Comparative evaluation of plasma biomarkers of Schistosoma haematobium infection in endemic populations from Burkina Faso.

Infection with Schistosoma haematobium causes urogenital disease associated with organ disfunction, bleeding, pain, and higher susceptibility to infections and cancer. Timely and accurate diagnosis is crucial for prompt and appropriate treatment as well as surveillance efforts, and the use of plasma biomarkers offers important advantages over parasitological examination of urine, including increased sensitivity and the possibility to use the same specimen for multiple investigations. The present study aims to evaluate the diagnostic performance of different plasma biomarkers in endemic populations from Burkina Faso, West Africa. Schistosoma spp. Circulating Anodic Antigen (CAA), cell free S. haematobium DNA (cfDNA), class M and G antibodies against S. haematobium Soluble Worm Antigen Preparation (SWAP) and Soluble Egg Antigen (SEA) were measured in 406 plasma samples. Results of each biomarker test were compared to those of CAA, a Composite Reference Standard (CRS) and Latent Class Analysis (LCA). An identical proportion of positive samples (29%) was observed as a result of CAA and cfDNA testing, with a substantial agreement (84%, Cohen k = 0.62) between the results of the two tests, and a comparable agreement with the results of CRS and LCA. A higher positivity was observed, as expected, as a result of specific antibody testing (47%-72%), with IgG showing a higher agreement than IgM with the three references. Also, higher IgG levels were observed in current vs past infection, and ROC analysis identified optimal cutoff values for improved testing accuracy. This study provides compelling evidence that can inform the choice of the most appropriate diagnostic plasma biomarker for urogenital schistosomiasis in endemic areas, depending on the purpose, context, and available resources for testing. Either CAA or cfDNA testing can be used for the diagnosis of patients and for epidemiological investigations, even in absence of urine filtration microscopy, whereas anti-SWAP or anti-SEA IgG can be employed for surveillance and integrated monitoring of control interventions against poverty-associated diseases.

Oleic acid triggers metabolic rewiring of T cells poising them for T helper 9 differentiation.

T cells are the most common immune cells in atherosclerotic plaques, and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, upregulates core metabolic pathways and promotes differentiation into interleukin-9 (IL-9)-producing cells upon activation. RNA sequencing of non-activated T cells reveals that oleic acid upregulates genes encoding key enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis links these expression changes to the differentiation toward TH9 cells, a pro-atherogenic subset. Spectral flow cytometry shows that pre-exposure to oleic acid results in a skew toward IL-9+-producing T cells upon activation. Importantly, pharmacological inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, oleic acid may affect inflammatory diseases like atherosclerosis by rewiring T cell metabolism.

Safety and infectivity of female cercariae in Schistosoma-naïve, healthy participants: a controlled human Schistosoma mansoni infection study.

BACKGROUND: A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently, we established CHI-S model using single-sex male-only Schistosoma mansoni (Sm) cercariae in Schistosoma-naïve individuals. Given important differences in antigenic profile and human immune responses to schistosomes of different sex, we pioneered a single-sex female-only CHI-S model for future use in vaccine development. METHODS: We exposed 13 healthy, Schistosoma-naïve adult participants to 10 (n = 3) or 20 (n = 10) female cercariae and followed for 20 weeks, receiving treatment with praziquantel (PZQ) 60 mg/kg at week 8 and 12 after exposure. FINDINGS: The majority (11/13) participants reported rash and/or itch at the site of exposure, 5/13 had transient symptoms of acute schistosomiasis. Exposure to 20 cercariae led to detectable infection, defined as serum circulating anodic antigen levels >1.0 pg/mL, in 6/10 participants. Despite two rounds of PZQ treatment, 4/13 participants showed signs of persistent infection. Additional one- or three-day PZQ treatment (1 × 60 mg/kg and 3 × 60 mg/kg) or artemether did not result in cure, but over time three participants self-cured. Antibody, cellular, and cytokine responses peaked at week 4 post infection, with a mixed Th1, Th2, and regulatory profile. Cellular responses were (most) discriminative for symptoms. INTERPRETATION: Female-only infections exhibit similar clinical and immunological profiles as male-only infections but are more resistant to PZQ treatment. This limits future use of this model and may have important implications for disease control programs. FUNDING: European Union's Horizon 2020 (grant no. 81564).

Photo-Uncaging of a Microtubule-Targeted Rigidin Analogue in Hypoxic Cancer Cells and in a Xenograft Mouse Model.

Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was "caged" by coordination of its thioether group to a photosensitive ruthenium complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell line monolayers, 3D lung cancer tumor spheroids (A549), and a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also remarkably in hypoxic conditions (1% O2). In vivo, low toxicity was observed at a dose of 1 mg·kg-1 when the compound was injected intraperitoneally, and light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the safety and efficacy of ruthenium-based photoactivated chemotherapy compounds in a tumor xenograft.