Research Article: Sexual Preferences in Nutrient Utilization Regulate Oxygen Consumption and Reactive Oxygen Species Generation in Schistosoma mansoni: Potential Implications for Parasite Redox Biology

Date Published: July 5, 2016

Publisher: Public Library of Science

Author(s): Matheus P. Oliveira, Juliana B. R. Correa Soares, Marcus F. Oliveira, Marc Liesa.

http://doi.org/10.1371/journal.pone.0158429

Abstract

Schistosoma mansoni, one of the causative agents of human schistosomiasis, has a unique antioxidant network that is key to parasite survival and a valuable chemotherapeutic target. The ability to detoxify and tolerate reactive oxygen species increases along S. mansoni development in the vertebrate host, suggesting that adult parasites are more exposed to redox challenges than young stages. Indeed, adult parasites are exposed to multiple redox insults generated from blood digestion, activated immune cells, and, potentially, from their own parasitic aerobic metabolism. However, it remains unknown how reactive oxygen species are produced by S. mansoni metabolism, as well as their biological effects on adult worms. Here, we assessed the contribution of nutrients and parasite gender to oxygen utilization pathways, and reactive oxygen species generation in whole unpaired adult S. mansoni worms. We also determined the susceptibilities of both parasite sexes to a pro-oxidant challenge. We observed that glutamine and serum importantly contribute to both respiratory and non-respiratory oxygen utilization in adult worms, but with different proportions among parasite sexes. Analyses of oxygen utilization pathways revealed that respiratory rates were high in male worms, which contrast with high non-respiratory rates in females, regardless nutritional sources. Interestingly, mitochondrial complex I-III activity was higher than complex IV specifically in females. We also observed sexual preferences in substrate utilization to sustain hydrogen peroxide production towards glucose in females, and glutamine in male worms. Despite strikingly high oxidant levels and hydrogen peroxide production rates, female worms were more resistant to a pro-oxidant challenge than male parasites. The data presented here indicate that sexual preferences in nutrient metabolism in adult S. mansoni worms regulate oxygen utilization and reactive oxygen species production, which may differently contribute to redox biology among parasite sexes.

Partial Text

The trematode Schistosoma mansoni is a long-living intravascular parasite and a major causative agent of human schistosomiasis, a chronic disease afflicting more than 240 million people worldwide [1]. Clinically, this illness is manifested in two distinct phases: an early acute one, when infected individuals exhibit mild symptoms such as fever, diarrhea and cough [2], and a late chronic phase, when severe clinical features including liver fibrosis, portal hypertension and hepatosplenomegaly, manifest [3]. These events are consequence of an intense inflammatory granulomatous reaction elicited by egg antigens deposited in intestine and liver [4–6]. Indeed, adult S. mansoni worms living in the mesenteric blood vessels are directly targeted by the host immune response [7,8]. Despite this, adult worms can live for decades within humans, implying the existence of efficient evasive mechanisms to counteract host immune response, which include i) reduced expression of antigenic proteins and the sequestering of host erythrocyte glycolipids at tegument surface [9,10], ii) the ability to mediate complement C3 degradation [8], iii) and the build-up of parasite antioxidant defenses along development [11–14].

In the present work, we demonstrate that in adult S. mansoni worms sexual preferences in nutrient utilization regulate endogenous parasite O2 consumption and ROS generation, which might differently contribute to redox biology among parasite sexes. A summary of the results presented here is schematically depicted in Fig 8. Blood-derived nutrients are absorbed through worm tegument or gut, and metabolized to their fundamental units. Glucose and glutamine are differentially oxidized through respiratory and non-respiratory pathways in adult worms, demanding distinct rates of O2 utilization among nutrients and parasite sexes. Glutamine metabolism plays a dominant role to sustain respiratory pathways in female worms, while glucose is the preferential substrate for this purpose in males. Interestingly, the opposite trend is observed in both non-respiratory O2 utilization and ROS formation among sexes, since glucose is the preferential substrate to generate ROS in females, while in male worms, glutamine prevails. Overall, respiratory rates are higher in males compared to females, while the rates of ROS production are higher in females. To cope with higher ROS levels generated endogenously by their own metabolism, redox adaptive mechanisms are more intensely activated in females than in males, mediating the build-up of antioxidant defenses, which ultimately confer higher tolerance to oxidative stress conditions. Therefore, we suggest that the higher levels of antioxidant defenses [67,78,85–87], and tolerance to redox challenges observed in female worms, seem to be a consequence of their higher endogenous ROS production generated by the parasite metabolism. Given that schistosomiasis clinically manifests by the inflammatory reaction triggered by antigens released by parasite eggs deposited in host tissues, targeting redox adaptive response mechanisms in adult worms might reveal an interesting venue for the development of new classes of schistosomicidal agents.

 

Source:

http://doi.org/10.1371/journal.pone.0158429