Publication Database

Metabolic Profiling of Ascaris suum Larvae and Macrophages Exposed to Artemisinin Derivatives, and Humoral and Peripheral Blood Transcriptomic Responses to Larval Ascariasis (2025)

Art

Hochschulschrift

Autor

Kidiavai, Zaneta D. Musimbi (WE 6)

Quelle

Berlin: Mensch und Buch Verlag, 2025 — VI, 115 Seiten

Sprache

Englisch

Verweise

URL (Volltext): https://refubium.fu-berlin.de/handle/fub188/48733

Kontakt

Institut für Immunologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51834
immunologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Background: Ascariasis predominantly affects low- and middle-income populations, driven by inadequate sanitation and poverty, and is frequently accompanied by coinfections. The parasite undergoes a hepato-tracheal migration, evading the host immune system while triggering Th2-dominated cellular and humoral immune response with anti-inflammatory mechanisms that support parasite survival and modulate host immunity. In tropical areas, STH infections often overlap with malaria, which is treated using artemisinin-based combined therapies, known for their potent antimalarial effects. While ARTs' anthelmintic properties have been studied for trematodes and cestodes, their effects on gastrointestinal nematodes like A. lumbricoides remain underexplored. ARTs have also demonstrated immunomodulatory effects, including shifting macrophage phenotypes from anti-inflammatory (M2) to pro-inflammatory (M1). This study aimed to understand ARTs' potential in modulating Ascaris infections and their impact on mitochondrial metabolism by exploring the effects of ART therapy on Ascaris larvae and IL-4-polarized macrophages. It further investigated the humoral and peripheral blood transcriptomic responses to larval ascariasis and examined how coinfection with Salmonella impacts these responses. Aims: 1) To determine the metabolic profile of A. suum egg-stage larvae and explore the influence of ARTs on the identified metabolic profile 2) To ascertain whether ARTs influence macrophage polarization 3) To investigate the systemic antibody response against Ascaris larval and adult somatic antigen, and adult excretory/secretory antigen at 5wpi 4) To investigate the systemic and local humoral response in larval ascariasis (2wpi) and assess whether a secondary bacterial infection impacts the identified anti-Ascaris humoral response. 5) To investigate the transcriptional profile of peripheral blood mononuclear cells (PBMC) of Ascaris infected pigs at 2wpi and assess whether a secondary bacterial infection impacts the identified expression profile. Results: This study identified metabolically distinct regions in Ascaris larvae that remained unchanged following ART exposure, despite a reduction in larval viability after 48 hours. The larvae's mitochondria remained functional at both 24 and 48-hour time points. In contrast ART treatment induced a metabolic shift in resting (M0) and IL-4-polarized (M2-like) macrophages towards high anaerobic glycolysis with a reduction in PDH activity and overall metabolic activity. At 5wpi, adult ES exhibited stronger antibody immunodetection of IgM, IgG, IgA and IgG subclasses whereas somatic adult and larval antigens did not. Ascaris infection induced seroconversion as early as 2wpi with both Ascaris single- and co-infected pigs displaying high levels of Ascaris-specific antibodies in the serum, bile and BAL fluid. Of note, mixed systemic IgG1/IgG2 was observed while IgA production was prominent in intestinal mLNs. Relative to Ascaris single-infected pigs, sIgA levels of coinfected pigs displayed no association with eosinophils in the BAL and further displayed lower levels of IgA producing B cells in the ileal mLNs. Ascaris infection had no detectable effect on the peripheral blood transcriptome, which, surprisingly, remained unchanged even in the presence of Salmonella coinfection. Conversely, coinfection dampened transcriptomic responses associated with AP-1-mediated inflammatory monocyte activation against Salmonella. Conclusions: This study highlights the metabolic compartmentalization within Ascaris larvae, with the pharyngeal region exhibiting high oxidative metabolism and DUOX activity, likely supporting neuronal activity, cuticle maintenance, and defense mechanisms. ARTs, particularly artesunate and artemether, influenced larval viability by inducing oxidative stress rather than direct metabolic disruption. In macrophages, artesunate shifted M2-like cells toward glycolysis, mimicking pro-inflammatory M1 polarization, which may impact immune regulation during Ascaris infections. These findings provide new insights into host-parasite interactions and the immunometabolic effects of ARTs, warranting further in vivo studies to assess their broader implications. Additionally, this work demonstrates a mixed Th1/Th2 systemic humoral response and an active mucosal immunity, marked by IgA and eosinophil activity, suggesting an early defense mechanism against larval migration. Nonetheless, these local humoral responses were impacted by Salmonella infection. Furthermore, genes involved in AP-1-mediated inflammation were suppressed in co-infected pigs, potentially contributing to the dampened anti-Salmonella monocytic response.