Impact of the host on Toxoplasm a stage differentiation

Abstract

The unicellular parasite Toxoplasma gondii infects warm-blooded animals and humans, and it is highly prevalent throughout the world. Infection of immunocompetent hosts is usually asymptomatic or benign but leads to long-term parasite persistence mainly within neural and muscular tissues. The transition from acute primary infection towards chronic toxoplasmosis is accompanied by a developmental switch from fast replicating and metabolically highly active tachyzoites to slow replicating and largely dormant bradyzoites within tissue cysts. Such developmental differentiation is critical for T. gondii in order to complete its life cycle and for pathogenesis. Herein, we summarize accumulating evidence indicating a major impact of the host cell physiology on stage conversion between the tachyzoite and the bradyzoite stage of the parasite. Withdrawal from cell cycle progression, proinflammatory responses, reduced availability of nutrients and extracellular adenosine can indeed induce tachyzoite-to-bradyzoite differentiation and tissue cyst formation. In contrast, high glycolytic activity as indicated by increased lactate secretion can inhibit bradyzoite formation. These examples argue for the intriguing possibility that after dissemination within its host, T. gondii can sense its cellular microenvironment to initiate the developmental program towards the bradyzoite stage in distinct cells. This may also explain the predominant localization of T. gondii in neural and muscular tissues during chronic toxoplasmosis.

Keywords: Toxoplasma gondii; bradyzoite; cell cycle; host cell; immune response; metabolism; parasite host-interaction; stage conversion.

Figure 1. FIGURE 1: T. gondii stage conversion and its regulation by the host (cell) microenvironment.

Within one to two weeks of infection, highly active tachyzoites (two parasitophorous vacuoles within human foreskin fibroblasts are depicted; left micrograph) convert to relatively dormant bradyzoites (a tissue cyst from mouse brain containing hundreds of individual bradyzoites is shown; right micrograph). Formation of long-lived bradyzoite-containing tissue cysts is crucial for parasite transmission to new hosts. Reconversion of bradyzoites to tachyzoites can occur in immunocompromised individuals (e.g. those with AIDS or transplant recipients (TPX)) leading to life-threatening disease. Distinct characteristics of the infected host cell or of bystander cells can trigger or inhibit differentiation towards the bradyzoite stage as indicated in the upper part of the figure. Noteworthy, parasite-intrinsic triggers may also govern stage differentiation (not depicted). See main text for further details.

Figure 2. FIGURE 2: T. gondii tissue cyst formation is supported by mature syncytial myotubes but not by proliferating myoblasts or fibroblasts.

C2C12 murine skeletal muscle cells (SkMCs) were differentiated in vitro to myotubes. Myotubes, myoblasts and fibroblasts were infected with T. gondii for 72 hours. Efficient myotube formation was verified by staining with an antibody against myosin heavy chain (MyHC), a marker of differentiation to mature SkMCs (red fluorescence). Total parasites irrespective of the parasite stage were labelled with an antiserum (blue fluorescence) and T. gondii tissue cysts were labelled with Dilichos biflorus lectin (DBL) recognizing the tissue cyst wall (green fluorescence). Representative images were recorded by confocal laser scanning microscopy.