Toxoplasma control of host apoptosis: the art of not biting too hard the hand that feeds you.

Abstract

Toxoplasma gondii is an obligate intracellular parasite that is able to infect a multitude of different vertebrate hosts and can survive in virtually any nucleated cell. The tachyzoite form of the parasite is very efficient at actively invading its host cells, where it establishes itself in a parasitophorous vacuole (PV). In this non fusogenic vacuole, the parasite is able to escape degradation from the endolysosomal system [1]. The host endoplasmic reticulum and mitochondria are recruited to the periphery of the PV membrane shortly after invasion (Fig. 1), possibly as a source of nutrient for the parasite [2]. Tachyzoites will subsequently undergo multiple rounds of cell division before being able to egress and, as a consequence, lyse the host cell (Fig. 1). To develop a suitable replicating niche, T. gondii is able to modulate gene expression in its host cell [3]. This is achieved through secretion of virulence factors from specialized organelles (Fig. 1): first, rhoptries are secreting socalled ROP proteins directly into the host cytosol as the parasite actively invades and forms the PV, then dense granules will release GRA proteins that will constitute a membranous nanotubular network inside the PV, or be exported at the PV membrane. These proteins are actively involved in the modulation of key host signaling pathways such as JAK/STAT (ROP16) [4], MAP kinase (ROP38, GRA24) [5,6], P53 (GRA16) [7] or NF-κB (GRA15) [8]. The ability to interfere with these pathways has a profound impact on the immune and inflammatory responses from the host and thus on parasite survival and virulence. Indeed, most of the Toxoplasma strains found in Europe and North America are highly clonal, but they can be subdivided into three main lineages (I, II and III), which differ markedly for their pathogenicity in vivo and, because of a differential expression of the aforementioned virulence factors, they have different strategies to induce or disrupt the host immune response (see [9,10] for a review). Of course, the in vivo situation is very complex as it involves a variety of host tissue and cell types that provide a diverse, and more or less favorable, background for the parasite to dwell in. One important host pathway impacted by parasite factors is apoptosis. Apoptosis is a genetically-programmed cell death mechanism [11]. There are two basic apoptotic signaling pathways: the extrinsic and the intrinsic pathways. The two apoptosis pathways converge on a common “execution” phase, which is driven by proteases known as caspases. Upon activation, these caspases cleave specific substrates and this will subsequently lead to the demise of the cell. The extrinsic pathway of apoptosis is initiated by the binding of death ligands such as the Fas ligand or TNF-α, to specific “death receptors” of the TNF receptor superfamily. The intrinsic pathway is activated by a variety of internal stimuli, including growth factor deprivation, DNA damage, oxidative stress, as well as invasion by pathogens. This pathway is largely centered around the mitochondria [12]. Bcl-2 family members, such as Bax and Bak, trigger a mitochondrial outer membrane permeabilization (MOMP) event that will, in turn, lead to the release of mitochondrial intermembrane space proteins, including cytochrome c (Fig. 1). Once in the cytosol, cytochrome c binds an adaptor molecule called apoptotic protease-activating factor 1 (Apaf-1), leading to its oligomerization to form a heptameric structure called the apoptosome [13] (Fig. 1). The apoptosome recruits and activates pro-caspase-9 that, in turn, cleaves and activates the executioner caspases-3 and -7 in mammals. As mentioned above, apoptosis is one of the ways mammalian cells can respond to an infection by pathogens [14]. As the death of the infected cell is usually concomitant with the death of the infecting agent, self-destruction can promote efficient pathogen clearance. Several intracellular pathogens, including T. gondii, have thus apparently evolved means of interfering with the apoptosis machinery in order to keep their host alive, at least for the time needed for them to replicate efficiently. On the other hand, one should note that a highly virulent type I Toxoplasma strain