Background: Schistosomiasis is a parasitic disease that affects more than 250 million individuals
worldwide. Compelling evidence suggests that schistosome eggs, rather than adult worms,
are responsible for significant tissue damage. S. mansoni eggs induce metabolic exhaustion and redox imbalance, which are critical for the
integrity of hepatocellular DNA. However, the precise mechanism by which egg antigens
transmit signals into host cells remains unclear. In this study, we investigated whether
S. mansoni egg antigens regulate the metabolic pathways of hepatocytes and enterocytes through
the insulin/insulin-like-growth-factor-receptor-1(IGF-1) receptor.
Methods: We employed RT-PCR array, western blotting, and immunohistochemistry to analyze markers
of insulin/IGF-1 receptor signaling in liver and colon tissue of mice infected with
S. mansoni. Additionally, we conducted functional experiments using colon epithelial cell lines,
which involved western blotting and assessment of AP-1 promoter activity.
Results:
S. mansoni infection in mice led to an upregulation of the following gene expression: Igf2,
Dok, Aebp1, Leptin, and Akt3, with Serpine1 being the most strongly induced. Conversely,
infection caused a decrease in the expression of Sos1, Irs1, and Gck, with G6pc being
the most strongly downregulated gene. Additionally, the activation of the insulin/IGF-1
receptor was pronounced in the perigranulomatous hepatocytes. Mechanistic experiments
utilizing the insulin/IGF-1 receptor inhibitor BMS 536924 revealed that S. mansoni egg antigens induced the activation of the insulin/IGF-1 receptor signaling cascade,
including the activation of the proto-oncogene c-Jun.
Conclusions: Our findings demonstrate that S. mansoni soluble egg antigens modulate the insulin/IGF-1 receptor signaling pathway in both,
murine and human hepatocytes and enterocytes, leading to an inhibition of gluconeogenesis.
This suggests that the parasite's soluble egg antigens may enhance insulin sensitivity
in the host. In a European cohort study serum IGF-1 correlates with the overall survival
of patients with HCC. Thus IGF-1 might serve as a useful additional parameter for
patient risk stratification. However, it remains unclear whether increased insulin
signaling influences the prognosis during S. mansoni infection.
