Programmed cell death (PCD) pathways are genetically programmed mechanisms that can trigger the cell to die or commit “cell suicide”. There are three major forms of programmed cell death that are now recognized: apoptosis (type I), autophagy (type II) and necrotic cell death or necroptosis (type III). While these cell death processes were once thought to occupy discrete cell states, evidence suggests that apoptosis, autophagy and necrosis are often regulated by similar pathways and share initiator and effector molecules and some subcellular compartments indicating that crosstalk exists between these three main forms of cell death pathways, resulting in a balanced interplay by which the cell decides its fate. PCD pathways have important roles in many cellular processes such as development and oncogenic transformation, but PCD pathways also play important roles in host defense and elimination of pathogens. Toxoplasma gondii is a microbial pathogen for which programmed cell death pathways are a key part of the host defense. T. gondii is an obligate intracellular protozoan parasite that infects approximately one-third of the world’s population. In most immunocompetant individuals, the chronic infection is asymptomatic due to an effective immune response that eliminates active parasite replication. The parasite has evolved immune evasion strategies that enable it to survive and persist long enough in the host however to establish a chronic infection in which the cyst stage persists within neurons in the brain and skeletal muscle in the periphery. T. gondii has evolved multiple mechanisms to resist killing by apoptotic, autophagic and necrotic cell death pathways, and the parasite’s manipulation of host PCD pathways plays a crucial role in host–parasite interactions and maintenance of the chronic infection. While most individuals chronically infected with T. gondii are asymptomatic, severe disease can occur in immunocompromised individuals where the infection reactivates from the brain causing severe necrotizing encephalitis, and increasing evidence indicates chronic cerebral toxoplasmosis in some individuals may lead to neuropsychiatric disorders such as schizophrenia and suicidal behavior. This review will focus on the role of PCD pathways in host defense of T. gondii and the parasite manipulation of these PCD pathways. A better understanding of the molecular components underlying the PCD pathways and the parasite manipulation of these pathways may yield new therapeutic targets for treatment of clinical sequelae of cerebral toxoplasmosis.
Overview of Programmed Cell Death (PCD) pathways and applications to
Toxoplasma gondii infection
Programmed cell death (PCD) pathways are genetically programmed mechanisms that can trigger the cell to die or commit “cell suicide”. There are three major forms of programmed cell death which are now recognized: apoptosis (type I), autophagic cell death (type II) and necrotic cell death or necroptosis (type III) [1–4]. Apoptosis, the best-characterized and dominant form of PCD, is a controlled physiological process of cellular self-destruction that removes dead cells without damage to the host. Apoptosis is critically important during development and morphogenesis and eliminates damaged cells such as cancerous cells or infected cells that may interfere with normal function. Necrosis, conversely, is a cell death process that is observed in response to severe stresses such that occurs after physical injury or prolonged ischemia and has been long thought to be an unregulated process. However, a programmed form of necrotic death, called necroptosis, is now recognized that can occur during physical traumas, in neurodegeneration, in cell death due to ischemia or infection and that, in contrast to unordered necrosis, has dedicated molecular pathways controlling necrotic cell death. Autophagy is predominantly a strategy for survival and not death, serving as a housekeeping mechanism of normal turnover of long-lived proteins and whole organelles and crucial to maintenance of healthy cells. However, autophagy can promote cell death during normal development and excessive autophagy, stimulated in times of stress such as nutrient deprivation and some diseases, can lead to what is now recognized as autophagic cell death [5–7]. While these cell death processes were once thought to occupy discrete cell states, evidence suggests apoptosis, autophagy and necroptosis are often regulated by similar pathways, share initiator and effector molecules and some subcellular compartments indicating a complex crosstalk exists between these three main forms of cell death pathways, resulting in a balanced interplay by which the cell decides its fate .
PCD pathways are also an important part of host defense against intracellular pathogens. The intracellular protozoal pathogen,
2. Apoptosis, necroptosis and autophagic cell death pathways: Morphological features and molecular components
Apoptosis, necroptosis and autophagic cell death pathways operate via distinct genetically programmed molecular mechanisms containing dedicated molecular components and leading to characteristic morphological features (Figure 1). Apoptosis operates via a caspase-dependent mechanism while necroptosis and autophagic cell death are caspase-independent processes, with autophagic cell death being cathepsin-dependent and necroptosis mediated via the receptor interacting protein kinase 3 (RIP3) and its substrate, the mixed lineage kinase-like domain protein, MLKL . Apoptosis results in mitochondrial membrane permeabilization, chromatin condensation and DNA fragmentation, resulting in cells become smaller (pknotic) and membrane blebbing into apoptotic bodies. Phagocytes, such as macrophages, subsequently engulf apoptotic cells and hence apoptosis is considered a noninflammatory form of programmed cell death. Necrotic cell death, in contrast to apoptosis, is marked by swelling of ER and mitochondrial organelles, increase in cell size, rapid rupture of the plasma membrane resulting in lysis of the cell and release of danger-associated molecular patterns (DAMPs) which stimulate inflammation. While necrosis has traditionally been considered to be “pathological cell death”, necroptosis is now recognized to occur via a regulated mechanism that is inhibited by caspases [9, 10]. Autophagy is the process by which cells recycle cellular constituents and involves engulfment of cytoplasmic material and intracellular organelles within double-membrane vesicles called autophagosomes that fuse with lysosomes to make autophagolysosomes that degrade the cellular cargo via cathepsins located in the autolysosomes. The molecular components and signaling pathways of each cell death processes are reviewed below, followed by the current understanding of the crosstalk that exists between these PCD pathways.
The term apoptosis was first used in 1972 by Kerr, Wyllie and Currie  to describe a form of cell death morphologically distinct from necrosis. Apoptosis has since been well studied and is now understood to be a regulated energy-dependent process mediated via cysteine-dependent aspartate-directed enzymes called caspases . Apoptosis is a homeostatic process that balances cell numbers and plays a crucial role in several physiological processes including embryogenesis to shape morphological structures such as fingers, in the establishment of functional synaptic connections in the nervous system, in development of the immune response to remove self-reactive lymphocytes and at the termination of the immune response to remove antigen-specific lymphocytes. Apoptosis is also used to rid the body of cells in various pathological conditions such as removal of cancerous cells, infected cells or cells damaged by noxious agents .
2.1.1. Signaling pathways and molecular components of apoptosis
Apoptosis is mediated via caspases which are present in the cytoplasm as pro-enzymes and when activated initiate a proteolytic cascade that results in apoptosis of the cell. There are three activation pathways that can initiate apoptosis: the extrinsic (death receptor) pathway, the intrinsic (mitochondrial) pathway and the granzyme pathway (Figure 2). There are about 14 known caspases which are divided into initiator and effector caspases. Initiator caspases, caspases 8, 9 and 10, are triggered by either the extrinsic, intrinsic or granzyme pathway, respectively. All three pathways converge on caspase 3, which activates effector caspases 6 and 7 that lead to apoptosis. A major target of effector caspases is poly-ADP-ribose polymerase (PARP) which is involved in DNA repair, cell survival, proliferation and differentiation.
The extrinsic pathway is initiated by binding of cell membrane receptors of Fas (CD95) or tumor necrosis factor (TNF) family receptor (TNFR), which after binding its relevant ligand of FasL or TNFα, respectively, trimerizes and attracts the docking proteins Fas-associated death domain (FADD) and TNF receptor-associated death domain (TRADD), respectively. FADD contains two death effector domains that can bind and cleave caspase 8. TRADD lacks death effector domains but binds FADD that then cleaves caspase 8. Activated caspase 8 then activates caspase 3. The intrinsic pathway is activated via changes in the mitochondria membrane potential which can be triggered via stress, toxic reagents, UV irradiation and inflammation. Changes in mitochondria membrane result in translocation of cytochrome c from the inner mitochondrial membrane into the cytoplasm. Cytochrome c binds to apoptosis protease activating factor 1 (APAF-1) which in the presence of ATP cleaves caspase 9. The intrinsic pathway is regulated by Bcl-2 which localizes to the outer mitochondria membrane. Bcl-2 members (Bcl-2 and Bcl-x) are anti-apoptotic while others such as Bax and Bad are pro-apoptotic. The granzyme activation pathway is stimulated by cytotoxic T lymphocytes (CTLs) or NK cell secretion of perforin, which creates pores in the target cell membrane allowing granzymes into the cytoplasm activating caspase 10 which can then activate caspase 3.
2.1.2. Apoptosis in physiological and pathological conditions and potential therapeutic application
Apoptosis is a tightly regulated process and is rarely observed in healthy animals because phagocytes rapidly remove apoptotic cells. Abnormalities in cell death regulation can be a significant component of diseases such as cancer, AIDS and neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Some of these conditions are characterized by insufficient apoptosis and others excessive apoptosis. Excessive apoptosis, for example, is a feature of neurodegenerative diseases while resistance to apoptosis characterizes many cancers. Understanding the mechanisms of apoptosis at the molecular level may provide therapeutic interventions in these diverse disease processes.
126.96.36.199. Autophagic cell death
Autophagy, which means literally to “eat oneself”, is a physiological response to stress such as starvation and is considered the major cellular mechanism for generating the needed metabolic sources of energy and metabolites during times of nutrient deprivation. Autophagy can also be used to remove damaged or unwanted organelles, such as mitochondria and long-lived proteins. Autophagy is a homeostatic mechanism that is predominantly a cytoprotective process [7, 13]. Other substrates are also now recognized as potential cargo for autophagy including lipids, nucleic acids, reticulocytes and intracellular pathogens and viruses. The concept of autophagic cell death has been a matter of debate, but it is now recognized as a type of programmed cell death mechanism that can lead to both apoptotic and necrotic cell death in certain circumstances such as extreme stress conditions [14, 15]. Autophagic cell death or type II programmed cell death is now used to refer to cell death process distinct from apoptosis that is caspase-independent and occurs with accumulation of double-membrane organelles called autophagosomes.
2.1.3. Signaling pathways and molecular components of autophagy
Autophagy delivers cytosolic materials to the interior of the lysosomes for degradation via a process involving the “
While the autophagy pathway is primarily a homeostatic process promoting cell survival, increased autophagosomal formation can occur coincidentally with cell dying indicating autophagy may be involved in regulated cell death pathways, most notably apoptosis [7, 13]. For example, in apoptosis-comprised cells, cells die via a caspase-independent mechanism characterized by autophagosome accumulation, implicating a role for autophagy in the cell death process. Autophagy and apoptosis may also be regulated coordinately as anti-apoptotic proteins that downregulate apoptosis can also downregulate autophagy. For example, members of the Bcl-2 family can bind to beclin-1, thus inhibiting the formation of initiation complex that is necessary to stimulate autophagy. Other studies indicate once apoptosis is activated, apoptosis effector molecules may suppress autophagy as beclin-1 is cleaved and inactivated by caspases. Finally, studies also indicate autophagy proteins may play a dual role in regulation of apoptosis and autophagy. For example, Atg5 may affect the extrinsic apoptotic pathway through interaction with FADD proteins, while Atg12 is an effector of intrinsic apoptotic pathway with both Atg5 and Atg12 acting as pro-apoptotic regulators.
Autophagy pathway has also been implicated in necrosis and necroptosis cell death. Evidence indicates autophagy may be able to act as an inhibitor of necrosis/necroptosis by preserving cellular functions, removing toxic products and maintaining cellular energy. For example, knockdown studies of components of autophagy pathways, such as beclin-1, have found cytotoxicity is exacerbated suggesting that autophagy has a cytoprotective role. Autophagy may be able to act as a buffer to metabolic stress, providing a mechanism to generate ATP to maintain metabolic viability and thus prevent necrotic cell death. Conversely, studies using a specific inhibitor of necroptosis, necrostatin-1, found both necroptosis and autophagy were inhibited, indicating autophagy may be induced by necrosis. Molecular components underlying the relationship between autophagy and necroptosis/necrotic cell death at this point are poorly understood.
2.1.4. Physiological and pathological roles of autophagic cell death and therapeutic implications
Thus, while autophagy is now recognized to play a role in apoptotic and necrotic cell death programs, this process is complex and incompletely understood. However, increasing evidence indicates autophagic cell death may be necessary for cell death in certain circumstances. It has been suggested autophagic cell death represents a failed adaptive mechanism that may have prevented death under milder conditions. Understanding of the relationships of autophagic cell death with other programmed cell death modalities will require further study. The study of autophagy in disease is an emerging area of research. Autophagy pathway and/or autophagic cell death pathways which result in failure to remove damaged organelles and/or damaged cells are now thought to contribute to various diseases such as cancer, neurodegenerative diseases such as Parkinson’s disease, aging and inflammation. Elucidation of the influence of autophagy with other cell death programs will be essential to the development of therapeutics targeting autophagy for treatment of these various diseases. In the context of infectious disease, autophagy also is now recognized to play an important role in intracellular pathogen defense, and it has been suggested that intracellular pathogen load could be a factor that disrupts the balance between cell survival and cell death .
Pathologists first used the term “necrosis” in the early 19th century to describe tissue destruction. Necrosis is characterized by organelle swelling and cell lysis, releasing the cellular content of cells and resulting in inflammation. The first indication that necrosis could occur in a regulated manner arose from observation that tumor necrosis factor (TNFα) could trigger apoptosis and necrotic forms of cell death. Caspase inhibition strongly exacerbates necrotic cell death, indicating caspase activity negatively regulates necrosis. This accumulating evidence led to the concept of “programmed necrosis” and the coining of the term necroptosis in 2005 to designate regulated necrotic cell death [4, 9]. Receptor-interacting protein kinase 3 (RIP3) and its substrate, the mixed lineage kinase-like domain protein (MLKL), are now recognized as the key activation steps and the molecular hallmarks of regulated necrotic cell death or necroptosis.
2.2.1. Signaling and molecular components of necroptosis
Programmed necrotic cell death can be activated when cells are stimulated by ligation of death receptors including CD95 (also known as FAS), TNF receptors (TNFRs) and TNF-related apoptosis-inducing ligand (TRAIL). Ligation of cell death receptors leads to the formation of complex 1, comprised of TNFR-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF2), receptor-interacting kinase 1(RIP1) and cellular inhibitors of apoptosis (CIAPs) (Figure 4). Upon the release of second mitochondria-derived activator of caspases (Smac) from the mitochondria, RIP1 is de-ubiquinated and dissociates from the death receptor and induces the formation of FADD-RIP1-caspase 8 pro-apoptosis complex II. Conversion of complex 1 to complex II indicates a change in cell fate from pro-survival to cell death. When caspase 8 is inhibited, RIP1 and RIP3 form the necrotic death domain complex, the necrosome, and their kinase activities become activated. RIP3 recruits it substrate monomeric MLKL from the cytoplasm and phosphorylates it. The phosphorylation destabilizes MLKL and drives its oligomerization which enables it to bind to phosphatidylinositol phosphate lipids (PIPs) and cariolipin (CL). Different PIPs and CLs orchestrate the translocation of MLKL to different membrane compartments including the mitochondria, endoplasmic reticulum, the Golgi, lysosomes and plasma membranes. In addition to activation via death receptors, it is also now clear that necroptosis can also be initiated by pathogen recognition receptors (PRRs) such as toll-like receptors (TLRs) and cytokines via activation of RIP3 through distinct upstream mechanisms.
2.2.2. Physiological and pathological roles of necroptosis and potential therapeutic applications
Programmed necrosis has been found to be important in host antiviral responses and a variety of tissue-damage related diseases such as acute pancreatitis, ischemic reperfusion injury, retinal detachment, atherosclerosis, neuronal loss in Gaucher’s disease, amongst others. It has been a paradigm that apoptotic cell death is anti-inflammatory with dead cells cleared by phagocytes while necrotic cell death leads to inflammation and tissue damage. Necrotic cells, however, can be internalized by macrophages although via macropinocytosis and thus in a manner distinct from phagocytosis of apoptotic cells, but they are nonetheless efficiently cleared by professional and nonprofessional phagocytes and hence rarely found in tissues. Large numbers of dying cells such as may occur in excessive tissue injury, autoimmune diseases such as systemic lupus erythematosus or infectious disease may lead to the defective clearance of necrotic cells and contribute to the persistent inflammation and tissue damage. However, smaller number of cells dying via necrosis or necroptosis may not necessarily lead to massive tissue damage and hence controlled necrotic cell death may not necessarily lead to massive tissue damage commonly associated with necrotic cell death.
Knockout of either RIP3 or MLKL genes in mice has been used to assess the physiological and pathological roles of programmed necrosis. These types of studies have confirmed that necroptosis is important in host antiviral responses and in some tissue-damage related diseases. Several inhibitors have been identified that can inhibit necroptosis. Necrostatins, for example, are small molecules that inhibit RIP1 kinase activity and thus inhibit necroptosis (Figure 4). RIP1 also contributes to other processes such as apoptosis and NK-kB activation, however, indicating other processes may also be affected by Nec-1. Targeting RIP3 or MLKL offer more specific inhibitors for study or treatment of necroptosis. A chemical inhibitor of MLKL called necrosulfonamide (NSA), for example, blocks necrosis by preventing oligomerization of MLKL and thus is a specific inhibitor of necroptosis (Figure 4). Use of these specific inhibitors of necroptosis will be essential to elucidate the role of necroptosis in cell death. As the role of programmed necrotic death is now known to occur in several human diseases, development of specific inhibitors of neroptosis could also have therapeutic uses.
2.3. Crosstalk between apoptosis, necroptosis and autophagy PCD pathways
As molecular components and regulation of each pathway has become better understood, it has become apparent that significant crosstalk exists between the three major pathways of programmed cell death, the focus of which has been the topic of several recent reviews [3, 8, 10, 13]. Extensive crosstalk exists between apoptosis and autophagy as discussed above in the section on autophagic cell death. The stimuli for apoptosis and autophagy are often the same and evidence indicates instances where they can cooperate, antagonize or assist each other. Caspases, Beclin-1 and/or the TOR kinase pathway have all been implicated in participating in the complex crosstalk between apoptosis and autophagy. Crosstalk between apoptosis and necrosis also appears to exist as receptors that stimulate apoptosis can also stimulate necroptosis. Energy is thought to play a central role in determining the interplay between these two pathways where instances of high ATP levels would enable a cell to undergo apoptosis while low ATP levels would favor necrosis. Other factors such as p53, Bcl-2 proteins and PARP1 are also suggested to play a role. Evidence also suggests a complex interplay between autophagy and necroptosis. Autophagy and necrosis can be activated in parallel or sequentially and can have either opposite or the same effects. Autophagy, for example, can protect against some types of necroptotic cell death with autophagy serving as the last resort before cell death via necrosis. The molecular basis for interlinked processes in autophagy and necroptosis and the impact of autophagy on necroptosis and other cell death pathways , however, remain unclear. While the molecular details are not fully understood, it is clear that a complex crosstalk and molecular interplay between apoptosis, autophagy and necroptosis occur and determine the ultimate fate of the cell to survive or die in a given situation or under a given stress signal. A better understanding of the mechanisms of apoptosis, autophagic cell death and necroptosis at the molecular level and the crosstalk between these cell death pathways would provide a deeper insight into different disease processes and may provide novel therapeutic strategies.
Toxoplasma gondii: Manipulation of programmed cell death pathways and impact on host–parasite interactions and maintenance of chronic infection
PCD can be important host cell defense mechanisms to eliminate intracellular pathogens.
While the host mounts an effective immune response against
Inhibition of apoptosis by infection with
While blockage of apoptosis is known to occur in a wide variety of host cells, modulation of apoptosis in cells of the central nervous system (CNS) is less well studied and results are ambiguous.
3.1.1. Parasite mechanisms modulating apoptosis
The parasite replicates within a membrane-bound compartment called the parasitophorous vacuole (PV), and hence it is not in direct contact with the host cell cytoplasm and regulators or effectors of apoptosis. However, parasite secretory molecules, which are either released into the host cell at invasion, secreted across the PV membrane (PVM) or act at the PVM cytosolic surface, have been identified which can modulate host cell apoptosis [25, 33]. These mechanisms are briefly summarized below.
3.1.2. Parasite mechanisms that stimulate apoptosis
Several mechanisms have been identified by which the parasite can stimulate apoptosis. In parasite-infected murine macrophages, supernatants can induce apoptosis of neighboring uninfected macrophages via nitric oxide . Induction of apoptosis has also been found to occur via nitric oxide secretion from activated microglia. Nitric oxide secretion from activated microglia can lead to neuronal cell death and may be an important mechanism by which infection leads to neuronal loss in the brain. The parasite secretory molecule, GRA1, has been identified as capable of inducing apoptosis of infected monocytes and uninfected bystander cells . Secreted GRA1 from sites of ongoing
3.1.3. Parasite mechanisms that inhibit apoptosis
Multiple mechanisms have been identified by which the parasite can inhibit apoptosis . Activation of NF-κB is a mechanism that inhibits apoptosis in fibroblasts and some other host cells [36–38]. Early after infection, the parasite induces rapid translocation of host cell transcription factor, NF-kB, into the nucleus, which activates cell survival pathways and induction of an anti-apoptotic state of the host cell. Nuclear translocation of NF-κB and subsequent gene expression requires activity of the host IκB kinase (IKK). The activation of NF-κB was associated with localization of phosphorylated IκBα subunits to the PVM that was mediated by a parasite-derived IκB kinase (TgIKK). TgIKK is produced as the parasite replicates, and thus allows for a continued phosphorylation of IκB and sustained inhibition of apoptosis. Thus,
Only a few parasite proteins that modulate apoptosis have been identified. The parasite serine–threonine phosphatase, called TgPP2C, was recently identified which downregulates apoptosis in host cells . TgPP2C is secreted into host cells from the PV and translocates to the host cell nucleus and has been shown to regulate growth and survival of the parasite. Using a yeast two-hybrid system, TgPP2C was found to interact with host cell protein, SSRP1 (structure-specific recognition protein 1), which binds to DNA and regulates DNA repair genes. It is speculated that SSRP1 might also be involved in expression of other genes involved in cell survival and apoptosis. Identification of other parasite molecules by which the parasite manipulates host cell apoptosis would facilitate a deeper understanding of host–parasite relationship and may lead to development of new therapeutic targets and antiparasitic drugs.
3.1.4. Parasite modulation of apoptosis: significance to pathogenesis
Autophagy has been found to play a role in host defense against many intracellular pathogens as the autophagy pathway can degrade intracellular pathogens via autophagolysosomes including
Interestingly, in non-immune-stimulated cells, evidence indicates the parasite can use autophagy to enhance its own survival. In the first 24 h after infection, host cell autophagy is upregulated and the parasite uses autophagy to acquire host cell nutrients, while at 24–36 h after infection when significant parasite replication has occurred, host cell autophagy is suppressed [46, 47]. This biphasic response may be due to the crosstalk that exists between apoptosis and autophagy. That is, inhibition of apoptosis occurs in infected cells during the first 24 h after infection and as a result of crosstalk, it has been suggested that autophagy is stimulated and then, vice versa, during the later stages of the intracellular infection cycle (> 24 h post-infection), as apoptosis inhibition wanes, suppression of autophagy increases. Thus, regulation of host cell autophagy by the parasite may be part of a cell survival mechanism in
3.3. Necrotic cell death
4. Parasite manipulation of PCD pathways: Conclusions and potential therapeutic implications
A better understanding of the mechanisms by which the parasite modulates apoptosis, autophagic and necrotic host cell death pathways will enhance our understanding of the host/parasite relationship in toxoplasmosis and may yield new therapeutic targets to treat pathological consequences of cerebral toxoplasmosis. For example, while the infection is asymptomatic in immunocompetant individuals, recent evidence indicates chronic infection may lead to psychiatric and other neurological disorders in some individuals. Some of these effects may be due to modifications of processes leading to cell death or resulting in dysregulated cell death, resulting in reduction in CNS cell numbers and specifically of neurons. Conversely, inhibition of apoptosis of astrocytes in the brain could be crucial for establishment of the parasite in this compartment, while inhibition of apoptosis of infected neurons may be essential for development of bradyzoite stage and thus crucial to long-term persistence of the parasite in the brain. The evidence indicates the parasite can manipulate both host cell apoptosis and autophagy pathways, indicating a sophisticated level of parasite control of host PCD pathways and elucidation of the molecular details of these mechanisms could lead to new therapeutic targets with which to control the infection. A better understanding of manipulation of apoptosis and other cell death pathways in the brain cells such as microglia, astrocytes and neurons is of particular importance. The identification of molecular components of PCD pathways crucial to parasite–host interactions in chronic toxoplasmosis could lead to development of new antiparasitic drugs and/or yield new potential therapeutic targets to treat pathological consequences of chronic cerebral toxoplasmosis in immunocompetant individuals and reactivated toxoplasmosis in immunosuppressed individuals. A similar harnessing of apoptotic, autophagic and programmed necrosis cell death pathways has been proposed to treat cancers, neurodegenerative disorders and other diseases, where PCD pathways have been identified as involved in pathogenesis . The dissection of the molecular mechanisms by which
Tsujimoto Y, Shimizu S. Another way to die: autophagic programmed cell death. Cell Death Differ 2005;12(2):1528–34.
Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 2004;16(6):663–9.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35(4):495–516.
Vandenabeele P, et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010;11(10):700–14.
Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010;12(9):823–30.
Mizushima N, et al. Autophagy fights disease through cellular self-digestion. Nature 2008;451(7182):1069–75.
Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell 2014;157(1):65–75.
Nikoletopoulou V, et al. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 2013;1833(12):3448–59.
Sun L, Wang X. A new kind of cell suicide: mechanisms and functions of programmed necrosis. Trends Biochem Sci 2014;39(12):587–93.
Chan FK, Luz NF, Moriwaki K. Programmed Necrosis in the Cross Talk of Cell Death and Inflammation. Annu Rev Immunol 2014; 33:4.1-4.28.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26(4):239–57.
Norbury CJ, Hickson ID. Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 2001;41:367–401.
Ryter SW, Mizumura K, Choi AM. The impact of autophagy on cell death modalities. Int J Cell Biol 2014;2014:502676.
Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 2015;22(3):367–76.
Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 2008;9(12):1004–10.
Paulus GL, Xavier RJ. Autophagy and checkpoints for intracellular pathogen defense. Curr Opin Gastroenterol 2015;31(1):14–23.
Nath A, Sinai AP. Cerebral Toxoplasmosis. Curr Treat Opt Neurol 2003;5(1):3–12.
Halonen SK, Weiss LM. Toxoplasmosis. Handb Clin Neurol 2013;114:125–45.
Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: from animals to humans. Int J Parasitol 2000;30(12–13):1217–58.
Okusaga O, Postolache TT. Toxoplasma gondii, the immune system, and suicidal behavior. In: Dwivedi Y. (Ed.) The Neurobiological Basis of Suicide. 2012: Boca Raton (FL).
Niebuhr DW, et al. Selected infectious agents and risk of schizophrenia among U.S. military personnel. Am J Psychiatr 2008;165(1):99–106.
Torrey EF, et al. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull 2007;33(3):729–36.
Luder CG, Gross U. Apoptosis and its modulation during infection with Toxoplasma gondii: molecular mechanisms and role in pathogenesis. Curr Top Microbiol Immunol 2005;289:219–37.
Liesenfeld O, Kosek JC, Suzuki Y. Gamma interferon induces Fas-dependent apoptosis of Peyer's patch T cells in mice following peroral infection with Toxoplasma gondii. Infect Immun 1997;65(11):4682–9.
Blader IJ, Koshy AA. Toxoplasma gondii development of its replicative niche: in its host cell and beyond. Eukaryot Cell 2014;13(8):965–76.
Contreras-Ochoa CO, et al. Toxoplasma gondii invasion and replication within neonate mouse astrocytes and changes in apoptosis related molecules. Exp Parasitol 2013;134(2):256–65.
Takahashi J, et al. Bax-induced apoptosis not demonstrated in the congenital toxoplasmosis in mice. Brain Dev 2001;23(1):50–3.
el-Sagaff S, et al. Cell death pattern in cerebellum neurons infected with Toxoplasma gondii. J Egypt Soc Parasitol 2005;35(3):809–18.
Shen DF, et al. Involvement of apoptosis and interferon-gamma in murine toxoplasmosis. Investig Ophthalmol Visual Sci 2001;42(9):2031–6.
Wang T, et al. Toxoplasma gondii induce apoptosis of neural stem cells via endoplasmic reticulum stress pathway. Parasitology 2014;141(7):988–95.
Handel U, et al. Neuronal gp130 expression is crucial to prevent neuronal loss, hyperinflammation, and lethal course of murine Toxoplasma encephalitis. Am J Pathol 2012;181(1):163–73.
Zhang YH, et al. Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis. Parasit Vectors 2014;7:372.
Sinai AP, et al. Mechanisms underlying the manipulation of host apoptotic pathways by Toxoplasma gondii. Int J Parasitol 2004;34(3):381–91.
Nishikawa Y, et al. Toxoplasma gondii infection induces apoptosis in noninfected macrophages: role of nitric oxide and other soluble factors. Parasite Immunol 2007;29(7):375–85.
D'Angelillo A, et al. Toxoplasma gondii dense granule antigen 1 stimulates apoptosis of monocytes through autocrine TGF-beta signaling. Apoptosis 2011;16(6):551–62.
Molestina RE, et al. Activation of NF-kappaB by Toxoplasma gondii correlates with increased expression of antiapoptotic genes and localization of phosphorylated IkappaB to the parasitophorous vacuole membrane. J Cell Sci 2003;116(Pt 21):4359–71.
Molestina RE, Sinai AP. Host and parasite-derived IKK activities direct distinct temporal phases of NF-kappaB activation and target gene expression following Toxoplasma gondii infection. J Cell Sci 2005;118(Pt 24):5785–96.
Payne TM, Molestina RE, Sinai AP. Inhibition of caspase activation and a requirement for NF-kappaB function in the Toxoplasma gondii-mediated blockade of host apoptosis. J Cell Sci 2003;116(Pt 21):4345–58.
Kim L, Denkers EY. Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis. J Cell Sci 2006;119(Pt 10):2119–26.
Cai Y, et al. Toxoplasma gondii inhibits apoptosis via a novel STAT3-miR-17-92-Bim pathway in macrophages. Cell Signal 2014;26(6):1204–12.
Yamada T, et al. Toxoplasma gondii inhibits granzyme B-mediated apoptosis by the inhibition of granzyme B function in host cells. Int J Parasitol 2011;41(6):595–607.
Gao XJ, et al. Protein phosphatase 2C of Toxoplasma gondii interacts with human SSRP1 and negatively regulates cell apoptosis. Biomed Environ Sci 2014;27(11):883–93.
Martens S, et al. Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases. PLoS Pathogens 2005;1(3):e24.
Van Grol J, et al. CD40 induces anti-Toxoplasma gondii activity in nonhematopoietic cells dependent on autophagy proteins. Infect Immun 2013;81(6):2002–11.
Subauste CS. CD40, autophagy and Toxoplasma gondii. Memorias do Instituto Oswaldo Cruz, 2009;104(2):267–72.
Orlofsky A. Toxoplasma-induced autophagy: a window into nutritional futile cycles in mammalian cells? Autophagy 2009;5(3):404–6.
Lee YJ, et al. Proliferation of Toxoplasma gondii suppresses host cell autophagy. Korean J Parasitol 2013;51(3):279–87.
Muniz-Feliciano L, et al. Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite. PLoS Pathogens 2013;9(12):e1003809.
Liesenfeld O, et al. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Experiment Med 1996;184(2):597–607.
Zhao YO, et al. Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. PLoS Pathogens 2009;5(2):e1000288.
Persson EK, et al. Death receptor ligation or exposure to perforin trigger rapid egress of the intracellular parasite Toxoplasma gondii. J Immunol 2007;179(12):8357–65.
Niedelman W, et al. Cell death of gamma interferon-stimulated human fibroblasts upon Toxoplasma gondii infection induces early parasite egress and limits parasite replication. Infect Immun 2013;81(12):4341–9.
Halonen SK. Role of autophagy in the host defense against Toxoplasma gondii in astrocytes. Autophagy 2009;5(2):268–9.
Melzer T, et al. The gamma interferon (IFN-gamma)-inducible GTP-binding protein IGTP is necessary for toxoplasma vacuolar disruption and induces parasite egression in IFN-gamma-stimulated astrocytes. Infect Immun 2008;76(11):4883–94.
Persson EK, et al. Death receptor ligation or exposure to perforin trigger rapid egress of the intracellular parasite Toxoplasma gondii. J Immunol 2007;179(12):8357–65.
Portt L, et al. Anti-apoptosis and cell survival: a review. Biochim Biophys Acta 2011;1813(1):238–59.