Genetics of innate immunity and UTI susceptibility

Abstract

A functional and well-balanced immune response is required to resist most infections. Slight dysfunctions in innate immunity can turn the 'friendly' host defense into an unpleasant foe and give rise to disease. Beneficial and destructive forces of innate immunity have been discovered in the urinary tract and mechanisms by which they influence the severity of urinary tract infections (UTIs) have been elucidated. By modifying specific aspects of the innate immune response to UTI, genetic variation either exaggerates the severity of acute pyelonephritis to include urosepsis and renal scarring or protects against symptomatic disease by suppressing innate immune signaling, as in asymptomatic bacteriuria (ABU). Different genes are polymorphic in patients prone to acute pyelonephritis or ABU, respectively, and yet discussions of UTI susceptibility in clinical practice still focus mainly on social and behavioral factors or dysfunctional voiding. Is it not time for UTIs to enter the era of molecular medicine? Defining why certain individuals are protected from UTI while others have severe, recurrent infections has long been difficult, but progress is now being made, encouraging new approaches to risk assessment and therapy in this large and important patient group, as well as revealing promising facets of 'good' versus 'bad' inflammation.

Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo

“…Innate immune cells, particularly macrophages and neutrophils, constitute an early line of defense against UPEC infection in vivo (25). We reasoned that Atg16L1 deficiency in these cells might contribute to the observed fast clearance of bacteriuria.…”

“…During the acute stage of infection (0-72 h), intracellular UPEC replicates rapidly and establishes cytoplasmic biofilms termed intracellular bacterial communities (IBCs) in bladders of both mice and humans (21,22). Major mechanisms for control of UPEC-induced UTI include exfoliation of the superficial epithelial cell layer containing IBCs into the urine and influx of innate immune cells (23)(24)(25)(26). However, despite the innate immune host response, a subset of UPEC still survives and establishes long-term reservoirs within urothelial cells, termed quiescent intracellular reservoirs (QIRs) (27), which are enclosed within vesicles decorated with late endosomal/lysosomal markers.…”

Bacterial control of host gene expression through RNA polymerase II

“…Bacterial pathogens, in contrast, gain a short-term advantage at these sites by expressing virulence factors that can dysregulate a range of host signaling pathways (5). Their virulence repertoire includes a diverse array of molecules that trigger specific host cell receptors and signaling pathways or inactivate the host defense, including capsules, complement inactivators (6,7), and secreted inhibitors of Toll-like receptor (TLR) and MyD88 signaling (8,9).…”

“…Their virulence repertoire includes a diverse array of molecules that trigger specific host cell receptors and signaling pathways or inactivate the host defense, including capsules, complement inactivators (6,7), and secreted inhibitors of Toll-like receptor (TLR) and MyD88 signaling (8,9). The failure of asymptomatic carrier strains to trigger disease-associated signaling pathways and pathology has generally been attributed to their lack of virulence (5,10,11). It is not clear if, in addition, asymptomatic carrier strains actively enhance their own persistence by modifying the host environment.…”

LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria

“…These urinary tract infections (UTIs) are most commonly caused by uropathogenic Escherichia coli (UPEC) 1,2 . UPEC can invade kidney tissue and specifically bind to the apical surface of collecting duct cells 3 .…”