A systematic search of the PubMed, Google Scholar, Cross Ref, Scopus, ISI web of Knowledge and Web of Science was carried out for articles published in English language until 20th September 2020. The search terms including indexing items as well as keywords to increase the output were Toxoplasma, latent infection, stage conversion, brain, behavior, and immunity. We also searched reference list of the state-of-the-art articles. We selected 74 research studies relevant to this review and wrote to some of main authors in the field for clarifying some of the negative or unpublished data.
1- When Toxoplasma infection is associated with heightened clinical signs and mortalities
The severity of illness or acuteness of toxoplasmosis is not only dependent on parasite strains but also on the immune status of the animal. For example, immunocompetent BALB/c mice overcome the acute phase of T. gondii infection and show an inverted-bell shaped curve for the number of clinical signs observed during the first three weeks of infection [11, 12]. The physical symptoms in immunocompetent BALB/c mice entail; arched back, erected fur, searching for warmness, sunken eyes, dropped upper eyelids, staggering gait, reduced locomotion, deficient touch and evacuation reflexes, and eventually the animal succumbs lying on belly [13, 14]. Whereas, in severe combined immunodeficient (SCID) and IFN-γ knockout mice always display the full repertoire of physical signs of toxoplasmosis, attaining the peak of signs at 10 days post-infection (dpi) and succumbing the acute stage within the second week of infection [15–17]. Moreover, some studies suggest that changes in the host behaviors during T. gondii infection could be also related to the differences in mouse strain. For instance, Kannan et al.  reported in 7-months T. gondii-post-infected BALB/c mice, ME49 strain caused impairment of spatial working memory while Progniaud strain was associated with increased body weight and hyperactivity. Furthermore, provided that widespread brain pathology caused by infection with ME49 strain of T. gondii, immunocompetent C57BL/6 mice displayed motor incoordination in footprint test and reduced general locomotor activity but the spatial and recognition memories were not affected . On other hand, no apparent clinical signs were recorded in immunocompetent BALB/c mice at 60 dpi with PLK strain of T. gondii . Numerous studies illustrated that infection with T. gondii that does not cause mortalities may reveal changes in the behavioral repertoire of the rodent intermediated host, and induce manipulative changes that may increase the likelihood of horizontal transmission of infection . Therefore, there is an apparent differences in the behavioral changes displayed by T. gondii-infected rodents that could be dependent on the parasite strain and animal species.
Besides the intensity of behavioral changes caused by T. gondii-infection in rodents may refer to the animal species or the parasite strain. Several research studies reported that there are some of these behavioral abnormalities are consistently found during T. gondii infection regardless of the animal species or the parasite strain such as; (i) memory deficits were observed in wild rats and emphasized by experimental approaches in both rats and mice [22–24], (ii) motor abnormalities were either in the form of lowered or enhanced generalized activities [25, 26], and (iii) reduced anxiety in open spaces, increased preference to novel food, and host manipulation in a form of diminished fear responses to cats’ urine and fur [27–29]. Taken together, the immune potentiation of rodent host against Toxoplasma infection was associated with low mortalities, shortened acute phase responses and appearance of depression-related behaviors within the context of repertoire of physical sings of illness.
2- When Toxoplasma infection is associated with diminished sickness symptoms and mortalities
Bradyzoite is a slow replicating intracellular parasite-filled cystic form of T. gondii that has the potential to persist for the host lifespan. It has been reported that the elicited immune responses to T. gondii differ during the proliferative tachyzoite stage from those of the dormant bradyzoite stage . It well-known that T gondii strains have been classified according to its virulence into three distinct clonal lineages: high, medium and low virulent strains, or commonly written as type I, II and III of virulence, respectively . However, a recently isolated strain of T. gondii belongs to type II clonal lineage named TgCatJpObi1 strain (Obi1), was identified, it has a robust ability of cyst formation within murine macrophages and human fibroblasts cells, without the exposure to stress factors required for bradyzoite induction . It has also an in vivo ability of cyst formation in mice. Furthermore, Obi1 harbors higher gene expression of virulence factors, like Gra15, Rop5, 16, 17, and 18, when compared to ME49 strain, causes neither change in body weights, clinical signs of sickness, nor any mortalities in BALB/c mice . To clarify this point, T. gondii undergoes genetic variability during the sexual reproductive stage of its lifecycle within the intestinal cells of feline main host, where shedding of diploid oocyst in the cat faeces which then undergo meiosis and sporulation in environment yielding haploid sporozoites . Studied on T. gondii genetic differences revealed that type I virulent strain harbor high levels of ROP18 and ROP16 (Reviewed by Hunter and Sibley . Further, it was reported that within the same archetypical genotypes there are variations in some of the key effector proteins like rhoptries (ROP5, ROP16, and ROP18), and dense granular GRA3, and GRA15) families secreted by isolated T. gondii strains from stray cats . Therefore, Salman et al. . suggested that factors responsible for parasite virulence and those of bradyzoite cyst formation found in such field strain, are likely to affect independently the host. Or there may be other influencing factors, or additional genes that contribute to the differences in virulence between T. gondii genotypes [35, 36]. In line with this, a recent study has identified single factor that is only responsible for T. gondii bradyzoite cyst formation in vivo and in vitro, similar to a Myb-like transcription factor and abbreviated as BFD1 . Therefore, to explain these mysterious characters of atypical strains of T. gondii, an additional experimental study with an extensive nature may be required. To sum, despite the identified virulence genes, diminished sickness symptoms and no mortality are exhibited by mice infected with a spontaneous cyst forming strain compared to the standard strain of the most similar clonal lineage.
3- When Toxoplasma-infected mice display sickness without depressive symptoms
Apart from the debate describing the depressive symptoms are either an adaptive or maladaptive to the Darwinian fitness, several retrospective studies simplified that the risk alleles responsible for depressive disorders are still existing and persisting in human population due to their significant role in host defense mechanisms against pathogens . These embrace the combined set of immunological and behavioral responses of the host to fight infection and danger via recognition receptors called pathogen-associated, and damage-associated molecular patterns; PAMPs and DAMPs, respectively . Furthermore, from the adaptive aspect, depressive behavior has been associated with acute phase response during the interaction of the host with the pathogen [39, 40]. During the course of T. gondii infection in immunocompetent mice, depressive symptoms appeared within the context of sickness signs. Therefore, there was some challenge in separating depressive symptoms from the physical symptoms of the disease, one strategy was to use a genetically modified animal model, as those deficient in innate or adaptive immunological responses to T. gondii infection such as severe combined immunodeficient (SCID), IFN-γ knockout mice in Table 1, Mahmoud et al. [16, 41] Rehan et al.  and TLR-2 knockout mice . Reduced sucrose preference used to measure one of major depressive symptoms called anhedonia, and sometimes described as the hall mark of depression and forced swim test to assess despair-related behaviors . Immunocompetent BALB/c mice during acute stage of T. gondii-infection exhibited anhedonia, assessed by reduced sucrose consumption, and despair-like behaviors, as evidenced by increased sedentary time in forced swim test . However, in IFN-γ knockout (KO) BALB/c and Toll-like receptor (TLR)-2 KO C57BL/6 mice, both immune-deficient animals displayed neither despair-nor anhedonic-like behaviors, with or without T. gondii infection [17, 24]. In addition, TLR-2 KO mice exhibited an increased anxiolytic behavior in form of increased fear conditioning and reduced fear memory in conditioned fear test .
It could assume that heightened immune defense mechanisms were associated with depression-related behaviors during T. gondii infection, in support to this notion, T. gondii-infected BALB/ mice with type II colonial lineage strain (PLK) displayed increased anhedonic and despair symptoms, and enhanced conditioned fear responses during acute stage but not during chronic infection . In parallel, deficiency of some components of normal behavior were also observed in immunodeficient mice model called an absent in melanoma 2 (Aim2) inflammasome, or mice deficient caspase 1 and caspase 11. Such mice showed anxiety-related behaviors during performing elevated plus maze and open field testing, but they performed normally in anhedonic and despair tests . Taken together, these studies suggest that in case of T. gondii-infected immunocompromised mice, as a result of deficiency of either adaptive or innate immune components of immunity, displayed full repertoire o sickness symptoms, but reduced depression-related behaviors.
4. When Toxoplasma get access in the brain to evade the immune system
In human and rodents T. gondii finds its convenience within the body by escaping the immune system to skeletal muscles and brain. Hence, nerve cells are the main focus of the neurotropic protozoan parasites T. gondii , so the brain is considered a predilection organ for the formation of lifelong bradyzoite cyst . Therefore, infection mostly happens via oral intake of cyst or oocyst, rapidly liberates tachyzoites which penetrate the enterocytes and disseminate throughout the body of the host. An intracellular tachyzoite forms a membrane-bound parasitous vacuole (PV) and settles in immunologically protected sites like brain, muscles, retina and fetus [45–47]. T. gondii as an intracellular parasite secretes cyclophilin 18 (TgCyp18) which binds to a cysteine-cysteine chemokine receptor 5 (CCR5), CCL2 and CXCL10, that attract more leucocytes to the site of infection [48–50]. The released proteases process and produce proteins necessary for the penetration of parasite into the host cells . After crossing the blood-brain barrier (BBB), tachyzoites settle in neurons, proliferate within the parasitous vacuole (PV) and then change to latent bradyzoite in different brain areas such as cerebral cortex and hippocampus in mice and human [52, 53]. In addition, T. gondii transmits vertically and results in a wide spread of bradyzoite cyst in brains of progeny or what is known as congenital toxoplasmosis . Provided the existence of latent cyst in brains of congenitally infected mice, deficient short-term memory was not associated with changes in brain neurotransmitter concentrations .
On other aspect, T. gondii helps keep a state of balance or homeostasis with the immune system of the host. The parasite protects itself from host’s inflammatory cytokines by creating the separating wall called parasitous vacuole (PV) . A discharge of T. gondii organelles, called rhoptry (ROP) proteins, when released into cytoplasm of infected cells initiates the formation of PV, which would be ready to be occupied by T. gondii . Secreted effector molecules of T. gondii and release of both pro-inflammatory and anti-inflammatory cytokines of the host are important to achieve this homeostasis with the host [47, 58]. Initially, T. gondii infection is manifested by release of inflammatory cytokines in acute phase followed by antiinflammatory cytokines in latent phase of infection . The, the production of IFN-α and IFN-β showed a simultaneous increase starting from 6 days post-infection (dpi) with T. gondii in the brain and 8 to 10 dpi in the spleen. Thereafter, an increase in IFN-γ expression was evident at 6 dpi in the spleen but not before 10 dpi in the brain . Where, the host major defense mechanisms against T. gondii multiplication depends on promoting natural killer (NK) and T-cell activities, and consequent IFN-γ production with subsequent activation of monocytes . On other hand, after the parasite bypasses the acute stage, the production of antiinflammatory IL-10 and suppressor of cytokine signaling protein-1 (SOCS1) favors braking of the heightened immune responses and the survival of T. gondii within brain cells, and therefore help the persistence of bradyzoite cyst [60, 61]. To conclude T. gondii invade the nervous system in pursue to the immune-privileged environment. The integral host immunity and the parasite virulence factors are important to maintain this defense mechanisms of host-Toxoplasma balance.
5. When Toxoplasma manipulate the host by stage conversion strategy
To what extend T. gondii is a much an opportunistic parasite can be emphasized by its intrinsic ability to switch from tachyzoite to bradyzoite forms and vice versa. Toxoplasma perform stage conversion to match the host immune status and keep its survival. For instance, in immune-deficient conditions or under chronic immunosuppressive therapy, recrudescence of T. gondii occurs and is associated with severe symptomatic toxoplasmosis in human and encephalitis as in immunocompromised patients, AIDS in particular [62, 63]. Such evidence was reproduced after reactivation of chronic toxoplasmosis by two weeks-treatment with an immunosuppressant drug, dexamethasone in BALB/ mice. Despite bradyzoite marker Bag1 gene expression was not affected, Sag1, tachyzoite marker, mRNA expression showed a marked increase after dexamethasone treatment. Clear anhedonic and despair-related behaviors with minimal sickness symptoms were displayed by mice after recrudescence . However, it was worthy to mention that the process of cyst rupture and formation may continue unabated even in the immune-competent host . To conclude Toxoplasma get benefits and keep its survival with the host by such amazing reversibility from tachyzoite to bradyzoite stages and help manipulate the host immune system to reach immune balance (Fig. 1, [Ref, 64–66]).