The bladder's response to infection

In the bladder, defence mechanisms against infection are very complex and involve the immune system and other systems. Although not all of these mechanisms are known exactly, it is known that up to 1000 different genes involved in bladder defence can be activated in the urinary system when faced with a bacterial infection. Here is a summary of the broad outline of the bladder's defensive response. 

     The first line of resistance of the bladder to active infection is due both to the anatomical design of the bladder and to antimicrobial substances secreted by the urothelium (the cells of the bladder wall). Urothelial cells are covered by a layer of mucus and have defence proteins in their membrane called "uroplakins". These two mechanisms serve to prevent the adherence of some bacteria to their surface, although others, such as uropathogenic strains of Escherichia coliare able to use precisely these molecules to penetrate bladder cells. In fact, E. coliin addition to having the ability to multiply rapidly in urine, it has many mechanisms to evade the bladder's natural defences, which we will now discuss.

     As I have already mentioned, the first line of defence against bladder infection is the urothelium with its mucus layer. The numerous bacterial receptors on its surface, called pattern recognition receptors (PRR), allow them to recognise different types of bacteria and immediately produce some pro-inflammatory cytokines, such as interleukin 6, interleukin 8 or interleukin 1β. These cytokines alert and attract immune cells to the urothelium. On the other hand, the epithelial cells themselves are able to directly produce some antimicrobial substances, called "antimicrobial peptides", such as cathelicidin LL-37, which starts to be secreted only five minutes after the onset of infection, β-defensin, ribonuclease 7, lipocalin 2, lactoferrin or pentraxin. Another way for the bladder to fight infection is to promote the death of urothelial cells and their shedding in the urine. This allows a large number of intracellular and surface-attached bacteria to be eliminated. The cells of the basal urothelium, where the stem cells are located, then begin to multiply rapidly in order to replace the sloughed cells. This prevents the underlying cells from being exposed for a long time to the aggression of urine and bacteria still present. In addition, the inflammation activates the urination reflex, which promotes frequent emptying of the bladder and thus the elimination of germs and infected cells. 

     Following the action of the first line of urothelial defence, the innate immune system goes into action to defend the bladder. The first immune cells to act in the inflammatory response are neutrophils, which emerge from the blood vessels and pass through multiple cellular and tissue layers to reach the bladder lumen to fight the infection. There, with the help of the antimicrobial peptide pentraxin, like that of urothelial cells, they will attract the bacteria and 'eat' them by a process called phagocytosis, destroying them once they are inside. The problem is that neutrophils, as they move into the bladder lumen, secrete a number of toxic substances, including a substance called "reactive oxygen species" or ROS, which is a very harmful product, causing a lot of tissue damage along the way. 

     Another type of immune cell that is very important in the defence of the bladder are mast cells. These cells reside in the bladder, mainly in the lamina propria, but also in the detrusor muscle. They can multiply and move wherever there is an infection. They come quickly, usually within the first hour after infection. They have granules inside them that are loaded with pro-inflammatory molecules, especially histamine, which they can release once they are activated. Mast cells regulate neutrophil activity. In addition to their role in initiating inflammation during infection, they also appear to be important in establishing homeostasis and accelerating tissue recovery after remission of infection by secreting anti-inflammatory cytokines such as interleukin-10. In some cases, if mast cells trigger this inflammation-resolving mechanism too early, premature and incomplete resolution of the inflammatory response may occur without complete eradication of the bacteria, leaving residual bacteria. 

     A third important cell type in bladder immunity is macrophages. These cells reside in the lamina propria of the bladder. When the inflammatory response is set in motion, they recruit other extravesical macrophages. Between the two types of macrophages, bladder and extravesical, a collaboration is established through the secretion of different cytokines, which ultimately results in the activation of neutrophils and the passage of neutrophils into the bladder lumen. In addition, they are responsible for clearing the cellular debris that remains after the "battle", thus promoting tissue recovery after inflammation. Like mast cells, macrophages are able to stop the inflammatory response. But if they do so earlier than they should, this may encourage some bacteria to persist in the bladder. 

     Finally, other cells involved in the innate inflammatory response in the bladder are natural killer cells, which are also indispensable for triggering the inflammatory response, mainly by recruiting neutrophils, although their exact role is not known.

     As for the adaptive immune response, very little is known about its role in UTIs. The adaptive response is that which occurs when immune cells of the innate system present antigens to lymphocytes so that the latter become activated and respond in a more specific way to the infection. The antigens are certain proteins from the invading bacteria that antigen-presenting cells (mainly dendritic cells and macrophages) pick up from the 'battlefield' and carry to the pelvic lymph nodes to show to the lymphocytes, which are located there. The lymphocytes are then activated, move to the bladder and specialise in fighting specifically that particular germ. This response, although slower than the innate response which is immediate, is much more precise and also allows the creation of "immunological memory". Thus, thanks to this memory, the next time the micro-organism in question attacks the bladder, the adaptive response will be activated much sooner and will allow the infection to be eliminated much more quickly and efficiently. This is the theory, but in the case of the bladder it is thought that lymphocytes do not play such a fundamental role in the defence response to infection, but rather in the immunomodulatory and tissue repair response, especially T-lymphocytes. Indeed, it is thought that the action of these T-lymphocytes could favour repeated urinary tract infections, as these cells would prioritise repair of the urothelium over complete elimination of bacteria, in order to prevent deep urothelial cells from being in contact with toxic substances in urine for too long after the superficial cells have been shed. These mechanisms would therefore favour the persistence of certain intracellular bacteria called "quiescent intracellular reservoirs" (QIR), which would remain "dormant" inside the urothelial cells and could reactivate some time later, causing a new urinary tract infection.

     In summary, the bladder response to infection is very complex and takes place at several levels: 

1. - The bladder mucosa with mainly urothelial cells and their antimicrobial peptides, as well as desquamation and activation of the micturition reflex to eliminate microorganisms; 
2. - The innate immune response with the activation of neutrophils, macrophages, mast cells and natural killer cells, where neutrophils are the cells primarily responsible for destroying bacteria, and macrophages, mast cells and natural killer cells are primarily responsible for activating the former, regulating their action and terminating the inflammatory response and repairing tissue damage after infection; 
3. - The adaptive immune response, with activation of T-lymphocytes mainly following antigen presentation by dendritic cells and macrophages, with an unclear role where the anti-inflammatory and reparative activity of T-cells seems to predominate.

     Considering the existence of all these defence mechanisms, one might wonder how it is possible that uropathogenic bacteria are so often able to overcome them and so easily produce UTIs, especially recurrent UTIs. In addition to the negative influence of many external causes, such as the emergence of increasingly resistant or virulent bacteria, toxins, nutritional deficits due to poor diet, stress, etc., it should be known that individual susceptibility is also a risk factor for UTIs. There are many genetic polymorphisms, which, although they do not result in severe immune deficiencies, can alter certain stages of the triggering of the immune response. Some of the best known are those that occur in the PRRs (pattern recognition receptors), which we have already discussed, and in particular in one of them called TLR4. These mutations give a disadvantage to people who suffer from them, as less activation of these receptors triggers a much more discrete immune response. In addition, a link between the different blood groups (ABO and also the lesser-known Lewis groups) and the increased risk of repeated urinary tract infections has been shown for some time. People who do not have an O group would be more susceptible. Another susceptibility factor would be age, as it is well known that over time a phenomenon called immunosenescence occurs, which decreases the effectiveness of the immune response to aggressions. Among other things, the bactericidal activity and migration capacity of neutrophils, which is so important for fighting bacterial infections in the bladder, is reduced. The activity of sex hormones is also related to the response to infections. Oestrogens have a protective effect on the vaginal mucosa, promoting the development of a healthy microbiota, mainly composed of lactobacilli. But we also know that in the bladder, oestrogens act directly at the local level, via oestrogen receptors on urothelial cells. These hormones are able to regulate the desquamation of the urothelium in the presence of infection and also the magnitude of the inflammatory response. In post-menopausal patients, urothelial desquamation is known to be less and the inflammatory response more exaggerated. They also have a higher bacterial load during infections and more difficulty in clearing bacteria. As for testosterone, some studies suggest that it may have a deleterious effect on the innate immune response. Thus, although urinary tract infections are much more common in women, mainly due to anatomical factors, greater male exposure to testosterone may play a role in the severity of infections in men, particularly pyelonephritis (kidney infections). 

     As you can see, the complexity increases as we analyse more factors related to UTIs. In particular, the bladder immune response and interaction with uropathogenic bacteria, as well as their virulence mechanisms and individual susceptibility remain an enigma to scientists today. In addition to the genetic mechanisms involved, on which little action can be taken, new drugs are being developed based on the antimicrobial peptides secreted by urothelial cells, which will be discussed later. These drugs could serve to modulate the anti-infective response and could be an alternative to antibiotic treatment, especially in cases of multidrug-resistant bacteria.

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