Phagocyte responses to protozoan infection and how Toxoplasma gondii meets the challenge.

The intracellular protozoan Toxoplasma gondii is arguably the most successful parasite on the planet. It exploits an uncommonly wide host range that encompasses essentially all warm-blooded animals including both mammalian and avian species. Sexual reproduction in the intestine of the definitive host, the cat, results in fecal shedding of up to 108 highly infectious oocysts. The presence of felines from equatorial latitudes to sub-arctic regions of the globe ensures widespread distribution of the parasite. Moreover, unlike closely related apicomplexans such as the Plasmodia, passage through the definitive host is not obligatory to complete the life-cycle, because T. gondii can be transmitted from one intermediate host to the next through predation and carnivorism [1]. While Toxoplasma causes asymptomatic infection in most hosts, the parasite may emerge as an opportunistic infection under immunodeficient conditions such as in AIDS patients and during congenital infection. This danger underscores the importance of the encounter between T. gondii and the host immune system in determining the success of this particular host-parasite interaction. It is well understood that complete evasion of immunity (or for that matter passive failure to trigger immunity) results in rampant infection and host death, an outcome undesirable for both host and parasite. At the same time, we are learning in greater detail the mechanisms employed by the host immune system to destroy Toxoplasma. The parasite must obviously avoid this outcome of immunity to ensure persistence. The global success of T. gondii (over 109 asymptomatic infections in humans alone) suggests that the parasite employs sophisticated molecular strategies to balance evasion versus activation of the host immune response. As summarized in Figure 1, the multiple ways this unifying principle plays out is revealed in studies on infection in phagocytes of innate immunity, namely dendritic cells (DC), macrophages, and neutrophils. These cells are among the first to encounter and be infected by Toxoplasma after the parasite crosses the intestinal epithelium. The studies together form a platform from which we can further understand the complex relationship between microbial pathogens and cells of the innate immune system. Figure 1 Integrating phagocyte function with T. gondii infection. Dendritic Cells Are Sentinels and Trojan Horses Early on it was recognized that DC were an early source of IL-12 driving protective Th1 responses to Toxoplasma. Further studies using an intraperitoneal infection model showed that ablation of CD11c+ DC results in failure to mount protective immunity and death during infection [2]. With the discovery of Toll-like receptors (TLR) and their ligands in the late 1990s, attention turned to the role of this system in sensing protozoan pathogens, in particular T. gondii [3]. Indeed, mice lacking MyD88, a central adaptor of TLR signaling, are extremely susceptible to infection. More specifically, it has been shown using cell-specific gene-deleted mouse strains that MyD88 expression in CD11c+ dendritic cells is required to resist Toxoplasma infection [4]. There is evidence for involvement of mouse TLR2, TLR4, TLR9, and TLR11 in the innate immune response to T. gondii [3]. Of these receptors, deletion of TLR11 has the most dramatic effect on loss of host resistance [5]. However, Tlr11−/− mice fail to recapitulate the extreme susceptibility phenotype of Myd88−/− mice. This has led to the suggestion that multiple TLR function together to provide optimal resistance, or alternatively that other untested TLR serve as the major MyD88-dependent receptor mediating protective immunity. Toxoplasma profilin (TgPRF), an actin polymerizing molecule, is the ligand recognized by TLR11 [5]. In DC, TgPRF stimulates TLR11-dependent IL-12 production. Interestingly, it was recently found that this response occurs through phagocytic uptake of parasite material followed by TLR11 activation from within the endolysosome [6]. Surface-expressed glycosylphosphatidylinositol moieties purified from tachyzoites have also been found to mediate TLR2 and TLR4 activation [3], although the in vivo importance of this phenomenon is not clear. While the TLR11/TgPRF interaction is significant in the rodent response to Toxoplasma, the importance of TgPRF in human infection is uncertain since we do not express functional TLR11. In addition to TLR-dependent recognition of Toxoplasma, there is clear evidence for MyD88-independent resistance. This is because Myd88−/− mice develop strong (albeit delayed) Th1 responses during oral infection, and the same mouse strain develops protective immunity following intraperitoneal infection with attenuated parasites [7]. In this regard, it was recently shown that release of tachyzoite dense granule protein GRA5 into the host cytoplasm by intracellular parasites bypasses MyD88 to activate NFκB and stimulate IL-12 synthesis [8]. The relative roles that profilin and GRA5 assume during normal infection have not yet been determined. However, GRA5 IL-12 inducing properties are parasite strain-specific, in that only one lineage (Type II) of the three predominant strains found in Europe and North America possess this activity [8]. On the other hand, there is no evidence that profilin acts in a parasite-strain-dependent manner. Another function of DC during the response to Toxoplasma is to serve as early reservoirs of infection [9], [10]. It has been suggested that parasites utilize DC in a “Trojan horse” strategy to disseminate throughout the host. Upon in vitro infection, DC acquire a hypermotility phenotype that is dependent upon host cell G-protein signaling triggered by the parasite. Intraperitoneal inoculation of tachyzoite-harboring DC spreads infection more rapidly than injection of extracellular parasites alone, suggesting that DC hypermotility promotes dissemination during in vivo infection, although whether a similar phenomenon occurs during oral infection is not clear [11]. Interestingly, hypermotility and in vivo dissemination of infected DC occur most efficiently with Type II Toxoplasma, the strain most frequently found in human infection [12].