Toxoplasma Co-opts Host Cells It Does Not Invade

Koshy, Anita A.; Dietrich, Hans K.; Christian, David A.; Melehani, Jason H.; Shastri, Anjali J.; Hunter, Christopher A.; Boothroyd, John C.

doi:10.1371/journal.ppat.1002825

Cited by 158 publications

(194 citation statements)

References 41 publications

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“…In addition, pSTAT6 nuclear translocation, which is dependent on ROP16, can be observed in vitro and in vivo in a percentage of uninfected cells, consistent with the idea that multiple rhoptry proteins are entering these uninfected cells (105). Importantly, rhoptry secretion into uninfected cells appears to be a widespread phenomenon and can be observed in diverse types of immune and nonimmune cells (105).…”

Section: Toxoplasma Modulation Of Uninfected Cells: Is the Parasite Ssupporting

confidence: 63%

“…Using these Toxoplasma-Cre parasites to infect reporter cells that express only a green fluorescent protein (GFP) after Cre excises a stop codon, GFP could be detected in both infected and uninfected cells (104). In addition, pSTAT6 nuclear translocation, which is dependent on ROP16, can be observed in vitro and in vivo in a percentage of uninfected cells, consistent with the idea that multiple rhoptry proteins are entering these uninfected cells (105). Importantly, rhoptry secretion into uninfected cells appears to be a widespread phenomenon and can be observed in diverse types of immune and nonimmune cells (105).…”

Section: Toxoplasma Modulation Of Uninfected Cells: Is the Parasite Ssupporting

confidence: 61%

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Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Blader

Koshy

2014

Eukaryot Cell

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b Intracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections. Toxoplasma gondii is an obligate intracellular protozoan that infects ϳ30% of the world's population and causes severe and lifethreatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence of Toxoplasma in humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by which Toxoplasma interacts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.T oxoplasma gondii is a protozoan, obligate intracellular parasite that is considered one of the world's most successful pathogens (1). Multiple factors contribute to this success, including a complex life cycle in which the parasite can be transmitted by both vertical and horizontal means, efficient propagation within both its primary (felines) and intermediate hosts, extensive mechanisms to evade and disarm host immunity, an ability to form chronic lifelong infections in intermediate hosts, and a wide host tropism in which the parasite can infect most nucleated cells of warm-blooded animals (2). Central to most of these factors is that Toxoplasma has developed the means to replicate efficiently within the hostile intracellular environment of its host cell. In this review, we highlight recent data that have shed light on how parasite growth is achieved by the parasite interacting with its host cell to manipulate host signaling cascades, transcription, cell survival pathways, and membrane transport. In addition, we discuss how parasites interact with neighboring host cells and propose how this may contribute to establishing a permissive microenvironment to improve its overall success. In particular, we focus on those processes that are essential for the growth of all parasite strains and we refer readers to recent reviews that highlight how polymorphic parasite molecules contribute to Toxoplasma virulence (3-5). NUTRIENT ACQUISITIONAs an obligate intracellular parasite that resides within a nonfusogenic vacuole, Toxoplasma must satisfy its nutritional needs by scavenging essential nutrients from its host cell. These nutrients include carbon sources (glucose and glutamine) to fuel its energy demands, specific amino acids, lipids, and other nutrients. Below, we discuss each of these and highlight pathways and processes that are unique to the parasite that could serve as novel drug targets (Fig. 1). GLUCOSE AND GLUTAMINE POWER THE PARASITEToxoplasma expresses a full complement of glycolytic and tr...

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Section: Toxoplasma Modulation Of Uninfected Cells: Is the Parasite Ssupporting

confidence: 63%

Section: Toxoplasma Modulation Of Uninfected Cells: Is the Parasite Ssupporting

confidence: 61%

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Blader

Koshy

2014

Eukaryot Cell

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“…Therefore, actively invaded cells will display both RFP and GFP fluorescence, whereas cells that have phagocytosed parasites or that were invaded relatively recently will display only RFP fluorescence. Cells displaying only GFP fluorescence are thought to result from parasites injecting proteins into cells that they do not subsequently invade (33). Using this model, we demonstrated that ∼2% of lamina propria neutrophils, compared with <0.1% of other CD45 + cells, expressed GFP and therefore were actively invaded by T. gondii (Fig.…”

Section: Significancementioning

confidence: 88%

Motile invaded neutrophils in the small intestine ofToxoplasma gondii-infected mice reveal a potential mechanism for parasite spread

Coombes

Charsar

Han

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laserscanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.neutrophil motility | dynamic imaging | gut | mucosal immunology T oxoplasma gondii infects around a third of humans worldwide and is widely dispersed in other warm-blooded hosts. Although clinical manifestations in the brain, eye, and developing fetus receive the most attention, T. gondii is an oral pathogen and first enters the body and establishes infection in the small intestine. Infection follows consumption of cyst-containing meat or oocyst-contaminated water and produce and is associated with the development of small intestinal pathology in a variety of nonhuman hosts (1). Most notably, experimental infection of C57BL/6 mice by the oral route results in an inflammation of the small intestine that shares immunological features with inflammatory bowel disease (2). This model is useful to further our understanding of host-pathogen interactions in the intestine and of common mechanisms underpinning the development of inflammatory bowel disease (3). Nevertheless, we have limited understanding of how and in which cells infection is established in the intestine, the extent to which the parasite replicates and spreads within the intestine, and how these factors contribute to the development of pathology (2, 4-9). The ability to label living parasites fluorescently and track them in the tissues of infected hosts provides an important tool for investigating these questions (10)(11)(12)(13)(14).Starting in the small intestine, T. gondii must travel long distances and surmount a variety of biological barriers to establish chronic infection in the brain. These barriers include the mucus, the intestinal epithelium, and the blood-brain barrier (7,15). Cells of the immune system are often highly motile and represent attractive transport vessels for pathogens seeking to reach and enter tissues while being protected from the external environment. Consequently, recent studies have focused on the role of immune cells in transporting parasites between tissues (4, 16-23). For example, cluster of differentiation 11b-positive (CD11b + ) cells have been implicated in the dissemination of T. gondii through the blood and across the blood-brain barrier (4, 19). Following oral infection, i...

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“…T. gondii can inject effector proteins into the host cell cytosol that activate the host cell transcription factors STAT3 and STAT6, two transcription factors associated with inhibition of IL-12 (36)(37)(38)(39). In addition, recent in vitro and in vivo studies that used parasites that inject Cre recombinase along with their normal cargo of rhoptry proteins (Toxoplasma-Cre parasites) combined with Ai6 mice bearing the Cre-dependent reporter (ZsGreen1 fluorescent protein) (40) revealed that the injection of rhoptry proteins into bystander cells (or multiple cells by serial injection) without invasion is one mechanism that results in a population previously designated uninfected-injected (U-I) cells (36,41,42). These previous studies indicated that U-I cells could also result from division of infected cells or from infected cells activated to kill and clear the intracellular parasite (41), and this study classifies all cells that are subject to these host-parasite interactions as U-I cells.…”

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confidence: 99%

Use of Transgenic Parasites and Host Reporters To Dissect Events That Promote Interleukin-12 Production during Toxoplasmosis

et al. 2014

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The intracellular parasite Toxoplasma gondii has multiple strategies to alter host cell function, including the injection of rhoptry proteins into the cytosol of host cells as well as bystander populations, but the consequence of these events is unclear. Here, a reporter system using fluorescent parasite strains that inject Cre recombinase with their rhoptry proteins (Toxoplasma-Cre) was combined with Ai6 Cre reporter mice to identify cells that have been productively infected, that have been rhoptry injected but lack the parasite, or that have phagocytosed T. gondii. The ability to distinguish these host-parasite interactions was then utilized to dissect the events that lead to the production of interleukin-12 p40 (IL-12p40), which is required for resistance to T. gondii. In vivo, the use of invasion-competent or invasion-inhibited (phagocytosed) parasites with IL-12p40 (YET40) reporter mice revealed that dendritic cell (DC) and macrophage populations that phagocytose the parasite or are infected can express IL-12p40 but are not the major source, as larger numbers of uninfected cells secrete this cytokine. Similarly, the use of Toxoplasma-Cre parasite strains indicated that dendritic cells and inflammatory monocytes untouched by the parasite and not cells injected by the parasite are the primary source of IL-12p40. These results imply that a soluble host or parasite factor is responsible for the bulk of IL-12p40 production in vivo, rather than cellular interactions with T. gondii that result in infection, infection and clearance, injection of rhoptry proteins, or phagocytosis of the parasite.

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Toxoplasma Co-opts Host Cells It Does Not Invade

Cited by 158 publications

References 41 publications

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Motile invaded neutrophils in the small intestine ofToxoplasma gondii-infected mice reveal a potential mechanism for parasite spread

Use of Transgenic Parasites and Host Reporters To Dissect Events That Promote Interleukin-12 Production during Toxoplasmosis

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