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Harnessing Invariant Natural Killer T Cells as Novel Therapeutics for Urinary Tract Infections
Parameth Thiennimitr, MD/PhD, Michael Hsieh, MD/PhD.
Stanford University, Stanford, CA, USA.

BACKGROUND: The rise of antibiotic-resistant strains of bacterial uropathogens is a major global concern for children’s health. Children are susceptible to developing febrile pyelonephritis and associated renal scarring, resulting in long-term sequelae such as hypertension. Given that we are on the verge of a post-antibiotic era, the development of therapeutic alternatives to antibiotics is urgently needed for pediatric urinary tract infections (UTI). Invariant natural killer T (iNKT) cells are known to play a role against infections, including uropathogenic E. coli (UPEC) and antibiotic-resistant strains of other bacterial species in the mouse UTI model. In this setting, prophylactic and therapeutic administration of the first generation iNKT cell agonist α-galactosylceramide (α-GalCer) can prevent and treat UTI, respectively. This preclinical finding suggested that iNKT cells have potential as an alternative therapeutic for antibiotic-resistant UTI. However, subsequent hepatitis and cancer clinical trials based on the prototypic α-GalCer iNKT cell agonist revealed serious side effects, such as severe flu-like symptoms and liver injury. Moreover, these trials demonstrated that multiple administrations of α-GalCer resulted in increased numbers of anergic iNKT cells, limiting its efficacy. This led to the abandonment of α-GalCer as a therapeutic for UTI. Newer generation iNKT cell agonists, such as GSL-1 and 7DW8-5, have been developed to overcome these limitations of α-GalCer, and have demonstrated immunotherapeutic effects in preclinical models of some infectious diseases. However, their immunotherapeutic effects on UTI are unknown. As a starting point to evaluate these newer iNKT cell agonists, we tested the hypothesis that these agonists exhibit equivalent or superior efficacy to α-GalCer in the mouse model of UTI.
METHODS: Female wild-type BALB/c and C57BL/6 mice were transurethrally infected with 105 colony-forming units (cfu) of the UPEC UTI89 cystitis strain. Then, 2 μg of the newer generation iNKT cells agonists (GSL-1 or 7DW8-5), the prototypic α-GalCer, or phosphate buffered saline (PBS) control were given intraperitoneally to infected mice at 4 and 48 hours after infection (4-8 mice per each group). Bacterial cfu from mouse bladder and kidney tissues were enumerated at 72 hours post infection on MacConkey agar plates. Bacterial cfu per gram of tissues underwent logarithmic transformation and the statistical significance of differences between groups was calculated.
RESULTS: Both newer generation iNKT agonists tested (GSL-1 and 7DW8-5) exert a significant bactericidal effect against UPEC UTI in mice, albeit in a strain-specific fashion. GSL-1 decreased bacterial burdens in both bladder and kidney tissues of C57BL/6 mice while 7DW8-5 showed an antibacterial effect only in the bladders of BALB/c mice.
CONCLUSIONS: Our results indicate that newer generation iNKT cell agonists, GSL-1 and 7DW8-5, confer a significant antibacterial effect against UPEC in the mouse UTI model that is equivalent to α-GalCer. The mouse strain-dependent effect of these agonists suggests that host genetics may determine responses to different iNKT cell agonists, and may in part explain the suboptimal effects of α-GalCer in clinical trials. Ongoing work will confirm these findings and ascertain associated mechanisms.

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