PD-1/PD-L1 immune checkpoint blockade has shown to be efficient in cancer therapy, by modulating immune cell responses in favor of the host thus inducing immunological memory and limiting tissue pathology. One of our previous study showed that PD-1/PD-L1 was also effective against both primary and secondary E. multilocularis infection (alveolar echinococcosis, AE) by regulating T cell immunity. This ensuing study tackles the potential to combine PD-1/PD-L1 blockade with conventional albandazole (ABZ) medication in experimental murine AE. Treatment was started at 6 weeks post E. multilocularis infection, and maintained for 8 weeks with twice/week anti-PD-L1 intraperitoneally, or 5 days/week ABZ perorally, or BOTH combined. As key parameters we assessed parasite weight, immune cell profile, tissue histology, and liver tissue cytokine levels. Findings showed that E. multilocularis infection alone led to the formation of an excess in inflammatory cytokines, Treg cells, and a decrease in Kupffer cells, in neutrophils and in high cytotoxicity upon NK and NKT cells. Combined therapy showed the highest effect against the parasite (lowest parasite mass recovered), while ABZ alone already increased the inflammatory immune response, and PD-L1 blockade alone increased T cell immune responses (mainly via Tregs) but with decreased inflammation and cytotoxic NK and NKT cells. Moreover, PD-L1 blockade increased numbers of Kupffer cells and neutrophils infiltrating the liver. This study suggests that the PD-1/PD-L1 pathway plays an important role by regulating adaptive and innate immune cells against E. multilocularis infection, without causing significant tissue damage.
Based on this, future studies will have to be designed, aiming at clinical trials with PD-1/PD-L1 blockade in human AE patients, which may yield into an alternative therapeutic approach to control AE especially in those patients who do not respond well to ABZ, or this approach may even putatively provide a curative therapeutical outcome in all AE patients receiving a combined PD-1/PD-L1 blockade and ABZ medication.
Metabolic signatures of urinary schistosomiasis and praziquantel pharmacokinetics in pre-school and school aged children from rural Côte d’Ivoire
Schistosomiasis has been linked to paediatric malnutrition and stunting in children, yet the causal pathways are not known. Moreover, praziquantel is the only treatment, yet its erratic absorption and excretion may play a role in variable treatment efficacy and can hamper efforts to inform proper dosing for pediatric populations. Metabolic profiling of biofluids has been successfully applied to elucidate the metabolic perturbations resulting from infections and their links to consequent morbidities, while pharmacometabolomics is an important tool for predicting and enhancing treatment outcomes. In this work, we characterized the metabolic effects of Schistosoma hameatobium infection (urinary schistosomiasis) before and after praziquantel treatment, in a clinical trial cohort of pre-school aged and school-aged children. In the health district of Azaguié, Côte d’Ivoire, 170 pre-school aged and 174 school aged children were screened, shown to be positive for S. haematobium and enrolled in the study. Children were stratified according to age category and infection intensity and randomized to receive 20, 40 or 60 mg/kg of praziquantel or a placebo. Urine samples were taken pre-treatment, 24 hours post-treatment, and at the 3-week follow up time-points of infected and 42 non-infected children. Samples were analysed using 1H NMR spectroscopy followed by unsupervised and supervised multivariate statistical analysis to investigate variation between groups. Infection was associated with TCA cycle and microbial co-metabolism. Moreover, a cross-analysis with matching pharmacokinetic data showed microbial co-metabolites were associated with higher praziquantel exposure both before and after treatment, hinting at a gut microbial role in praziquantel absorption. The results are compared to our previous findings in intestinal schistosomiasis to outline potential mechanisms of schistosomiasis-associated paediatric stunting as well as a potential role for gut microbial modulations to standardize praziquantel treatment outcomes.