Toxoplasma gondii: Mode of Infection and Effect on Neurological Cells: Difference between revisions

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<br>By [Alexander S. McQuiston]<br>
<br>By [Alexander S. McQuiston]<br>


==Introduction==
==<b>Introduction</b>==
[[Image:Bradyzoite_cyst_and_tachyzoite.gif‎|thumb|300px|right|The left shows a bradyzoite cyst with the dense cyst wall surrounding the bradyzoites. The right shows tachyzoites inside the parasitophorous vacuole. Bradyzoites will slowly reproduce asexually in the cyst and tachyzoites will rapidly reproduce asexually [http://www.monografias.com/trabajos16/toxoplasmosis-congenita/toxoplasmosis-congenita.shtml#EMBARAZO CDC].]]
[[Image:Bradyzoite_cyst_and_tachyzoite.gif‎|thumb|300px|right|The left shows a bradyzoite cyst with the dense cyst wall surrounding the bradyzoites. The right shows tachyzoites inside the parasitophorous vacuole. Bradyzoites will slowly reproduce asexually in the cyst and tachyzoites will rapidly reproduce asexually [http://www.monografias.com/trabajos16/toxoplasmosis-congenita/toxoplasmosis-congenita.shtml#EMBARAZO CDC].]]


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==How <i>T. gondii</i> Infects Host Cells==
==<b>How <i>T. gondii</i> Infects Host Cells</b>==
[[Image:Tachyzoite_Invasion.jpg‎‎|thumb|300px|right|This displays a tachyzoite invading a target cell. The apical pole is already inside the host, but the rest of the cell has not been encapsulated. Constriction can be seen in the middle of the tachyzoite which makes invasion slightly more difficult [http://www.nature.com/nrmicro/journal/v6/n1/images/nrmicro1800-f2.jpg NATURE].]]
[[Image:Tachyzoite_Invasion.jpg‎‎|thumb|300px|right|This displays a tachyzoite invading a target cell. The apical pole is already inside the host, but the rest of the cell has not been encapsulated. Constriction can be seen in the middle of the tachyzoite which makes invasion slightly more difficult [http://www.nature.com/nrmicro/journal/v6/n1/images/nrmicro1800-f2.jpg NATURE].]]


<br><i>T. gondii</i> infect warm blooded animals by 3 main pathways (in order of most to least common): horizontally transferred via ingestion of the parasite when eating undercooked meat from livestock that was infect prior to slaughter, horizontally transferred via the ingestion of oocyst that can be found in water and soil that has been contaminated with cat fecal matter, and vertically transferred from mother to fetus during pregnancy (Carruthers et al. 2007; Tenter et al. 2000). Once T. gondii infects its host, it must be able to create a balance between altering cellular processes in order to produce ideal conditions while not causing damage that would render an immune response.<br>
<br>Most often, <i>T. gondii</i> is ingested in the form of oocyst or a tissue cyst containing bradyzoites (Carruthers et al. 2007; Tenter et al. 2000). Once inside the gut of the host organism, proteolytic enzymes breaks down the proteins that the cyst wall is made of, releasing the sporozoites found within the oocyst or tissue cyst (Werk et al. 1985). The sporozoites act as free parasites that are able to move through the intestinal epithelial, differentiate into tachyzoites, and invade epithelial cells (Gopal et al. 2008).<br>


<br><b>The Invasion</b><br>
<br>There are two ways in which parasites are able to invade hosts: phagocytosis or active invasion. Active invasion requires energy from the parasite while phagocytosis does not require energy from the parasite and occurs when the host cell engulfs the parasite. T. gondii is thought to go through active invasion based on the time it takes for the parasite to get inside the host cell and with the involvement of the host during the invasion process. The total time elapsed between first contact by the parasite and the final invasion of the parasite is between 15 and 40 seconds, a much more rapid event than phagocytosis and the host cell uses energy to produce extracellular structures (Werk et al. 1985).
<br>Before invasion begins, <i>T. gondii</i> must find a target cell and specifically orient itself in relation to the target. The invasion is initiated by the apical pole of T. gondii coming in to contact with the target cell. The apical pole of T. gondii includes a conoid and rhoptries. A conoid is a cone shaped organelle that is thought to play a major role in the initial penetration of the parasite. The conoid creates an indentation in the membrane of the host cell which causes the host to produce extracellular protrusions called pseudopods that stabilizes the connection between the host cell and the apical pole of parasite (Werk et al. 1985).  The production of extracellular pseudopods is considered active invasion because the host cell’s protrusion production requires energy. As the conoid indents the host cell’s membrane and the host cell’s pseudopods stabilize the host-parasite connection site, rhoptries secrete specialized proteins, called penetration enhancing factors (PEFs), which decreases the viscosity of the host’s membrane (Werk et al. 1985). By decreasing the viscosity allows for easier penetration and rupturing of the host cell’s membrane. PEFs function has been observed to be determined by low concentrations of ions. For example, a high concentration of ions such as Ca2+ decreases the fluidity of cellular membranes which ultimately decreases host cell viscosity making invasion more difficult.  The rhoptries also secrete proteins that contribute to the development of host cell extracellular protrusions and a vacuole around the parasite (Werk et al. 1985).<br>
<br>The newly formed vacuole is known as a parasitophorous vacuole that consists of both host cell membrane lipids and rhoptry content. Vacuole formation begins when the parasite makes about a 1.5 μm “cut” in the host cell’s membrane that the parasite uses to enter the cell (Hirai et al. 1966). Microcinematography has previously displayed a constricting pattern along the length of the parasite as it entered through the opening (Hirai et al. 1966). As the parasite enters the host, the parasite is able to extend its conoid and apical pole inside the host cell. As the parasite becomes medially constricted, the extracellular protrusions are then hypothesized to aid in pulling the opposite pole into the cell (Werk et al. 1985).<br>
<br><i>T. gondii</i> has also been previously observed to move during the invasion. The movement has been described as a form of drilling or spinning (Hirai et al. 1966). Drilling or spinning motions have the ability to increase the rate at which the parasite invades the host cell. The invagination made by rhoptries and the conoid in the host cell’s membrane is extremely small and decreases invasion efficiency. A drilling or spinning movement by the parasite could increase the size of the original invagination and make the final steps of invasion easier (Werk et al. 1985).<br>


<br><b>Inhibiting Invasion</b><br>
<br>There are not many ways in which <i>T. gondii</i> invasion is able to be inhibited. One way, stated earlier, is the concentration of ions such as Ca2+ (Werk et al. 1980). As the concentration increases, the fluidity of a target host cell’s membrane can decrease making invasion more difficult. Another factor that has been observed to reduce invasion rate of <i>T. gondii</i> is the presence of cytochalasin. Cytochalasin is a metabolite that is able to block the production of long actin filaments. The extracellular protrusions produced by the host cell thought to aid in invasion are composed of actin filaments. Disrupting the ability of the host cell to produce actin filaments would not allow the host cell to aid in invasion (Werk et al. 1985).<br>


 
<br><b>Infecting Neurological Tissue</b><br>
 
<br>As <i>T. gondii</i> sporozoites enter the gastrointestinal tract they differentiate in to tachyzoites. The tachyzoites travel around the intestinal epithelial invading epithelial cells, before targeting specialized cells that are circulated (macrophages) throughout the body to reach neurological tissues such as the brain (Carruthers et al. 2007). Invading macrophages to travel around the body provides the tachyzoites with protection from any immune responses. As the tachyzoites travel around the body they eventually reach the brain where they invade neurological cells such as neurons, astrocytes, and glial cells (Carruthers et al. 2007). Once inside these neurological cells and after facing stresses, tachyzoites go through differentiation to become bradyzoites. Differentiation has been hypothesized to a result of an inability to manipulate a host’s cell cycle or there is a decrease in nutrients needed to multiply rapidly (Kamerkar et al. 2012). The parasitophorous vacuole that is used to protect the tachyzoite within the host cell differentiates in to a cyst wall that surrounds the newly formed bradyzoites creating an intracellular tissue cyst. Tissue cysts are the ultimate reason for chronic infection of <i>T. gondii</i>. These cysts that were once thought to be a dormant, static phase of <i>T. gondii</i> that was used to simply infect other host organisms, has been found to lead to the infection of new neurological cells and play a major role in host behavioral changes (Weiss et al. 2011).<br>
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 





Revision as of 22:28, 22 April 2015


By [Alexander S. McQuiston]

Introduction

The left shows a bradyzoite cyst with the dense cyst wall surrounding the bradyzoites. The right shows tachyzoites inside the parasitophorous vacuole. Bradyzoites will slowly reproduce asexually in the cyst and tachyzoites will rapidly reproduce asexually CDC.


Toxoplasma gondii is one of the most common cyst parasites around the world due to its ability to infect almost all warm blooded organisms, including humans (Gaskell et al. 2009). Some estimates of T. gondii infections are reported to be as high as a third of the world’s population (Tenter et al. 2000; Weiss et al. 2009). More specifically, T. gondii is an intracellular heteroxenous parasite belonging to the apicomplexan phylum. The apicomplexan phylum is a large group of parasitic protists that contain specialized organelles required for target host invasion starting at the apical pole (Dubey et al. 1998; Weiss 2011)). Infection of T. gondii causes toxoplasmosis in both healthy and immunocompromised organisms. When the parasite infects healthy organisms the disease is normally asymptomatic, but if the parasite infects an immunocompromised organism, such as an AIDS patient, diseases like encephalitis can occur (Carruthers et al. 2007). Along with medical diseases, T. gondii has also been hypothesized to cause a variety of neurological disorders such as schizophrenia (Weiss et al. 2009).


T. gondii has both intermediate and definitive hosts. The intermediate hosts include a wide variety of warm blooded animals from rodents to humans, but only has one definitive host, felines (cats) (Tenter et al. 2010). T. gondii is also capable of both asexual and sexual reproduction. When the parasite is in an intermediate host it reproduces asexually, and when the parasite is in its definitive host it is able to reproduce sexually. The ultimate goal of T. gondii is to infect its definitive host so it can sexually reproduce and then go on to infect other organisms (Webster et al. 2007). An interesting way T. gondii has been able to facilitate its transmission from an intermediate host to its definitive host is by invading target host cells and then manipulating host cellular behavior and physiological processes (Prandovsky et al. 2011; Webster et al. 2007).



Life Stages


There are three main infectious stages, all intracellular, of T. gondii: tachyzoites, bradyzoites (cyst forming), and sporozoites. Both tachyzoites and bradyzoites asexually multiply while oocysts sexually multiply (Dubey et al. 1998).


Tachyzoites

Tachyzoites are responsible for the acute infection by rapidly multiplying inside a host which causes the overall population of the parasite to grow. It can also be considered the more aggressive parasite stage because this stage of the parasite moves around the body and invades target host cells (Carruthers et al. 2007). Sporozoites go through differentiation into tachyzoites once the infection is ready to take place. Tachyzoites will multiply within a cell until cell lysis and the new parasites can move on to infect more target host cells. Tachyzoites are mainly found within intestine epithelial cells (Dubey at al. 1998).


Bradyzoites

Bradyzoites are considered to be slower metabolic and reproductive parasites. Following the invasion by tachyzoites, tachyzoites can go through differentiation in to bradyzoites if certain environmental factors are met such as a decrease in reproductive success or if the tachyzoite can no longer manipulate host cellular processes (Kamerkar et al. 2012). Once differentiated in to bradyzoites and the formation of a cyst wall forms around the bradyzoites, the bradyzoites slowly divide and fill up the cyst. Cysts are mainly found in neurological tissue and muscle tissues. Bradyzoites were originally thought to be static structures that caused chronic toxoplasmosis, but recent studies have shown that they play a role in behavioral manipulation and also break down host cells in order to invade new cells (Dubey et al. 1998).


Sporozoites

Sporozoites are the only T. gondii stage that sexual reproduce. When bradyzoites reach a definitive host (a cat), they differentiate into sporozoites. Sporozoites are found within oocysts that reside in the intestinal tract of cats (Tenter et al. 2000). Sporozoites are expelled from the definitive host in fecal matter. This stage of T. gondii is spore-like and can survive outside of the definitive host in soil and water for about a year. Sporozoites contribute to infection of intermediate hosts via ingestion (Dubey et al. 1998).




How T. gondii Infects Host Cells

This displays a tachyzoite invading a target cell. The apical pole is already inside the host, but the rest of the cell has not been encapsulated. Constriction can be seen in the middle of the tachyzoite which makes invasion slightly more difficult NATURE.


T. gondii infect warm blooded animals by 3 main pathways (in order of most to least common): horizontally transferred via ingestion of the parasite when eating undercooked meat from livestock that was infect prior to slaughter, horizontally transferred via the ingestion of oocyst that can be found in water and soil that has been contaminated with cat fecal matter, and vertically transferred from mother to fetus during pregnancy (Carruthers et al. 2007; Tenter et al. 2000). Once T. gondii infects its host, it must be able to create a balance between altering cellular processes in order to produce ideal conditions while not causing damage that would render an immune response.


Most often, T. gondii is ingested in the form of oocyst or a tissue cyst containing bradyzoites (Carruthers et al. 2007; Tenter et al. 2000). Once inside the gut of the host organism, proteolytic enzymes breaks down the proteins that the cyst wall is made of, releasing the sporozoites found within the oocyst or tissue cyst (Werk et al. 1985). The sporozoites act as free parasites that are able to move through the intestinal epithelial, differentiate into tachyzoites, and invade epithelial cells (Gopal et al. 2008).


The Invasion

There are two ways in which parasites are able to invade hosts: phagocytosis or active invasion. Active invasion requires energy from the parasite while phagocytosis does not require energy from the parasite and occurs when the host cell engulfs the parasite. T. gondii is thought to go through active invasion based on the time it takes for the parasite to get inside the host cell and with the involvement of the host during the invasion process. The total time elapsed between first contact by the parasite and the final invasion of the parasite is between 15 and 40 seconds, a much more rapid event than phagocytosis and the host cell uses energy to produce extracellular structures (Werk et al. 1985).
Before invasion begins, T. gondii must find a target cell and specifically orient itself in relation to the target. The invasion is initiated by the apical pole of T. gondii coming in to contact with the target cell. The apical pole of T. gondii includes a conoid and rhoptries. A conoid is a cone shaped organelle that is thought to play a major role in the initial penetration of the parasite. The conoid creates an indentation in the membrane of the host cell which causes the host to produce extracellular protrusions called pseudopods that stabilizes the connection between the host cell and the apical pole of parasite (Werk et al. 1985). The production of extracellular pseudopods is considered active invasion because the host cell’s protrusion production requires energy. As the conoid indents the host cell’s membrane and the host cell’s pseudopods stabilize the host-parasite connection site, rhoptries secrete specialized proteins, called penetration enhancing factors (PEFs), which decreases the viscosity of the host’s membrane (Werk et al. 1985). By decreasing the viscosity allows for easier penetration and rupturing of the host cell’s membrane. PEFs function has been observed to be determined by low concentrations of ions. For example, a high concentration of ions such as Ca2+ decreases the fluidity of cellular membranes which ultimately decreases host cell viscosity making invasion more difficult. The rhoptries also secrete proteins that contribute to the development of host cell extracellular protrusions and a vacuole around the parasite (Werk et al. 1985).

The newly formed vacuole is known as a parasitophorous vacuole that consists of both host cell membrane lipids and rhoptry content. Vacuole formation begins when the parasite makes about a 1.5 μm “cut” in the host cell’s membrane that the parasite uses to enter the cell (Hirai et al. 1966). Microcinematography has previously displayed a constricting pattern along the length of the parasite as it entered through the opening (Hirai et al. 1966). As the parasite enters the host, the parasite is able to extend its conoid and apical pole inside the host cell. As the parasite becomes medially constricted, the extracellular protrusions are then hypothesized to aid in pulling the opposite pole into the cell (Werk et al. 1985).

T. gondii has also been previously observed to move during the invasion. The movement has been described as a form of drilling or spinning (Hirai et al. 1966). Drilling or spinning motions have the ability to increase the rate at which the parasite invades the host cell. The invagination made by rhoptries and the conoid in the host cell’s membrane is extremely small and decreases invasion efficiency. A drilling or spinning movement by the parasite could increase the size of the original invagination and make the final steps of invasion easier (Werk et al. 1985).


Inhibiting Invasion

There are not many ways in which T. gondii invasion is able to be inhibited. One way, stated earlier, is the concentration of ions such as Ca2+ (Werk et al. 1980). As the concentration increases, the fluidity of a target host cell’s membrane can decrease making invasion more difficult. Another factor that has been observed to reduce invasion rate of T. gondii is the presence of cytochalasin. Cytochalasin is a metabolite that is able to block the production of long actin filaments. The extracellular protrusions produced by the host cell thought to aid in invasion are composed of actin filaments. Disrupting the ability of the host cell to produce actin filaments would not allow the host cell to aid in invasion (Werk et al. 1985).


Infecting Neurological Tissue

As T. gondii sporozoites enter the gastrointestinal tract they differentiate in to tachyzoites. The tachyzoites travel around the intestinal epithelial invading epithelial cells, before targeting specialized cells that are circulated (macrophages) throughout the body to reach neurological tissues such as the brain (Carruthers et al. 2007). Invading macrophages to travel around the body provides the tachyzoites with protection from any immune responses. As the tachyzoites travel around the body they eventually reach the brain where they invade neurological cells such as neurons, astrocytes, and glial cells (Carruthers et al. 2007). Once inside these neurological cells and after facing stresses, tachyzoites go through differentiation to become bradyzoites. Differentiation has been hypothesized to a result of an inability to manipulate a host’s cell cycle or there is a decrease in nutrients needed to multiply rapidly (Kamerkar et al. 2012). The parasitophorous vacuole that is used to protect the tachyzoite within the host cell differentiates in to a cyst wall that surrounds the newly formed bradyzoites creating an intracellular tissue cyst. Tissue cysts are the ultimate reason for chronic infection of T. gondii. These cysts that were once thought to be a dormant, static phase of T. gondii that was used to simply infect other host organisms, has been found to lead to the infection of new neurological cells and play a major role in host behavioral changes (Weiss et al. 2011).


T. gondii's Effect on the Brain

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Conclusion

References