Alternative to antibiotics for treating UTIs uses body’s own cell defense mechanism

New knowledge of intracellular activity that rids bacteria from cells in the bladder could provide the missing link to treat urinary tract infections (UTIs) without antibiotics, preventing resistance.

The process cells use to secrete chemicals also appears to be the way to clear them of UTI causing bacteria, according to a study published in Immunity by researchers from Duke Health and Duke National University of Singapore Medical School. We spoke with Yuxuan Phoenix Miao about a novel approach for UTI treatment boosting the body's export ability.

Research Gate: Can you explain your findings?

Yuxuan Phoenix Miao: In this study, we identified a new mechanism that infected cells employ to clear bacteria which cause UTIs. We found that the process which cells use to secrete chemicals also appears to be the way to clear urinary tract infections. Bacterial pathogens hide within a membranous vesicle in the bladder cells. We revealed that a protein complex important for secreting hormones called ‘Exocyst’ can precisely recognize and locate bacteria hiding in those vesicles, then promote transport of these bacteria-laden vesicles towards the cell surface, and throw the bacteria out of the bladder cell. We further found that our bladder cells can specifically tag those bacteria-laden vesicles with certain proteins involved in immune recognition, so that the Exocyst can distinguish which vesicle has a bacteria hiding inside. This cross-talk between immune system and cellular secretion system ensures precise action of the bacteria export.

How the cell recognizes and clears UTI causing bacteria like uropathogenic Escherichia coli (UPEC).
How the cell recognizes and clears UTI causing bacteria like uropathogenic Escherichia coli (UPEC). Courtesy of: Yuxuan Phoenix Miao.

RG: How did you discover the cell’s machinery for secreting hormones as a defense mechanism adding to the lysosomal system of degrading cellular waste?

Miao: When we were studying the lysosome-mediated bacteria clearance which was published last year, we noticed that this mechanism cannot explain all the bacteria export results.  Even though we blocked the lysosomes-mediated bacteria expulsion, a significant number of bacteria were still exported, hinting towards additional, yet unknown mechanisms. This interesting finding inspired us to continue our investigations. We reasoned that any bacterial clearance event must be initiated by certain immune recognition pathways. Driven by this hypothesis, we first identified the immune-related molecules activating bacteria export (e.g. TRAF3). By systematically examining the binding partners of TRAF3 with mass spectrometry, we identified that this immune regulation molecule can act as ´pick-me-up´ signal to recruit the cell’s secretion machinery – the Exocyst – to the bacteria-laden vesicles to achieve bacteria export.

RG: What does this discovery tell us about the way the body’s immune system reacts against bacterial infection?

Miao: From this new study, we are truly amazed at how our immune system works to defend our body. We can see that it involves elegant mechanisms to mobilize multiple cellular systems, including the cellular secretion machinery, in order to magnify the clearance effect. One of the benefits from using the expulsion strategy to clear the bacterial infection, instead of directly killing the bacteria is that it would require extra energy to actually kill bacteria. In addition, the bacterial pathogens find multiple ways to evade from intracellular killing. However, the immune system in our bladder can resolve these problems by simply borrowing the power of the cellular trafficking machinery . It throws the bacteria out of the bladder cells where they cannot hide from professional immune cells  and our body can even clear these exported bacteria by flushing them out with urine.

This new discovery, together with our findings from last year, reveal that our bladder is equipped with a multi-layered bacteria expulsion system. The lysosome-mediated expulsion from our paper last year is actually a backup strategy when the Exocyst-mediated expulsion fails to eradicate intracellular bacteria. Now, we can say that when the bacterial pathogens invade the bladder cells, the immune recognition molecules are immediately mobilized and trigger Exocyst-mediated expulsion trying to clear the infection. Some of the bacteria may escape this initial wave of expulsion, but they can still be targeted by the lysosome-mediated expulsion maximizing the effect.

Blue Spur Flower, source of Forskolin. Credit: Dick Culbert via flickr.

RG: The plant extract Forskolin seems to have a strong impact on UTIs even in the absence of antibiotics. What missing link is still needed to use the herb as a potential new treatment for UTIs?

Miao: Previous studies from our lab have found that Forskolin can dramatically enhance the bacteria clearance effect by promoting the bacteria export process. However, it is unclear how Forskolin achieves this effect. Now that we have identified the pathway which the bladder cells use to export bacteria, we can start to examine whether Forskolin enhances bacteria expulsion by promoting the function of the Exocyst and if so, how. These questions are critical to clarify, because the answers will provide the basis for optimizing the therapeutic options to use Forskolin as treatment for urinary tract infections. Especially the missing link on how Forskolin might enhance the function of the Exocyst could help us to design more powerful expulsion enhancers to maximize bacteria export and potentially reduce the use of antibiotics.

RG: Do you expect the bacteria causing UTIs to outwit the body’s response and develop a shielding mechanism?

Miao: We have to admit that the bacteria pathogens are also smart. Although our bodies are equipped with multi-layered defense systems, bacteria themselves also develop fascinating ways to outwit the body’s response during the long battle between the pathogen and our body. There will be no exception to the now newly discovered bacteria export processes. That’s why UTIs remain a major public health issue causing trouble for many people, despite the fact that the expulsion process is a powerful self-defense mechanism.  Foreseeing this issue is the major reason for us to aim our future studies at uncovering chemicals, such as Forskolin, which can potentially enhance the function of the Exocyst and magnify the expulsion effect. We hope this strategy can help us to outmaneuver bacteria and eventually win the battle.

RG: Can you think of any other disease area where your findings could lead to the development of new drugs?

Miao: It will be very interesting to investigate whether the cells from other body sites are equipped with similar defense mechanisms. Similar expulsion events are indeed reported with other types of infections, such as Cryptococcus neoformans. Therefore, examining other infections to discover if enhancing expulsion could help to clear those as well will be an interesting direction for the future.

RG: What are the next steps in this research?

Miao: The critical next step will be investigating if the known expulsion enhancing reagents, such as Forskolin, function through the Exocyst-mechanism and if so, how they achieve the effect. Another direction will be to screen for more effective expulsion-enhancing chemicals, trying to provide alternative therapies for reducing the use of antibiotics.

Feature image: Steven Fruitsmaak via Wikimedia.