Fed up of stocking up on cranberry juice to stave off painful peeing….well researchers from the University of Michigan have made an important step towards making a vaccine to prevent urinary tract infections (UTIs), if the immunity seen in mice can be reproduced in humans. The findings by Alteri and colleagues were published this week in PLoS Pathogens (its open-access so go take a look at the paper for yourself).
UTI is a bacterial infection that affects any part of the urinary tract (including kidneys, ureter, bladder and urethra). They are incredibly common; it is thought 53% of women and 14% of men will experience a UTI during their lifetime. They are significant healthcare burden; in the United States alone, UTIs have an estimated annual cost of $2.4 billion each year. There are two types of UTI. Lower UTIs affect the bladder (cystitis) and urethra (urethritis) with symptoms of a mild fever, the urge to urinate frequently, smelly, bloody or cloudy urine, and that oh so infamous pain or burning sensation when you need to urinate. Upper UTIs affect the ureter and the kidneys (pyelonephritis) and include symptoms of high fever, nausea and vomiting, chills and shaking and localised pain in your lower back. Upper UTIs are potentially more serious since they can cause kidney damage. UTIs can be treated with antibiotics but there is increasing evidence of antibiotic resistance. Furthermore, recurrent infections occur frequently. An estimated 27% of women experience a second infection, and 2.7% of those suffer a third infection, within 6 months from the initial infection. Uropathogenic (pathogens that infect the urinary tract) Escherichia coli (UPEC) is the most likely cause of an uncomplicated UTI and so the researchers wanted to develop a vaccine to prevent infection by these bacteria.
The researchers used large-scale reverse vaccinology (pioneered by Rino Rappuoli and first used for vaccines against meningococci, the bacteria that cause meningitis). This combines bioinformatics, genomics and proteomics, to quickly and efficiently identify proteins in UPEC that are novel vaccine targets. The researchers looked for proteins to act as antigens, substances that would trigger an immune response to produce protective antibodies (a protein which binds foreign antigens to identify and neutralise them). The researchers screened 5,379 predicted bacterial proteins in the UPEC strain E. coli CFT073 and identified six proteins that matched vaccine candidate criteria including proteins that were highly expressed in vivo, specific to pathogens and induced during growth in human urine. The vaccine candidates were all pathogen-associated iron receptors (ChuA, Hma, Iha, IreA, IroN and IutA). These receptors are required for uptake of iron and are present on the surface of the bacteria. Each of the iron receptor proteins were expressed and purified and these antigens were cross-linked to cholera toxin, which acts as an adjuvant (a substance that increases the ability of an antigen to stimulate the immune system). Mice were inoculated with each antigen-adjuvant complex in their nasal passage. The researchers investigated whether mice could be protected from UTI and measured the immune response that occurred in the mice after vaccination.
Vaccination with Hma, IreA and IutA significantly protected mice against colonisation with UPEC strains in the kidneys and bladder. Spleen cells from vaccinated mice significantly secreted IFNγ and IL-17, which are protective proinflammatory cytokines (proteins released by cells which act as signalling molecules and help generate an immune response). Also, mice secrete protective antigen-specific antibodies following vaccination, which correlated with protection against infection with UPEC. Increased levels of IgA (an antibody found in mucous) were measured in urine and high levels of IgM (an antibody part of the primary immune response to a foreign antigen) and IgG (an antibody that is part of the secondary protective immune response) were measured in serum.
Vaccination with iron receptors elicits protective immunity from experimental UTI in mice. Iron receptors are promising vaccine candidates to protect against UPEC infections in humans and future clinical trials will determine whether the immunity seen here can be reproduced in humans. Interestingly, uptake of iron is a critical function required specifically by pathogenic bacteria in order to survive, but often not in commensal bacteria (normally harmless bacteria which are part of our natural microflora on and inside our bodies). Vaccines that include iron receptors could be used to prevent infections by other pathogenic bacteria. Also, the researchers show that vaccination in nasal mucous membranes induces an immune response in mucosal tissue elsewhere in the body, in this case the urinary tract. Although a successful UTI vaccine may be a long way off this paper details key research which should help its development.
Both these webpages give detailed info on symptoms, diagnosis and treatment of UTIs:
Medline Plus topic page on UTIs
NHS direct topic page on UTIs