Toxoplasmosis: causes and pathogenesis

Causes of toxoplasmosis

The cause of toxoplasmosis is Toxoplasma gondii (subdomination of Protozoa, type Apicomplecxa, order Coccidia, suborder Eimeriina, family Eimeriidae).

In the human body and animals, T. Gondii passes through several stages of development: trophozoite (endozoite, tachizoite), cysts (cystoseite, bradizoite), and oocysts. Trophozoites with a size of 4-7x2-4 μm resemble the shape of a crescent moon. Cysts are covered with a dense shell, up to 100 microns in size. Oocysts are oval in shape, 10-12 microns in diameter.

According to genotyping data, three groups of toxoplasmic strains are distinguished. Representatives of the first group cause congenital toxoplasmosis in animals. In humans, strains of the second and third groups of toxoplasm are detected, and representatives of the latter group are more often detected in patients with HIV infection. The antigenic structure of various stages of development of toxoplasm has been determined and it has been established that trophozoites and cysts have both common and characteristic antigens only for each of them.

T. Gondii is an obligate intracellular parasite that penetrates into the intestinal epithelial cells and multiplies in them through endodiogeny. Then trophozoites (tachyzoites) with blood and lymph flow go to other organs and tissues (lymph nodes, liver, lungs, etc.). Where they actively penetrate into the cells. In the affected cells, there are accumulations of endozoites of one generation, surrounded by a membrane of the parasitophore vacuole (the so-called pseudocysts). As a result of the host's immune response, the parasites disappear from the blood and in the infected target cells dense, coated cysts are formed. In the chronic course of the disease, T. Gondii in the form of intracellularly located cysts retain viability indefinitely. Cysts are localized mainly in the brain, cardiac and skeletal muscles, uterus, eyes.

The main hosts of T. Gondii - representatives of the family Felidae (feline) can simultaneously be intermediate hosts, because in their body toxoplasm can move from the intestine to the cells of various organs. By means of metronium, the parasite multiplies in the intestinal epithelial cells; as a result, merozoites are formed. Some of them give rise to male and female sex cells - gammonts. After exiting the enterocytes, the male gamonts divide many times, forming microgametes ("spermatozoa"); from the female gamontes macrogamets ("egg cells") are formed. After fertilization, an immature oocyst is formed, which, with fecal masses, is excreted into the environment. Under favorable conditions, the maturation of oocysts (sporogonia) lasts from 2 days to 3 weeks. Mature cysts are resistant to the effects of adverse environmental factors and can remain viable for up to a year or longer.

[1], [2], [3], [4], [5], [6]

Pathogenesis of toxoplasmosis

From the place of implantation (most often - hollow digestive organs) toxoplasma with lymph flow enters the regional lymph nodes, where they multiply and cause the development of lymphadenitis. Then, parasites enter the blood in large quantities and are spread throughout the body}, resulting in foci of lesions in the nervous system, liver, spleen, lymph nodes, skeletal muscles, myocardium, eyes. Due to the multiplication of trophozoites, the infected cells are destroyed. Around the foci of necrosis and the accumulation of toxoplasm formed specific granulomas. Under the normal immune response of the organism, trophozoites disappear from the tissues and the process of formation of cysts begins (the inflammatory reaction around them is weak). Toxoplasmosis passes from the acute phase to the chronic phase, and even more often into chronic carriage with the preservation of cysts in the tissues of the organs. In adverse conditions for the body (acute diseases and stressful situations that exert an immunosuppressive effect), the cyst shells are destroyed; released parasites, multiplying, affect intact cells and enter the bloodstream, which is clinically manifested by exacerbation of chronic toxoplasmosis. Inflammatory infiltrates and necrosis is found in skeletal muscles, myocardium, lungs and other organs. In the brain there are inflammatory foci with subsequent necrosis, which sometimes leads to the formation of petrification. In the retina and choroid of the eye, there is a productive-necrotic inflammation. The malignant course of toxoplasmosis takes on the background of the unfolded picture of AIDS, with the development of a generalized form of the disease, which in a number of cases is the cause of death of patients.

In response to toxoplasm antigens, specific antibodies are produced and the immune response develops according to the type of HRT.

With congenital toxoplasmosis as a result of parasitemia, the pathogen is entered into the placenta, forming the primary focus, and from it with the blood stream enters the fetus. He becomes infected regardless of the presence of clinical manifestations in the pregnant woman, but the outcome depends on the time of the pregnancy infection occurred. Infection in the early stages of embryogenesis results in spontaneous miscarriage, stillbirth, causing severe, often incompatible developmental disorders (anencephaly, anophthalmia, etc.) or leads to the development of generalized toxoplasmosis. When infecting in the third trimester of pregnancy, asymptomatic forms of the course prevail, the late clinical signs of which appear in months and years.

The life cycle of toxoplasm

The causative agent of toxoplasmosis is an obligate intracellular parasite, the possibility of intranuclear parasitism of toxoplasm has been proved. The causative agent was discovered in 1908 independently by the French Nicolas and Manso in Tunisia in the gondy rodents and the Italian Splendor in Brazil in rabbits. The generic designation of toxoplasm reflects the semilunar form of the asexual stage of the parasite ("taxon" - arc, "plasma" - form), species - the name of rodents (gondies).

From a general biological point of view, T. Gondii is characterized by signs that allow it to be viewed as a parasite with very deep adaptations. It is found on all continents and at all geographical latitudes, can parasitize and multiply in hundreds of species of mammals and birds, is capable of infecting the most diverse tissues and cells of its hosts.

In 1965, Hutchison first experimentally proved that the transmission of T. Gondii is attended by cats. In 1970, scientists in England, Denmark and the United States almost simultaneously and independently of each other found in the feces of toxoplasmosis cats oocysts, very similar to those of coccidia. Thus, the toxoplasm belonged to coccidia, and the life cycle of the parasite, consisting of two phases: intestinal and extra-intestinal, or non-cava, was completely deciphered.

The intestinal phase of the toxoplasmic life cycle includes the development in the cells of the intestinal mucosa of the final host, such as the domestic cat and other feline (wild cat, lynx, Bengal tiger, ocelot, snow leopard, jaguarundi, air).

The full cycle of development (from oocysts to oocysts) of T. Gondii can be carried out only in the body of representatives of the feline family. The life cycle of toxoplasm includes 4 main stages of development: schizogony, endodiogeny (internal budding), gametogony, sporogony. These stages take place in different ecological environments: schizogony, gametogony and the beginning of sporogonia occur only in the intestines of representatives of the family of felines (the final owners of toxoplasm), sporogonia terminates in the external environment, endodiogeny occurs in the cells of the tissues of the intermediate host (including humans) and cells of the main host - feline.

Before proceeding to a detailed examination of the life cycle of toxoplasm, it is necessary to touch upon the question of the terminology of the stages of the parasite. In view of the fact that the cycle of development of toxoplasm has been deciphered only in 1970, and many details are not clear until now, the questions of terminology of toxoplasm are being clarified, and different authors offer their terms for the same stages of the parasite.

Thus, in the case of acute invasion, the terms "proliferative form", "endodiosoit", "endozoite", "trophozoite", and "tachysozoit" are used to designate the tissue (extra-intestinal phase of development of toxoplasmosis, asexual stage-endodiogeny), and the stage characteristic of chronic the course of infestation, denoted by the terms - "cystic form", "zoe", "cystose" and "bradizoite". At this level of knowledge about the life cycle of toxoplasm, in the opinion of most domestic studies, the most appropriate terms are: endozoite - asexual tissue stage of toxoplasm, usually rapidly multiplying, localized in toxoplasm or in vacuoles of the cell, characteristic of acute infection; the onset of cystosis is tissue forms localized within the cyst and characteristic of chronic infection.

All other terms for the designation of tissue stages of the life cycle of toxoplasm should be considered synonymous with "endozoite" and "cystozoite."

The terminology of the stages of development of toxoplasm in the intestinal epithelium of the main host is similar to that of typical coccidia.

Intestinal phase of development of toxoplasm

Intestinal phase of development of toxoplasma in the body of the final host. The intestinal stage of development begins with infection (perorally) of feline - the main hosts of the parasite as oocysts with sporozoites, and vegetative forms - endozoites and cystoseites, swallowed with the tissues of intermediate hosts. Cystozoites enter the intestine in tissue cysts, the shell of which is quickly destroyed by the action of proteolytic enzymes. Endozoites and cystoseoids released from the shell penetrate the cells of the intestinal mucosa and multiply by intensive ascent (endodiogeny and schizogony).

After about 2 days, as a result of repeatedly repeated cycles of asexual reproduction (schizogony), a special type of schizonts is formed - merozoites, which give rise to the next stage of development of the parasite - gametogony.

When the cat gets into the intestines of mature oocysts of toxoplasma released from the membranes, sporozoites penetrate the cells of the ciliated epithelium of the intestine and also start to reproduce by schizogony. Asexual reproduction from one schizont forms from 4 to 30 merozoites. Sub-microscopic studies have shown that the shizont is surrounded by a pellicle, which consists of the inner and outer membranes. One or more mitochondria of the ribosome, a nucleus, a well developed endoplasmic reticulum, and a conoid at the anterior end were found. There are no subpellicular tubules.

Unlike coccidia, in the schizogony of toxoplasm, merozoites are formed near the nucleus, and not at the periphery of the schizont. In the intestine of feline toxoplasma pass several successive schizogonia, after which the merozoites give rise to the sexual stage of parasite development (gametogony). Gametocytes (immature sex cells) are found about 3-15 days after infection throughout the small intestine, but more often in the ileum of the cat. Begins gametogonia by the formation of microgametocytes, which occurs in the lower part of the small intestine and in the large intestine of the main host. The development of microgametocytes is accompanied by a number of consecutive divisions of the egg. 12-32 microgamets are formed on the periphery of the macrogametocyte by exagination of its membrane. They have the shape of a strongly elongated crescent with sharp ends and along with the flagella reach 3 μm in length, and also have 2 bundles (the third rudimentary), with which they move in the lumen of the intestine and move to the macrogamete.

The development of macrogamethocyte occurs without division of the nucleus. The gametocyte increases in size (from 5-7 to 10-12 microns in length), the large nucleus with the nucleolus becomes compact, a large amount of glycogen accumulates in the cytoplasm, many ribosomes, mitochondria and endoplasmic reticulum are found.

Fertilization, i.e. The fusion of macro- and microgamets occurs in the epithelial cell, resulting in the formation of a zygote that forms a dense shell and turns into ookinet, and then into an oocyst. The oocyst form is round-oval with a diameter from 9-11 to 10-14 microns. For some time, the oocysts remain in the cells of the epithelium, but then fall into the lumen of the intestine, and toxoplasm enters the next stage of development - sporogony, which continues in the feces and in the external environment. Mature oocysts have a dense colorless two-layered shell, due to which they are resistant to various environmental factors, including a number of chemical agents. With sufficient humidity, temperature and access to oxygen a few days later, two sporocysts are formed inside the oocysts with four banana-shaped sporozoites in each. Sporocysts, in turn, have a dense two-layered shell. Their dimensions are on the average from 6-7 x 4-5 to 8 x 6 μm. Sporozoites are similar in structure to endozoites and cystozoites - tissue stages of toxoplasm. Mature oocysts with sporozoites are invasive stages of the parasite both for the final host (feline) and for intermediate hosts, including for humans. In a moist environment, sporozoites in oocysts remain invasive until 2 years.

Extra-intestinal (tissue) phase of development of toxoplasm in the body of intermediate hosts

In cells of various tissues of intermediate hosts, including humans, asexual reproduction occurs by endodiogeny, i.e. Formation of two daughter cells within the maternal. In the years 1969-1970. The method of multiple internal budding, to which the term endopolyenia is proposed, is revealed. These two modes of asexual reproduction, along with schizogonia, were also found in the intestines of the host host of the parasite - the cat.

The tissue phase of the development of toxoplasm begins when the animals and humans (intermediate hosts) enter the intestine or the sexual stages of parasite development-the oocyst with sporozonts, or asexual stages (endozoites and cystoses) with the tissues of the infected animals. In the small intestine under the influence of proteolytic enzymes, sporozoites released from the oocysts, or from the cysts or cystosoites or endozoites penetrate the epithelial cells of the intestinal mucosa, where asexual reproduction begins - endodiogeny and endolipogeny.

As a result of reproduction, endozoites appear. After 2-10 hours from the moment of introduction into the cell of sporozoite (endozoite) from the destroyed host cell, 12-24-32 daughter endozoites leave. The newly formed endozoites are actively introduced into neighboring cells. In the small intestine of the host, local necrotic foci are formed, from which the endozoites can enter the blood and lymphatic vessels and then into various tissues. Dissemination of endozoites along the organism of the intermediate host is also facilitated by phagocytosis of the parasite by the cells of the reticuloendothelial system. At this stage, rapid asexual reproduction by endodiogeny is repeated cyclically. Outside the cell, endozoites are in the period of time after exiting the destroyed cell and before entering the new cell. They multiply only in living cells, where their cluster resembles cyst. But these accumulations of endozoites are localized directly in the cytoplasm or in the cytoplasmic vacuole. The tender envelope around such parasite accumulations is formed by the host cell in the acute stage of toxoplasmosis. These clusters do not have their own shell, so in reality they are pseudocysts. If endozoites are localized in cytoplasmic vacuoles, then such vacuoles are called parasitophore.

Gradually around the clumps of endozoites a parasitic membrane is formed, and toxoplasm passes into a new stage - the true tissue cyst. The formation of a complex cyst shell involves parasites themselves, and this occurs with chronic toxoplasmosis. Such membranes are impervious to antibodies and ensure the viability of the parasite for many years, and sometimes for life. As a rule, the cysts are inside the cell, although extracellular localization is also proved. The diameter of cysts is from 50-70 to 100-200 microns. With the formation of cysts endozoites in it are transformed into a new stage - cystozoites. In a mature cyst, there may be several thousand cystozoites.

The biological purpose of tissue cysts is very high. First of all, cysts ensure the survival of the parasite in the immune system and thereby increase the chances of infection with toxoplasmosis in both the final and new individuals of the intermediate hosts. The formation of the cystic stage is an important stage in the life cycle of toxoplasm, since the stage of cyst - cystozoite - is much more resistant to external factors. So, if the swallowed endozoites under the action of gastric juice die within a minute or two, the cystozoites remain viable in this environment for 2-3 hours, although the cystic membrane under the action of pepsin is destroyed almost instantly. It has been experimentally proved that from cystoseites in the intestine of a cat with a higher constancy and faster, i.e. Rather, the intestinal phase of the development of toxoplasm in the body of the final host is completed.

Thus, from the description of the life cycle of toxoplasm it follows that the intermediate hosts (wild and agricultural animals, as well as humans) are carriers of the vegetative (tissue) stages of the parasite, such as endozoites in cysts. It is with them in diagnosing toxoplasmosis that doctors, veterinarians and parasitologists have to deal.

The ultrastructure of endozoites and cystozoites is identical to that of coccid merozoites. From the point of view of a parasitologist-epidemiologist and a clinician, it is very important to know a number of features of the biology of toxoplasm. Primarily, toxollasis is a feline parasite, in the body of which it is able, without the involvement of other hosts, to complete both the intestinal and extra-intestinal (tissue) phases of development. Thus, felines can simultaneously perform the functions of intermediate and final hosts and ensure the phase development of toxoplasma from oocysts to oocysts. But toxoplasma - a parasite is not monoxenous: in its life cycle intermediate hosts take part, although their participation is not necessary; therefore for toksoplazmy facultative heterogeneity is characteristic. And endozoites and cystozoites - stages from intermediate hosts - not only the final hosts, but also new intermediate hosts (carnivores and humans) can become infected. Here there is, as it were, the passage or ligation without the participation of the final host and without the release of toxoplasma into the external environment.

In many animals (mice, rats, guinea pigs, hamsters, rabbits, dogs, sheep, pigs) and in humans, transplacental transmission of toxoplasma at the endozoite stage is noted, thereby causing congenital toxoplasmosis.

[7], [8], [9], [10]