Kundik, A. | Search bioRxiv

bioRxiv2024

Two-Photon NAD(P)H-FLIM reveals unperturbed energy metabolism of Ascaris suum larvae, in contrast to host macrophages upon artemisinin derivatives exposure

Soil-transmitted helminths (STH) are widespread, with Ascaris lumbricoides infecting millions globally. Malaria and STH co-infections are common in co-endemic regions. Artemisinin derivatives (ARTs)--artesunate, artemether, and dihydroartemisinin--are standard malaria treatments and are also known to influence the energy metabolism of parasites, tumors, and immune cells. Herein, we explore the potential of ARTs to influence ascariasis either by directly affecting larvae or indirectly by modifying macrophage responses. Ascaris suum third-stage larvae and porcine IL-4 polarised (M2-like) macrophages were exposed to ARTs in vitro, and their metabolism was evaluated using two-photon NAD(P)H-FLIM. Both larvae and M2-like macrophages exhibited a steady-state bioenergetic profile of high oxidative phosphorylation and low anaerobic glycolysis. In A. suum larvae, two metabolically distinct regions were identified, with particularly high DUOX activity in the pharynx compared to the midgut. The metabolic profile of both larval regions were, however, unperturbed by ARTs exposure. In contrast, exposure of M2-like macrophages to ARTs induced a metabolic shift towards high anaerobic glycolysis and reduced metabolic activity, suggesting a possible indirect effect of ARTs on the helminth infection. Overall, two-photon NAD(P)H-FLIM proved to be a powerful tool for studying specific metabolic pathways in Ascaris larvae and host macrophages, offering valuable insights into the metabolic mechanisms of drug action on both parasite and host.

biophysics↗

bioRxiv2024

Concurrent Ascaris infection modulates host immunity resulting in impaired control of Salmonella infection in pigs

Ascaris is one of the most widespread helminth infections of humans and pigs, leading to chronic morbidity in humans and considerable economic losses in pig farming. Additionally, pigs are an important reservoir for the zoonotic bacterial pathogen Salmonella, where pigs can serve as asymptomatic carriers. Here, we investigated the impact of an ongoing Ascaris infection on the immune response to Salmonella in pigs. We observed higher bacterial burdens in experimentally coinfected pigs compared to pigs infected with Salmonella alone. Ascaris-infected pigs exhibited numerous hallmarks of a type 2 immune response in organs impacted by larval migration, including increased Th2 cells, increased IL-4 production, eosinophilia, and increased expression of CD206, a marker for alternatively activated macrophages. While we observed only mild changes in frequencies of CD4+ Treg, Ascaris- infected pigs had increased frequencies of CD8+ Treg. We show that type 2 immune signals enhance susceptibility of macrophages to Salmonella infection in vitro. Furthermore, Ascaris impaired Salmonella-induced monocytosis and TNF- production by myeloid cells. Hence, our data demonstrate widespread immunomodulation during an acute Ascaris infection that facilitates the microbial spread into gut-associated lymphoid tissue in a Salmonella coinfection. ImportanceIn experimentally infected pigs we show that an ongoing infection with the parasitic worm Ascaris suum modulates host immunity to render pigs more susceptible to invading Salmonella. Both infections are widespread in pig production and the prevalence of Salmonella is high in endemic regions of human Ascariasis, indicating that this is a clinically meaningful coinfection. We observed a type 2 immune response to be induced during an Ascaris infection correlating with an increased susceptibility of pigs to the concurrent bacterial infection.

immunology↗