Guanylate binding proteins directly attack Toxoplasma gondii via supramolecular complexes

A microscopic parasite called Toxoplasma gondii causes a serious disease known as toxoplasmosis in humans and other mammals. Once inside the body, the parasite can infect host cells, where it hides inside a cell structure called a vacuole. However, this triggers self-defense mechanisms in the infected cells that help to control the spread of the parasite in the body. Proteins called guanylate binding proteins – which are normally found as small units in healthy host cells – bind to each other and form larger “complexes” that promote immune responses in that particular cell. However, it was not known how the guanylate binding proteins congregate to form the complexes, or how this activates the cell’s defenses. Here, Kravets et al. use sophisticated fluorescence microscopy techniques with living cells to study the roles of guanylate binding proteins in immune responses during T. gondii infection. The experiments show that the proteins are stored as larger units in structures within healthy cells that allow them to relocate quickly to the vacuole when the parasite is detected. Once there, the guanylate binding proteins form large complexes that can contain thousands of protein units. The process requires energy that is released from the break down of a molecule called GTP, and specific chemical modifications to the guanylate binding proteins to allow them to bind to each other. Further experiments found that the guanylate binding proteins in the complexes assist in weakening the structure of the vacuoles, and that subsequently, one type of protein – called GBP2 – directly attacks the parasite itself. Kravets et al.’s findings set the stage for the development of new therapies that help to fight T. gondii infections.