Urinary Tract Infection
Urinary tract infections (UTIs) are one of the most common bacterial infections, causing considerable morbidity in females. Infection is highly recurrent despite appropriate antibiotic treatment. 50% of all women will have a UTI at some point in their lifetime. 20-40% of these women will suffer recurrences of UTI with serious deterioration in the quality of life including pain and discomfort, disruption of daily activities, increased healthcare costs, and few treatment options other than long-term antibiotic prophylaxis. Disturbingly, multi-drug resistant uropathogens are becoming more prevalent and globally distributed making UTI an increasingly pressing public health concern. In our interdisciplinary research program, we have combined clinical and basic science approaches to detail a highly complex acute pathogenic cycle for uropathogenic Escherichia coli (UPEC), the most common causative agent of UTIs and the host response to infection. Our work has led to an increased understanding of UTIs including molecular mechanisms of susceptibility, establishment and progression of disease, epidemiology and determination of factors that influence disease outcomes and sequelae.
Collaborators: Thomas “Mac” Hooton, Ann Stapleton, Macro Colona.
UPEC Pathogenesis: Using our mouse model of urinary tract infection, we have delineated an acute pathogenic cascade that initiates when UPEC enter the mammalian bladder. Using type 1 pili, UPEC adhere to mannosylated residues on the bladder surface and invade into the superficial epithelial cells of the bladder. UPEC then enter the cytoplasm and rapidly replicate to form large intracellular bacterial communities (IBCs), with >104 bacteria per mature IBC within a few hours of invasion. IBCs are transient in nature. Once they mature bacteria detach from the IBC and flux out of the host cell and go on to infect new host cells, repeating the IBC cycle. This pathway allows UPEC to gain a foothold in the host, building up in numbers in an intracellular niche protected from much of the host immune response. Further, UPEC filamentation upon fluxing from the IBC allows UPEC to resist the action of neutrophils in the bladder lumen. We have found that this cycle is critical for establishment of infection in naive animals and clinical studies have shown evidence of both IBCs and bacterial filaments in humans. Currently, work determining bacterial mechanisms important in promoting the IBC cycle and long-term colonization of the bladder by UPEC are elucidating important aspects of disease progression and potential therapeutic targets.
Host Response: The host response to UPEC infection is a complex process that involves exfoliation of epithelial cells, release of cytokines and chemokines and the influx of inflammatory cells into the bladder. Bladder epithelial cells, which normally turn over only once in ~6 months, can be shed upon infection and regenerated within ~48hrs. This process involves TLR4 and cell death pathways within the superficial facet cells of the bladder, which are triggered by infection, and an upregulation of differentiation pathways in the underlying transitional epithelial cells. The resultant shedding of infected superficial facet cells is an important defense to expel bacteria from the bladder in the urine stream. However, this shedding also exposes underlying epithelial cells to infection. Elaboration of pro-inflammatory molecules such as interleukin 6 (IL-6) and granulocyte chemotactic cytokines such as IL-8 are observed in human urine during acute UTI and in our murine models. We are currently further delineating the epithelial response to infection and correlations between the levels of host response to infection and the outcome of infection. In addition we are investigating the role that differing microbiomes have on the host response to infection of the urinary tract. These studies are elucidating potentially important avenues of study for clinical susceptibility to deleterious disease outcomes, such as chronic infection and frequent recurrent UTIs. Collaborators: Marco Colona, Ashlee Earle
Recurrent and Chronic UTI: Reflective of different disease manifestations in humans, the outcome of experimental UPEC infection differs among inbred mouse strains. We find, in C57BL/6 mice, that quiescent intracellular reservoirs (QIRs) form in the bladder within 7-10 days of acute infection. QIRs are distinct from IBCs and are comprised of fewer than 15 bacteria persisting in a membrane-bound dormant state within transitional epithelial cells. QIRs are capable of emerging from dormancy to cause recurrent infections and bacteriuria and may represent one mechanism for recurrent UTI (rUTI) in humans. In contrast to C57BL/6 mice, C3H and CBA background mouse strains upon single inoculation of bacteria are susceptible to long-lasting, chronic cystitis characterized by persistent, high titer bacteriuria (>104 colony forming units (CFU)/ml), as well as high titer bacterial bladder burdens at sacrifice >4 weeks post-infection (wpi), chronic inflammation, and urothelial necrosis. Severe pyuria and elevated serum levels of IL-6, G-CSF, KC, and IL-5 within the first 24 hours post infection (hpi) predict with high certainty that chronic infection will develop. These events may reflect, in part, the natural course of cystitis in women, as placebo-controlled studies demonstrate that a majority of women remain bacteriuric for weeks after an acute episode of cystitis if not treated with antibiotics, despite overall improvement of symptoms. Further, in C3H/HeN mice, we found that a history of chronic cystitis is a significant risk factor for a subsequent recurrence of severe chronic cystitis. Understanding how prior infection influences a new infection is needed in order to understand clinical recurrent UTI.