Structural Basis for Antagonism of Human Interleukin 18 by Poxvirus Interleukin 18-binding Protein

Joshua Shandera

Mentor: Dr. Yan Xiang

Human interleukin-18 (hIL-18) is a cytokine that plays an important role in inflammation and host defense against microbes. Its activity is regulated in vivo by a naturally occurring antagonist, the human IL-18-binding protein (IL-18BP). Functional homologs of human IL-18BP are encoded by all orthopoxviruses, including variola virus, the causative agent of smallpox. They contribute to virulence by suppressing IL-18 immune responses. Here, we reveal the crystal structure of an orthopoxvirus IL-18BP, ectromelia virus (mousepox) IL-18BP (ectvIL-18BP), in complex with hIL-18. EctvIL-18BP interacts with 3 cavities on the hIL-18 surface through extensive hydrophobic and hydrogen bonding interactions. Most of the ectvIL-18BP residues that participate in these interactions are found both human and viral homologs, explaining their functional equivalence. EctvIL-18BP blocks a common receptor-binding site on IL-18, thus preventing IL-18 from activating its receptor. When the residue K53 was mutated to alanine (K53A), the affinity was reduced 100-fold. Our structure provides insights into how IL-18BPs regulate hIL-18 activity. Knowing how the binding interface works allows research into the design of inhibitors against orthopoxvirus IL-18BP (for treating orthopoxvirus infection) or hIL-18 (for treating certain inflammatory and autoimmune diseases).

Collaborators: Brian Krumm, Xiangzhi Meng, Yongchao Li and Junpeng Deng