Abstract
First described in Ctenodactylus gundi and simultaneously in rabbit, Toxoplasma gondii, an etiological agent of toxoplasmosis, affects different species of vertebrates and invertebrates, presenting different manifestations depending on the host. Ocular toxoplasmosis is one of the mean manifestations of toxoplasmosis in humans, affecting 2% of infected individuals in Europe and North America. Otherwise many aspects of ocular toxoplasmosis still await answer. One of the major factors limiting this process is the difficulty to obtain human samples, doing necessary the use of experimental models. By the way, animal models do not express reality of human disease. The present study defines a compilation of report cases and results that supports the choice of an ideal experimental animal model of ocular toxoplasmosis. Actual literature bears new researches contributing in the choice of a specific experimental animal model. Moreover, the choice must consider behavior, period of life, and maintenance in captivity and ocular toxoplasmosis manifestation. Previous studies contribute for a best-chosen experimental animal model, by the way fragmented information makes difficult to compare mostly animal models picked that do not present efficiency enough. In conclusion, experimental animal models are able to bring relevant information about the course of ocular toxoplasmosis.
Keywords
- experimental model
- ocular toxoplasmosis
- animal model
1. Introduction
Ocular toxoplasmosis, a vision‐threatening ocular disease, is the most common cause of infectious uveitis [4]. It is one of the mean manifestations of toxoplasmosis in humans, affecting up to 30% of the humans worldwide. In Europe and North America, development of ocular toxoplasmosis is around 2% of infected individual. In Brazil, uveitis is estimated to be caused by toxoplasmosis in 60–85% of lesions cases [5]. Highlighting Erechim, Southern Brazil with a high frequency of humans infected usually transmitted by ingestion of uncooked meat containing cysts [6]. Ocular toxoplasmosis was first described in 1923 by Jankû, and subsequently by Levaditi in 1928. Whereas it was just in 1952 that
One of the major factors limits is the difficult to obtain human infected material. Once
2. Ocular toxoplasmosis
Accordingly literature, the
The most affected structure in ocular toxoplasmosis is the retina. Retina is the nervous tissue of the bulb of the eye, responsible for transduce photon stimulus into electric impulse. And for that transduction occurs, it is necessary that the integrity and well function of the 10 layers of retina tissue, identified in Figure 1, from the inner tissues to outer in the following order: inner limiting membrane, nerve fibers layer, ganglion cells, inner plexiform, inner nuclear layer, outer plexiform and nuclear layers, outer limiting membrane, segments of photoreceptors, and retinal pigmented epithelium. In evidence, toxoplasmic retinochorioiditis affects straight the retina as a structure, but most damaged layers are nuclear plexiform and ganglion layers, as well as the segments of photoreceptor, once RPE presents a migration, causing a discontinuity forming great interstitial lacunae. Also is observed inflammatory cells in the inner plexiform layers, also responsible for none well function of retina tissue [11].
The retina is the first area involved, furthermore choroids, vitreous humor, and anterior chamber might be also involved, but never will it happen before retina. The most common sign of acute ocular toxoplasmosis is a focal and in major times, unilateral retinal lesion [12]. But, in some individuals it was observed too, bilateral lesion, occlusive vasculitis, diffuse necrotizing retinitis and scleritis. Retinochorioiditis is commonly observed in congenital and acquired toxoplasmosis [13] resulting in acute disease and infection reactivation. It is possible to affect one or both eyes, presenting it in three different forms. Forms can be didactically differentiated (Figure 2) as punctual, multiple, and satellite lesions. In other worlds, punctual lesion might indicate primary infection, while multiple and satellite lesions, might indicate reactivation of disease. In addition, satellite lesions it is characterized by a combination of an active lesion with a healed retinal scar [10]. By the way, it is not dependent if it is acquired or congenital toxoplasmosis [4].
Clinical finds may be influenced by clonal type of
3. Acquired toxoplasmosis
Acquired toxoplasmosis occurs principally for ingesting of raw meat, vegetables, and water contemned with oocysts of
4. Congenital toxoplasmosis
Congenital toxoplasmosis is a result of an infection in prenatal presenting clinic morphologies before birth, or just along the first quarter of gestational period, been present in the forms of anencephaly, hematological abnormalities, loss vision, and blindness or even death [4, 20]. But the majority of manifestations are rare, been subclinical at birth. It can be possible to present lesions along the life. Congenital ocular toxoplasmosis can present itself neonatal, or lately, but it is more common in the last quarter of gestational period. Retinal destruction is a very frequent sequel of congenital disease [8] presenting a predilection for macular involvement [4]. A congenital ocular lesion appears to be the highest risk of systemic infection when compared to acquire ocular toxoplasmosis. Congenital ocular toxoplasmosis has been estimated to affect 3000 kids born in the USA each year. It affects 70–90% of patients, been the most common manifestation of disease. By the way, great majority of kids appears asymptomatic. Report cases indicate that some of them develop chorioretinal lesions, from scars until vision loss [7].
5. Experimental models of ocular toxoplasmosis
First animal model of toxoplasmosis was guinea pig, established by Markham in 1937. But just in 1951, the first animal model for ocular toxoplasmosis was established by Hogan, using intracarotid injection in rabbits. Following same lineage, in 1953, Frenkel managed an intraperitoneal injection in hamster. Lately nonhuman primates, cats, pigs, and dogs started been used as model [4]. Accordingly history of experimental animal models for toxoplasmosis, author and method used exposed in following time line (Figure 3).
In impossibility to obtain sample from human with acute ocular infection, animal models has been developed to supply and find answers [4]. In spite of, any animal model of ocular toxoplasmosis must consider some criteria: parasite entry, onset of disease and manifestation, self‐limitation of ocular inflammation, and model of recurrence, parasite strain used, and experimental manipulation of disease processing and treatment [10]. Ocular toxoplasmosis animal models should answer how disease happens in humans, as close as possible, from entry of parasite to development of disease. Furthermore, strains of parasite is so important as route of infection, once some strains show certain defect achieving system of host. The most used strains are: RH, ME‐49, Beverly, PLK, and Fukaya. Strains from type I was isolated from patients and animals. Type II lesser extent type I strains are used in animal models of ocular infection.
It is important to highlight that toxoplasmosis affects individuals in different forms, and in some cases do not express the disease how it is described in literature, otherwise it is of major importance to express how parasite is able to hand on the intermediate and definitive host. In immunosuppressed host, toxoplasmosis may lead them to death, unless accomplished of correct treatment. Actually known as corticosteroid, sulfadiazine, and pyrimethamine. Those medics relapse disease, doing necessary in some experimental models. Besides, pathogenicity of
Nowadays, it is known that some variation of mice is more susceptible than other, seeing the severity of infection course. Adult rats do not become ill, differently from the youngers from the same species, which can dies of toxoplasmosis. Ungulates are the most resistant hosts to toxoplasmosis, whereas some marsupials, and nonhuman primates are highly susceptible to
Retinochorioiditis in laboratory animals may vary, because interferences with parasite proliferation and viability, and the inoculation route (perioral, intraocular, intraperitoneal, conjunctival, or parenteral administration [23].
6. Methods of infection
Any experimental animal model of ocular toxoplasmosis has a set of specific features: specie, parasite strain, stage and concentration of parasites per milliliter of the inoculum, and infection route. Also important, parasite entry must be rigorously chosen. Parasite entry groups: intracarotid injection; intraperitoneal and oral infection, and presents different recurrences of the disease. Intracarotid injection is performed in bigger experimental models like nonhuman primates, cats, and rabbits. Animals must be anesthetized, accordingly Institutional Animal Care and Use Committee, and the right common carotid artery has to be isolated surgically. Using a 27‐gauge hypodermic needle, the inoculum must be performed [24].
Intraocular injection allows purport an ocular toxoplasmosis, and has been used in nonhuman primates, guinea pigs, rabbits, and mice. It is possible to perform intracamerally, periretinally, or intraretinally. The disadvantage of this method is that it can cause mechanical damage to retina, which may interfere in results of the course of the disease. First experiments, using this method consisted on retinal injections through the pars plana, crossing the vitreous cavity. Before introducing needle it was necessary a sclerotomy in the pars plana. Place where the needle was introduced [25]. Notwithstanding, administration by instillation, consist of an application over the surface of the eye, and it has shown close results to intraocular injection and in addition maintains integrity of ocular tissue [2]. Instillation is conduced using one drop of solution containing a determined concentration of parasites directly on eye surface.
The most used method, intraperitoneal injection consists of an inoculum inside the peritoneal cavity. This method is easy to perform and successfully leads to ocular toxoplasmosis and, it has many reports in hamsters and mice. Perioral via is described in literature, by introducing a solution containing oocytes in determined concentration inside the mouth of the animal. Equally important gavage is executed with an instrument that certified that experimental animal model received the right dosage, introducing a solution containing oocytes direct into the stomach of experimental model. But it does not reproduce the ocular toxoplasmosis in majority of cases, further results, or depending on the strain no result. Nevertheless performing perioral demonstrated promising results. For congenital ocular toxoplasmosis experimental models, still been an inoculum in pregnant mice, or embryonated eggs. Normally, pregnant mice are infected via intraperitoneal or perioral. Alternatively, an injection of Tachyzoite free forms in embryonated eggs, allow simulating directly embryo infection.
7. Diagnose in experimental model
In experimental model, identification of toxoplasmosis can be made finding
8. Guinea pig model
Guinea pigs were one of the first experimental animal models used for this purpose, in an accidental experiment [26]. While working with the submaxillary gland virus of guinea pigs, Markham had noted that some of animals were dying after experiments. Asymptomatic and temperature abruptly fell. However, they have rarely been used for further investigation of the disease after first experiments, with little information about. In a study of acquired transmission, a conjunctiva penetration of tachyzoites in this model was preceded, and authors found invasion of conjunctiva epithelia and goblet cells within 15 minutes post infection [27]. Replicating study within 4 hours was possible to identify a high concentration of antibodies. In conclusion,
9. Rabbit model
Rabbits are known to have a genetically determined low resistance against infection. With exacerbated inflammation accordingly to virulence and antigenicity of the parasite strain. Toxoplasmosis in this animal model was described first by Hogan in 1951 [29]. Infection with RH strains is able to produce chorioretinal lesions similar those described in cats and humans, however, concomitantly meningoencephalitis and rapid death. This describe how susceptible is this model. The most common route of infection in this experimental animal model is intravitreal inoculum, developing retinochorioiditis, equally in nonhuman primates. In rabbits as the same in nonhuman primates model is possible to observe pigmented scars after disease remission.
Intraocular infection combined with ophthalmoscopy in rabbits is easy to perform. The infection is described as a dissemination of retinochorioiditis, vitreal infiltration, and retinal detachment [30]. First affecting retina before choroid, differing from
10. Hamster model
As experimental model, hamsters had experimental ocular toxoplasmosis, described by Frenkel in 1953 [31], using RH strains showed necessity of therapy while CJ did not generate ocular lesions. In fact the use of ME‐49 strains do, intraperitoneal or perioral may influence on ocular toxoplasmosis [7].
Golden Hamster, when infected with RH or CJ strains of
11. Dog model
There are few studies in experimental dog model, but Fialho’s study is one of the first studies using dogs as experimental models, with mean alterations: ocular lesions [33]. In dogs are present retinitis, choroiditis and pseudocyst in ciliary epithelium [34]. During days post inoculation, there was only as a clinical sign a submandibular lymph node enlargement. Considering that gavage, intraperitoneal and intravenous demonstrated similar finds. With nonrelevant difference. Indicating that the immune response was observed in all animals. Similar to humans, dogs present ocular toxoplasmosis evolution from simple papillary edema to blindness and ocular necrosis. Morphological alterations in this experimental model are highly considered, once in humans are described in literature as late manifestation of toxoplasmosis, acquired or congenital. It is also demonstrated in experimental dog model [34]. Accordingly author’s results can be reproduced in only 30 days. Turning dogs excellent experimental models. By the way, its maintenance and costs turn this experimental animal model expensive and labored. Once it is seem as a pet animal. Not been easily accepted as an experimental model, for the society and committee for the use of laboratory animals.
12. Murine model
In majority toxoplasmosis in murine model, shows itself as asymptomatic, and widely prevalent, but clinically is relatively rare [21]. They are easily accessible, with complete genome sequenced, exist many knock‐outs and a large number of immunological reagents available.
Beverly JKA introduced mice as animal model in 1959, for congenital experiments [35]. Furthermore, it presents certain resistance to toxoplasmic encephalitis that is controlled by gene action. On the other hand, some vary lineage, like C57BL/6 do not have this haplotype generating spontaneously eye lesions [8]. C57BL/6 shows a high parasite load after 7 days of reinfection associated with deterioration of retinal architecture. When mice are infected by instillation or intraocular injection, both methods unleash ocular toxoplasmosis. Highlighting that instillation must replace with excellence infection of bulb of the eye, obtaining in a short period of time an infection, approaching in 7 days [2]. Considering period of obtaining results, NMRI mice infected, with same strain of
Rats as an experimental model described by Wildfuhr, in 1954 [36], but with little information about this author’s studies, present high resistance to toxoplasmic infection, because of this, that experimental animal model is used only when compared to human adults disease.
Murine model mimics likely time of exposure, establishment of cysts in humans and is easy of manipulation. Instead, it has the disadvantages of producing different degrees of severity and ocular lesions and hard monitoring, because of size of the eye [24]. Hence with many advantages, murine model may offer a great spread of methods and variable results, but it is necessary such a great number of animals to perform statistically relevant analyses.
13. Bird model
As a natural host of
On the other hand, embryonated eggs have actually shown itself as good model to test pathogenicity of strains of
Chicken embryo has shown itself, as an excellent performance when compared to other congenital ocular toxoplasmosis animal model, although does not exclude them. Its maintenance, usability, stereo environment, and easy to obtain, qualify this model as a great experimental model [40] and can present great studies when correlated to the control of environmental contamination, by controlling prevalence of infected chickens [38].
14. Nonhuman primate model
This experimental animal model of ocular toxoplasmosis, was first described in a bid of replace rabbit model proposed by Nozik and O’Connor in 1968 [25]. First experiment in this model was described using intraocular inoculum containing RH strains of
15. Felidae model
Clinical toxoplasmosis has been diagnosed in wild
In addition, an advantage of this method of infection for this experimental model is the low concentration of tachyzoites inoculated via carotid, showing retinal inflammation, different from human. In humans, this characteristic is about a reactivation of congenital infection, multifocal, and self‐limiting.
Routes of inoculation as subcutaneous and intraperitoneal, performed with a large number of tachyzoites of RH strains, leads cat too fast to death. Oral administration produces only sporadic ocular lesions, but has shown as not a good via. After exposure, there is dissemination of
16. Pig model
Pigs present a potential infection for humans, from eating under‐cooked meat [22]. This experimental animal model infected orally [41] or by intramuscular injection presented apathetic and lethargic among 2 and 9 days post infection. Besides, it is possible to see some aggressiveness attitude during chronic phase. By the way, nonlesion was allowed to identify. Using RH strains of
17. Sea mammals model
Many sea mammals are described with toxoplasmosis. In Philadelphia, at a zoo, a case of a sea lion that has died was discovered during necropsy, with cysts of
18. Ungulates model
Since 1992, ungulates and nondomestic ruminants have been reported clinically; at the same time, nonexperimental study describes clinically infection by toxoplasmosis. Actually, reports of a
19. Marsupials model
Toxoplasmosis is a serious disease of Australian marsupials, local zoo report countless death, as suddenly die, without clinical or neurological signs, loss of vision, diarrhea, or respiratory distress. Virtually any organ can be affected [43]. Even so, some species of wallabies were identified with high levels of antibodies, like adult black‐faced kangaroos, this allows to comprehend that not all exposed wallabies die of toxoplasmosis. But, some tests of vaccine (S‐48) with live, or modified and nonpersistent strain of
20. Conclusion
Experimental animal models do not express disease how it happens in humans. However, they are able to bring relevant information about the course of ocular toxoplasmosis. Mice in general are the most usual models nowadays. Adult birds do not express the disease, being a reservoir with no clinical manifestation, but avian embryos allow studies about congenital ocular toxoplasmosis, while hamsters provide information about infection. Nonhuman primates, instead the route of infection, may present important facts of the disease, while cat as the definitive host also presents ocular alteration. Other models do not have experimental description, by the way, case report help to fill the blanks for new contributions of methods, experimental model, and strain of parasite. The choice of an ideal experimental animal model is extremely important to understand and contribute for improvements on prospective treatments.
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