune mediators and that host genetics directly influence the magnitude of this response.

Molecular Analysis of Asymptomatic Bacteriuria Escherichia coli Strain VR50 Reveals Adaptation to the Urinary Tract by Gene Acquisition

“…Despite equivalent adherence to epithelial cells, E. coli CFT073 triggered a significantly stronger IL-6 cytokine response than E. coli VR50. This property may be associated with the ability of E. coli VR50 to colonize the bladder in high numbers without provoking a host inflammatory response and is consistent with the low IL-6 response observed in individuals deliberately colonized with E. coli 83972 (89). It remains to be determined if VR50 is able to suppress RNA polymerase II-dependent host gene expression, as has been reported recently for E. coli 83972 (19).…”

The innate immune response during urinary tract infection and pyelonephritis

“…IL-10 deficient mice have higher bacterial loads in the bladder, urine and kidney compared to controls [31]. Other cytokines/chemokines have been implicated in various UTI models and patient populations including IL-1, RANTES/CCL5, MCP-1, TNF-α, IFN-α [10,32]. …”

Bacterial control of host gene expression through RNA polymerase II

“…The urinary tract response to E. coli 83972 inoculation in a placebo-controlled study was previously examined (18) and low, but detectable, increases in urinary neutrophils and cytokines were observed. These responses were below the levels reported during symptomatic UTIs (19,20).…”