The role of TGF-β signaling and apoptosis in innate and adaptive immunity in zebrafish: a systems biology approach

Background: The immune system is a key biological system present in vertebrates. Exposure to pathogens elicits various defensive immune mechanisms that protect the host from potential threats and harmful substances derived from pathogens such as parasites, bacteria, and viruses. The complex immune system of humans and many other vertebrates can be divided into two major categories: the innate and the adaptive immune systems. At present, analysis of the complex interactions between the two subsystems that regulate host defense and inflammatory responses remains challenging. Results: Based on time-course microarray data following primary and secondary infection of zebrafish by Candida albicans, we constructed two intracellular protein-protein interaction (PPI) networks for primary and secondary responses of the host. 57 proteins and 341 PPIs were identified for primary infection while 90 proteins and 385 PPIs were identified for secondary infection. There were 20 proteins in common while 37 and 70 proteins specific to primary and secondary infection. By inspecting the hub proteins of each network and comparing significant changes in the number of linkages between the two PPI networks, we identified TGF-beta signaling and apoptosis as two of the main functional modules involved in primary and secondary infection. Smad7, a member of the inhibitor SMADs, was identified to be a key protein in TGF-beta signaling involved in secondary infection only. Indeed, the Smad7-dependent feedback system is related to the TGF-beta signaling pathway and the immune response, suggesting that Smad7 may be an important regulator of innate and adaptive immune responses in zebrafish. Furthermore, we found that apoptosis was differentially involved in the two infection phases; more specifically, whereas apoptosis was promoted in response to primary infection, it was inhibited during secondary infection. Conclusions: Our initial in silico analyses pave the way for further investigation into the interesting roles played by the TGF-beta signaling pathway and apoptosis in innate and adaptive immunity in zebrafish. Such insights could lead to therapeutic advances and improved drug design in the continual battle against infectious diseases.