The Schistosomiasis SpleenOME: Unveiling the Proteomic Landscape of Splenomegaly Using Label-Free Mass Spectrometry

Abstract

Schistosomiasis is a neglected parasitic disease that affects millions of people worldwide and is caused by helminth parasites from the genus Schistosoma. When caused by S. mansoni, it is associated with the development of a hepatosplenic disease caused by an intense immune response to the important antigenic contribution of adult worms and to the presence of eggs trapped in liver tissue. Although the importance of the spleen for the establishment of immune pathology is widely accepted, it has received little attention in terms of the molecular mechanisms operating in response to the infection. Here, we interrogated the spleen proteome using a label-free shotgun approach for the potential discovery of molecular mechanisms associated to the peak of the acute phase of inflammation and the development of splenomegaly in the murine model. Over fifteen hundred proteins were identified in both infected and control individuals and 325 of those proteins were differentially expressed. Two hundred and forty-two proteins were found upregulated in infected individuals while 83 were downregulated. Functional enrichment analyses for differentially expressed proteins showed that most of them were categorized within pathways of innate and adaptive immunity, DNA replication, vesicle transport and catabolic metabolism. There was an important contribution of granulocyte proteins and antigen processing and presentation pathways were augmented, with the increased expression of MHC class II molecules but the negative regulation of cysteine and serine proteases. Several proteins related to RNA processing were upregulated, including splicing factors. We also found indications of metabolic reprogramming in spleen cells with downregulation of proteins related to mitochondrial metabolism. Ex-vivo imunophenotyping of spleen cells allowed us to attribute the higher abundance of MHC II detected by mass spectrometry to increased number of macrophages (F4/80+/MHC II+ cells) in the infected condition. We believe these findings add novel insights for the understanding of the immune mechanisms associated with the establishment of schistosomiasis and the processes of immune modulation implied in the host-parasite interactions.

Proteomic Profiling of the Liver, Hepatic Lymph Nodes, and Spleen of Buffaloes Infected with Fasciola gigantica

“…A proteomic investigation of Schistosoma mansoni infection in an animal model showed that altered spleen proteome modulates host immune responses [34]. In the present study, the altered proteins of the spleen were not significantly enriched in any immune-related response during F. gigantica infection.…”

Schistosome and intestinal helminth modulation of macrophage immunometabolism

“…Changes in the catabolic metabolism of the murine host’s spleen have been observed during acute infection with S. mansoni . Several pathways related to the TCA cycle, respiratory transport and amino acid metabolism were differentially expressed in infected mice at the peak of the acute phase as determined by a large‐scale, label‐free shotgun proteomics approach, with many of these alterations attributable to macrophages, highlighting the impact of schistosome infection on the metabolic modulation of organ‐specific macrophage populations 133 …”

HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein

“…After necropsy, the liver, spleen, heart, and kidneys of each mouse were weighed and carefully examined. Splenomegaly is a hallmark of the inflammation induced by helminth infections 30 ( Figure 3 d). Neither nelfinavir nor albendazole treatment resulted in a significant reduction of spleen weights ( Figure 3 d).…”