IL-18BP mediates the balance between protective and pathological immune responses to Toxoplasma gondii.

Interleukin-18 (IL-18) promotes natural killer (NK) and T cell production of interferon (IFN)-γ, a key factor in resistance to Toxoplasma gondii, but previous work has shown a limited role for endogenous IL-18 in control of this parasite. Although infection with T. gondii results in release of IL-18, the production of IFN-γ induces high levels of the IL-18 binding protein (IL-18BP). Antagonism of IL-18BP with a "decoy-to-the-decoy" (D2D) IL-18 construct that does not signal but rather binds IL-18BP results in enhanced innate lymphoid cell (ILC) and T cell responses and improved parasite control. In addition, the use of IL-18 resistant to IL-18BP ("decoy-resistant" IL-18 [DR-18]) is more effective than exogenous IL-18 at promoting innate resistance to infection. DR-18 enhances CD4+ T cell production of IFN-γ but results in CD4+ T cell-mediated pathology. Thus, endogenous IL-18BP restrains aberrant immune pathology, and this study highlights strategies that can be used to tune this regulatory pathway for optimal anti-pathogen responses.

Exploring synergy and its role in antimicrobial peptide biology.

Antimicrobial peptides will be an essential component in combating the escalating issue of antibiotic resistance. Identifying synergistic combinations of two or more substances will increase the value of these peptides further. Several potential pitfalls in conducting synergy testing with peptides are discussed in detail. As case studies, we describe observations of AMP synergy with peptides, antibiotics, and metal ions as well as some of the mechanistic details that have been uncovered. The Bliss and Loewe models for synergy are presented prior to recommending protocols for conducting checkerboard, minimal inhibitory concentration, and time-kill assays. Establishing mechanisms of action and exploring the potential for resistance will be crucial to translate these studies into the clinic.