Intracellular pathogens under attack

T he immune system provides a formidable barrier that prevents us from being overwhelmed by the numerous microbial pathogens that we encounter every day. However, many pathogens manage to escape the immune system by invading cells and replicating within them. To counter these pathogens immune cells produce a powerful cytokine called interferon-g that reprograms the invaded cells to express hundreds of antimicrobial proteins. These proteins transform the cells into a hostile environment for pathogens. Among the most abundant of the antimicrobial proteins is a group of enzymes that bind and hydrolyze guanosine triphosphate (GTP). Nucleotide binding allows these enzymes, which are called guanylate-binding proteins (GBPs), to form oligomers (Kravets et al., 2012; Praefcke et al., 2004). Several GBPs also contain hydrophobic groups that enable them to associate with membranes. GBPs are highly conserved in vertebrates and essential for the cellautonomous defense in vivo against many intracellular pathogens. Mice deficient in GBPs are highly susceptible to infections with a protozoan parasite called Toxoplasma gondii that is commonly found in the developed world, and which can cause serious and often fatal infections in people with weakened immune systems (Yamamoto et al., 2012). T. gondii replicates within host cells in a membranous compartment known as the parasitophorous vacuole (PV). Intriguingly the antimicrobial function of GBPs is tightly linked with their ability to target and disturb the membrane of this vacuole (Degrandi et al., 2007; Degrandi et al., 2013; Selleck et al., 2013). However, relatively little is known about the ways in which proteins co-operate to restrict pathogen replication. Now, in eLife, Klaus Pfeffer, Claus Seidel and co-workers at the Heinrich-Heine University Düsseldorf – including Elisabeth Kravets, Daniel Degrandi and Qijun Ma as joint first authors – report a comprehensive analysis of how different GBPs assemble into large complexes to control the replication of T. gondii (Kravets et al., 2016). They also demonstrate for the first time that in addition to targeting the PV, the GBPs attack the parasite directly. Kravets et al. used a technique called multiparameter fluorescence imaging spectroscopy (MFIS) to study fluorescently-tagged murine GBP2 in real-time. The data show the preassembly of dimers and oligomers containing mainly GBP2, but also GBP1 and GBP3, in vesicle-like structures in the cytosol of uninfected Copyright Broz. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Related research article Kravets E, Degrandi