Using label-free shotgun proteomics and systems biology to explore the complex immune dynamic of splenomegaly during acute schistosomiasis mansoni.

Abstract

Schistosomiasis is a neglected tropical disease that affect millions of people worldwide and it is caused by the infection with parasites of the genus Schistosoma. When caused by S. mansoni, schistosomiasis is characterized by the formation of liver granuloma, due to the presence of eggs trapped in the tissue, and the concurrent development of liver fibrosis that could lead to life lasting chronic complications. In this context, the spleen has been demonstrated to be a very responsible organ, with splenomegaly being one of the major hallmarks of schistosomiasis. Nevertheless, it has received little attention in terms of which immune and molecular mechanisms could be governing this host-parasite interplay and the development of this condition. In this study, we used mass spectrometry-based shotgun proteomics combined with systems biology tools to explore the complex molecular dynamic in the spleen at the acute phase of inflammation in a mice model of infection by S. mansoni. More than fifty hundred proteins were identified in the spleen proteome, and 325 of them were differentially expressed between infected and control individuals. Functional enrichment analyses showed that most differentially expressed proteins were categorized within pathways of innate and adaptive immunity, DNA replication, vesicle transport and catabolic metabolism. There was a significant enrichment of pathways associated with antigen processing and presentation, with an increased expression of MHC class II proteins and the negative regulation of cysteine and serine proteases. Indications of metabolic reprogramming were also found, with the downregulation of a set of proteins related to mitochondrial metabolism. It was also possible to establish a link between the variation in protein expression in the spleens with variations in subpopulations of spleen cells as revealed by flow cytometry analyses. These suggested the increased proportion of MHC-II-presenting macrophages with the higher abundance of MHC-II proteins measured by mass spectrometry. With this, we presented the first proteomic shotgun analysis of the spleen during schistosomiasis, offering new insights on the understanding of immune mechanisms associated with the establishment of the disease and other processes of immune modulation related to the host-parasite interplay.