Lena Russ’s research while affiliated with Justus-Liebig-Universität Gießen and other places

Schistosomiasis, a parasitic disease caused by Schistosoma spp., affects more than 250 million people worldwide. S. mansoni in particular affects the gastrointestinal tract and, through its eggs, induces a Th2 immune response leading to granuloma formation. The relationship between egg load and immune response is poorly understood. We investigated whether the quantity of parasitic eggs influences the immune response in S. mansoni-infected hamsters. The hepatic and intestinal egg load was assessed, and cytokine expression as well as the expression of three major egg-derived proteins were analyzed in monosex- and bisex-infected animals by qRT-PCR. Statistical correlations between egg load or egg-derived factors Ipse/alpha-1, kappa-5, and omega-1, and the immune response were analyzed in liver and colon tissue. Surprisingly, no correlation of the Th1 cytokines with the hepatic egg load was observed, while the Th2 cytokines Il4, Il5, and Il13 showed an inverse correlation in the liver but not in the colon. A longer embryogenesis of the parasitic eggs in the liver could explain this correlation. This conclusion is supported by the lack of any correlation with immune response in the colon, as the intestinal passage of the eggs is limited to a few days.

Background & aims: Schistosomiasis is one of the most prominent parasite-induced infectious diseases affecting more than 250 million people. S. mansoni causes metabolic exhaustion and a strong redox imbalance in the liver causing parenchymal damage and may predispose for cancer. We investigated, whether oxidative stress provokes hepatocellular proliferation upon S. mansoni infection. Methods: Cell cycle, replication stress response, and proliferation were analyzed on transcriptional and protein level in the livers of S. mansoni-infected hamsters and by mechanistic gain and loss of function experiments in human hepatoma cells. Major results were validated in human biopsies of S. mansoni-infected patients. Results: S. mansoni infection induced licensing factors of DNA replication and cell cycle checkpoint cyclins in parallel with a DNA damage response in hamster hepatocytes. Moreover, even unisexual infection without egg effects, as a reflection of a chronic inflammatory process, resulted in a moderate activation of several cell cycle markers. S. mansoni soluble egg antigens induced proliferation of human hepatoma cells that could be abolished by reduced glutathion. Conclusions: Our data suggest that hepatocellular proliferation is triggered by S. mansoni egg-induced oxidative stress.

Background & Aims Schistosomiasis, is a parasitic infection, which globally affects more than 200 million people. Schistosome eggs, but not the adult worms, are mainly responsible for schistosomiasis-specific morbidity in the liver. It is unclear if S. mansoni eggs consume host metabolites, and how this compromises the host parenchyma. Methods Metabolic reprogramming was analyzed by MALDI-MSI imaging, LC- and HPTLC-HRMS, metabolite quantification, confocal laser scanning microscopy, live cell imaging, quantitative real-time PCR, western blotting, assessment of DNA damage, and immunohistology in hamster models and functional experiments in human cell lines. Major results were validated in human biopsies. Results Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes. Administration of ROS scavengers ameliorates these deleterious effects. Conclusions Our findings indicate that S. mansoni eggs completely reprogram lipid and carbohydrate metabolism by soluble factors, which results in oxidative stress-induced cell damage in the host parenchyma. Lay summary The authors demonstrate that soluble egg products of the parasite S. mansoni induce hepatocellular reprogramming causing metabolic exhaustion and a strong redox imbalance. Notably, eggs mobilize, incorporate, and store host lipids, while the metabolic reprogramming causes oxidative stress-induced DNA damage in hepatocytes, independent of the host´s immune response.

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.