Why are some urinary tract infections chronic?

ResearchBlogging.orgChronic infection is, in a way, the new emerging infectious disease. Many pathogens are relatively tenacious when they infect elderly individuals or individuals who are otherwise not fully immunocompetent, and such individuals are, thanks to modern medical technology and practice, more common in the population. Resistant bacteria can cause chronic infection. It is interesting to see more research oriented specifically towards the problem of chronic infection as a problem in and of itself, and a paper just out by Hannan, Mysorekar, Hung, Isaacson-Schmit and Hultgren, in PLoS Pathogens, is an interesting and important example of one such research project.

The paper is Early Severe Inflammatory Responses to Uropathogenic E. coli Predispose to Chronic and Recurrent Urinary Tract Infection, and, since PLoS is an OpenAccess journal, it is available here.

Urinary tract infections in human females are often chronic, recurring as painful inflammations as well as the regular production of the offending strain of E. coli even between bouts of inflammation. Other times the infections are readily dealt with using antibiotics. Why the difference? The research reported here sought explanations other than infection by resistant strains of bacteria (which is certainly an issue as well). Essentially, the experimenters infected mice that were essentially the same in most but not all respects with the same E. coli, but at varying levels. Some of the mice ended up with chronic infections, and some did not.

Some of the mice possessed normal amounts of run of the mill TLR4 signaling molecules. In other words, the capacity for the immune system of the mice to recognize an infection and start the process of developing a response was intact. Other mice had immune systems that were deficient in this area or otherwise unable to respond vigorously to the infection.

Counter-intuitively, the mice with the very excellent immune systems responded to the infection in such a way that the tissues of their bladders were damaged. This damage facilitated a chronic infection. Those mice with sub-par immune systems did not have this problem and, on average, did not develop chronic infections. (This also depended on the dose of the infection, and I'm oversimplifying a great deal.)

In addition, once a mouse did develop a severe infection, the chance of subsequent chronic infection was greater.

In summary, we have discovered a new basis for understanding UTI [Urinary tract infection] that provides a possible mechanism for both chronic and recurrent infection. We propose that, in females that are genetically predisposed to enhanced mucosal TLR4 signaling, initial episodes of UTI ... may be particularly severe ... If allowed to progress past the early acute stage before initiation of antibiotic therapy, these individuals could then develop altered bladder mucosal responses to gram-negative uropathogens. Upon repeated exposure to gram-negative uro- pathogens, these individuals would then be at increased risk for developing severe, symptomatic rUTI.

In addition, the scientists looked at physical reservoirs for (small numbers of) pathogenic bacteria that may be the seed for repeated infections in mice, and speculated that such a reservoir may be present in humans.

How will this affect future research and treatment options? As you know, much research is not about solving specific 'end user' problems, but rather, about knowing more stuff about stuff. But this research seems closer to practical application than a lot of other research. It would seem that reducing specific immune responses (in a limited way) could be part of treatment. Also, having a genetic factor at the table can help to design better drugs that may assist the antibiotics. There is nothing in this research that should guide actual human females dealing with actual urinary tract infections. But there is progress being made.

Intelligent design indeed.

Don't forget to drink your cranberry juice! CLICK HERE to find out if cranberry juice actually works.

Hanan, T.H., Mysorekar, I.U., Hung, C.S., Isaacson-Schmid, J.L., & Hultgren, S.J. (2010). Early Severe Inflammatory Responses to Uropathogenic E. coli Predispose to Chronic and Recurrent Urinary Tract Infection
PLoS Pathogens, 6 (8) : 10.1371/journal.ppat.1001042

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I hate to promote treatments without any proper evidence to back them, but cranberry juice worked really well for me to prevent the recurrance of my UTIs when multiple courses of antibiotics only served to reduce the infection rather than completely remove it (I was tested at the end of each course and still showed bacteria in my urine). Continuing my regime of antibiotics, the infection cleared up when I started drinking cranberry juice as well. Continuing to drink cranberry juice I didn't have a recurrance of the infection. I certainly wouldn't promote cranberry juice as an alternative to antibiotics, or as a cure (NEVER heard anyone promote that), but it seems that antibiotics + cranberry works better than just antibiotics. Has anyone tested this, rather than just debunking the woo position of "cranberry cures UTIs"?

A large number of women also anecdotally show that cranberry juice reduces the symptoms (pain) when one cannot get to a doctor in a timely manner to get antibiotics.

Your skeptical search engine didn't turn up any evidence either way on the cranberry issue, though it turned up an interesting point: that antibiotic resistance is fairly high in bacteria types that cause UTIs. Sounds like that could be a contributor to chronic infection.

By Katherine (not verified) on 12 Aug 2010 #permalink

I've heard that drinking certain things affects the Ph of urine, which in turn affects infections or things related to infections. That is the reason I heard cranberry juice works.

I'm going to run this cranberry juice thing down and blog it. Mark my words!

Hmm. I wonder if the same could happen in malaria. We don't do nearly enough reinfection studies.
Also? IL-6 + G-CSF + IL17A?? That just SCREAMS IkappaB zeta.

One thing I don't understand- why did they use these different strains of CH3 mice instead of c57b/6 Tlr4-/-?

One thing I don't understand- why did they use these different strains of CH3 mice instead of c57b/6 Tlr4-/-?

What would the c57 jobbies be good for?

From a previous paper studying chronic inflammation response (in this case, asthma) using the same mouse model:

The tlr4â/â and tlr2â/â mice were provided by Dr xxxxx (Osaka University, Osaka, Japan), and backcrossed for 8â10 generations onto a C57BL/6J background. Age- and gender-matched C57BL/6J mice were purchased from..blah blah blah.

A CH3 mouse indicates an inbred strain (20 generations of brother-sister matings, or full-sib matings) resulting in a group of 98% genetically homozygous animals.

C57BL/6, or "C57 black 6" or just "black 6" is a common inbred strain of lab mouse. It is probably the most widely used "genetic background" for genetically modified mice for use as models of human disease.


Why they used this strain to TLR4+/- trait selection:

'The immune response of mice from the C57BL/6 strain distinguish it from other inbred strains like BALB/c.

For example the immunological response to the same pathogen in C57BL/6 mice is often of an opposite spectrum compared to BALBb/c mice, namely C57BL/6 shows Th1 and BALB/c shows Th2 response in response to an intracellular pathogen, where a Th1 response results in a resistant (healer) phenotype (since the pathogen is intracellular), whereas a Th2 response results in a susceptible (nonhealer) phenotype.'

Th1 modulation is proinflammatory and Th2 is anti-inflammatory.

They're looking for modulation in Th2 cytokines in chronic inflammation response model. Can't do that with most mice strains. Toll-like receptors (TLRs) play an essential role in the innate immune system by initiating and directing immune response to pathogens. Th2 cytokines down-regulate TLR expression.

Interesting selection of a paper to feature here; kinda outside of your expertise box, Greggy.

Cranberry juice-UTI science.

Pinzón-Arango, P.A. Liu, Y., and T.A. Camesano. Role of cranberry on bacterial adhesion forces and implications for E. coli-uroepithelial cell interactions. Journal of Medicinal Food, 2009, 12:259-270.

Cranberry Juice Keeps Infections At Bay. ACS News

'Urine from volunteers who drank cranberry juice cocktail prevented bacterial adhesion and biofilm formation. Bacteria treated with urine from volunteers who drank water, on the other hand, were still able to stick to the probe and form biofilms.'

Now you know why, twice over.

Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells. J Immunol. 2006 May 15;176(10):5805-14. J Immunol. 2006 May 15;176(10):5805-14.

(open access article)

Thanks passerby! (but why did you XXX out Akira? anyone studying TLRs could fill in the blanks). Yeah, I know about the B/6s vs. balb/cs, in my world they are "subject" and "carrier" mice (there is also a GREAT paper that knocked down myd88 in both and then looked at malaria. *swooning sigh*).

ok, so no black6- this depends too heavily on a Th2 response (though I'm still not quite clear on what does happen in the black6).

But aren't there any balb/c tlr4-/-? *Googles*
(from Jackson Labs)
"The Lps-d mutation arose in C3H/HeJ sometime between 1960 and 1968. In 1977 a C3H/HeJ female, derived from the colony of David Sachs at NIH, was crossed with a BALB/cAnPt male and the Tlr4Lps-d allele was transferred onto the BALB/cAnPt background by continued backcrossing. At that time it was thought that Tlr4 and Tyrp1 were tightly linked so the black mice, those that would be carrying the C3H/HeJ-derived dominant B (wild-type) allele of Typr1 rather than being homozygous for the BALB/cAnPt-derived recessive b allele and Tyrc allele, were selected at each generation to continue the backcross. At N6 intercrossing made the strain homozygous for Tlr4Lps-d and Tyrp1B. Backcrossing to BALB/cAnPt was resumed from N6F22. When backcrossing reached N20, the strain was intercrossed to generate this strain homozygous for Tlr4Lps-d and Tyrp1B but not Tyrc. The congenic interval encompassing Tyrp1B and Tlr4Lps-d includes at least from D4Mit151 through D4Mit26. In March 1977, this strain was imported into The Jackson Laboratory from Dr. Stephanie Vogel at Uniformed Services University of the Health Sciences. "
So you get a tlr4 mutant in blab/c from the CH3s anyway.
And the mouse strain they're using is from way prior to genome sequencing and the technology for targeted mutations. Even though it seems to introduce extraneous variables to me (not a targeted mutation), it's probably a really well characterized set of mice. Still, I wish the authors had made a chart or something comparing all their C3H variations for those of us who *aren't* familiar with their characteristics.

Passerby, I didn't realize that you were an area of expertise troll. Now, please go back and rewrite your fact filled comment so that most of the readers of this blog could get something useful out of it, and we can continue the conversation!

@Katherine -
"... but it seems that antibiotics + cranberry works better than just antibiotics. Has anyone tested this, rather than just debunking the woo position of "cranberry cures UTIs"?

Low dose antibiotics every day + cranberry juice seems to help me quite a lot. I'm not a scientist ... I would also like to see this tested.

Recap for clarity:
*Greg says the authors think that greater TLR4 signaling, leading to greater inflammatory response, is actually Bad for mice.
*I want to know why the authors didn't test the role of TLR4 using the most specific method available (the mice that they used differ in TLR4, but also in other factors).
*Passerby points out that this disease won't progress in the same way in the mouse strain where you can test TLR4 very specifically.

@Passerby-the more I think about it, the more I wonder why Th2 responses are relevant. Chronic infection models are not the same as chronic inflammation for asthma. The authors of the PLoS paper particularly emphasize the intracellular bacterial communities. Is it strange that the Th1 prone B6 are resistant to chronic infection by such? The *problem* is robust inflammatory response in a Th2 prone background. Maybe you end up with Tregs, I don't know.

@Greg- I'm kind of bothered by you saying: "Counter-intuitively, the mice with the very excellent immune systems responded to the infection in such a way that the tissues of their bladders were damaged. This damage facilitated a chronic infection." Personally, I'd argue that the very excellent immune systems are in the mice that all clear the infection after a week (the C57B/6 mice).
It's just that within the subset of mice that are going to have a certain type of immune response (specifically: Th2, T-helper cell polarized), it's not good to have a very high inflammatory burst early because it damages the bladder, leading to persistent infection. Also, you gloss over the fact that 25% of the mice with sub-par TLR4 die.

Becca, given a mouse that is alleged to have a typical mouse immune system and a mouse that is alleged to have a genetically broken (or otherwise broken) immune system, I would say that a "correct" immune response in the latter and a "bad" immune response in the former verges on being a poster-child case for the word "counterintuitive."

The real situation on the ground is more complex than that. That is usually the case when the word "counterintuitive" is used ... the word "counterintuitive" often precedes a further exploration of the situation that may lead to better understanding and a re-evaluation of what is "intuitive."

It's kinda like a literary device.

I'll try simpler.

So here's the "excellency of immune system" rank order: CH3 strain with defunct TLR4 < CH3 with intact TLR4 < or = * B6 with intact TLR4

*depending on the definition of excellency

And here's "outcome of disease" rank: CH3 with defunct TLR4, subset that are dead < CH3 strain with intact TLR4 (chronically infected) < CH3 strain with defunct TLR4, subset that are alive and recovered < B6 mice with intact TLR4 (also alive and recovered)
I grant you that the fact that the CH3 strain with defunct TLR4 > the CH3 strain with intact TLR4 is counter-intuitive.

The fact that the dead mice are also those that have the least excellent immune system is intuitive. The fact that B6 mice do the best in both parameters is also intuitive, using the same premise that a robust inflammation helps fight infection (assuming you know anything about B/6 mice).

AGHH! that'll teach me not to preview. Forgot the less than signs can look like tags. Hang on, I will graph...

I wouldn't trust any anecdotes of cranberry juice "working" for UTIs for the simple reason that it's become an article of folk wisdom so you would expect a strong placebo effect too. Also wouldn't trust any studies where the treatment group was drinking juice for the same reason so presumably that's why a number of studies used tablets or concentrates.

By Myotis rufopictus (not verified) on 18 Aug 2010 #permalink

Though if cranberry juice is a placebo, it might be worthwhile to ride the crest of its fad-dom, since without the vote of popular misconception, its efficacy (objective or not) may not last much longer.

Before suggesting cranberry juice is a placebo, or that research on the topic isn't sufficient to answer the question, may I suggest you read the summary of research that Greg links to in comment #12?

I also solved my UTIs naturally using a combination of various dietary, exercise, supplement, and life-style changes. I would not have been able to do it without helpful research like that is found in this article! Check out savvy.is/mayabenami for a personal consulting session tailored to your symptoms!