Toxoplasmosis caused by Toxoplasma gondii parasite has a world - wide distribution effecting one third of the world population. A number of parasite and host factors determine the outcome of prevalence, disease severity and tissue damage ranging from asymptomatic self - limiting infection in health adults to serious destructive inflammatory consequences in congenitally infected infants and in individuals with a weakened immune system.

There is strong experimental evidence that the cytokines play a major role in the pathogenesis of Toxoplasma gondii and manipulation of these cytokines can put forth a beneficial or damaging effect on the host and thus modulate the disease pathology. The importance of interferon gamma (IFN-γ) was clearly demonstrated when the neutralization of interleukin (IL) IL-12 and of IFN-γ using anti-IFN-γ & anti-IL-12 monoclonal antibodies (MAb) resulted in reactivation and loss of control on the parasite’s multiplication leading to disease. Cytokine IL-27 was deemed as an endogenous suppresser on IL-17, the inflammatory cytokine that is capable of enhancing the inflammatory response in the brain. Although Toxoplasma is an intracellular pathogen thereby requiring a cell mediated immune response from the host, the cytokine IL-10 protects the infected mice from an exaggerated cellular immune response by inhibiting the production of pro - inflammatory cytokines: IL-12, IFN-γ, and TNF-β. Following Toxoplasma infection the host triggers a sequential balanced cytokine response to limit the infection and the disease pathology. However, cytokines can sometimes exert a negative effect on the host and augment the disease leading to severe irreversible tissue damage.

Iqbal J, Al-Awadhi M (2016) Toxoplasmosis: Role of Cytokines in Disease Modulation & Tissue Pathology. Ann Clin Pathol 4(7): 1090.

•    Cytokine
•    Tissue pathology
•    Toxoplasma gondii

T. gondii: Toxoplasma Gondii; IFN- γ: Interferon Gamma; TNF: Tumour Necrosis Factor

Toxoplasma gondii belonging to the phylum Apicomplexa, is an obligate intracellular parasite that can invade and replicate in almost all nucleated cells of virtually all warm blooded animals, including humans. It has a world - wide geographical distribution affecting one third of the world population. Humans may acquire the infection by ingestion of oocysts or congenitally by transplacental transmission from the infected mother [1]. The prevalence of T. gondii -specific antibodies in adults increases with age but differs widely due to temperature and humidity variation, as well as different population and ethnic groups within the same country [2-4]. In the USA and UK, approximately 16-40% of the population is infected, whereas in Central America and Continental Europe 50-80% people are infected [5].

A number of parasite and host factors determine the outcome of infection. The most important factors appear to be the mode of infection, parasite strain and host immunogenic characteristics [6,7]. The majority of infected immune competent healthy adults are asymptomatic however; it may cause serious destructive inflammatory consequences in congenitally infected infants [8] and in individuals with a weakened immune system [9,10]. During the early stages of pregnancy, the presence of fetal antigens in the circulation, low levels of progesterone and 17-β estradial may alter the immune responses of the mother thus increasing the susceptibility to active infection which may cause apoptosis of placental cells and fetal resorption inducing the congenital malformations in the growing fetus [11,12].

Though T. gondii parasite has been shown to have low genetic diversity and a clonal population but there is a growing evidence that the three genetically different type-I, type-II and type-III parasite strains may determine the outcome of infection and tissue pathology in the host. Type I strains are shown to be highly virulent and cause rapid death in mice, whereas the outcome of infections with type II and III strains depends on the challenge dose and genotype of the host [13-15].

Figure (1) presents geographic association between parasite strains (“Types” or “Haplogroups” I through XVII), prevalence of human infection, severity of human infection and mouse virulence.

Within the Toxoplasma parasite life cycle, two stages have been observed; the sexual stage which is rather distinct and highly specific as it occurs only within the gut epithelial cells of feline species. On the contrary, asexual stage has a large repertoire capable of infecting several vertebrate intermediate species including humans. In the intermediate hosts, the oocysts (bradyzoites) change from their slow - growing phase into tachyzoites, the rapid replication phase infecting almost any nucleated cell they encounter, multiplying intracellular leading eventually to host cell lysis. Following infection, an immune competent individual develops immunity to the tachyzoites changing the parasite to the slow multiplying stage (bradyzoites). The bradyzoites stage ensures the survival of the parasite within the cysts in the muscles and central nervous system by shielding it from the host’s immune surveillance. However, in immune compromised hosts, the parasite rapidly changes to the rapidly replicating stage causing an active multi-organ infection [16].

Toxoplasma parasite-host cell interaction

Toxoplasma host cell invasion is an active, parasite - driven process accompanied by release of a number of polymorphic parasite proteins and factors that interact with the host cell and thus may alter the host resistance to infection and tissue pathology. These proteins and factors are released from apical secretory organelles. Over the past 15 years it has become increasingly clear that many of these secreted effectors manipulate host immune defense mechanisms and determine differences in parasite virulence (Figure 2) [17,18].

A single mutation in a secreted rhoptry protein (ROP16) determines activation of the immune communication pathway called the “STAT6 signaling pathway” by the Toxoplasma strains and thus the host immune response to worm infections.

Toxoplasma parasite either turns this pathway on or off depending on the strain type and ROP16 version (allele) it encodes. Different parasite strains encode particular combinations of active and inactive effectors. Thus, a little P53 activation, less MAPK and NF-kB signaling, but strong ERK by one strain could be perfect to establish a chronic infection in one species, but lethal or pathogenic in others - mice or humans (Figure 2) [17,18].

Role of pro-inflammatory cytokines

IFN-γ & TNF: A complex network of cytokines produced by interacting immune cells significantly contribute to immunity against the parasite, pathologic hypersensitivity reactions leading to tissue pathology and the course of infection in the host. Earlier, the studies have documented that the control of Toxoplasma infection in mouse with non - virulent strains is achieved by a vigorous IFN- γ -dependent Th1 pro - inflammatory cytokine response by Toxoplasma - specific T cells [19,20]. These cells either produce protective cytokines inducing toxoplasmacidal activity or cytokines that are involved in T - cell proliferation in the infected organs [21]. In fact, there is growing experimental evidence that these two aspects of T - cell function may be differentially regulated in different organs by different strains of Toxoplasma gondii. Another important task of IFN-γ is to prevent the reactivation of Toxoplasma encephalitis in mice. When produced in excess, pro - inflammatory cytokines may lead to tissue damage and thus, a delicate balance between pro and anti - inflammatory cytokines is necessary for the effective control of the parasite and survival of the host.

The production of IFN-γ also activates macrophages to produce tumor necrosis factor - alpha (TNF-α) which synergizes with IFN-γ to initiate production of the anti - microbial molecule, nitric oxide (NO). IFN-γ also controls other effector mechanisms that fight T. gondii infection, including generation of reactive oxygen intermediates (ROI), iron deprivation, tryptophan starvation and activation of the p47 GTPases (Miller et al., 2009 thesis). The anti - parasitic activity for the latter is due to the accumulation of certain p47 GTPase family members at T. gondii -containing vacuoles and successive disruption of the parasitophorous vacuole membrane (PVM) and the parasite [22]. In murine models of ocular toxoplasmosis, treatment with either anti-IFN-γ or anti-TNF-α monoclonal antibodies resulted in a dramatic increase in the inflammatory process, retinal - pigmented epithelial pathology, and chorioretinal scars, demonstrating that IFN-γ and TNF-α are critical in controlling parasite growth [23].

Role of IL-12 & IL-18

In T. gondii infection caused by oral route, IL-12 acts synergistically with IL-18 to produce IFN-γ by NK cells. IFN-γ synergizes with IL-12 to drive the differentiation of Thp to Th1 phenotype, express IL-12 receptor on T cells, and inhibit the antagonist IL-4 to prevent the differentiation of Thp towards Th2 phenotype [24]. Conversely, IL-18 seems to have an opposite role where it was found that IL-18 can incite intestinal necrosis and inflammation and mice deficient in this cytokine displayed better survival, decreased parasite load, and only moderate necrosis of the villi and mucosa [25]. On the other hand, IL-12 seems to have a more beneficial role because IL-12 deficient mice displayed severe pathology, decreased survival (as wild types) and increased parasite burden. Hence, although IL-18 is a potent enhancer of IL-12, its production may mediate intestinal pathology while IL-12 is involved in controlling the parasite. In addition, the role of IL-12 was further demonstrated by in vivo depletion studies documenting the ability of exogenous IL-18 to enhance resistance to T. gondii infection with IL-12, IFN- γ and NK cells [25].

Role of TGF-β

Transforming growth factor (TGF-β) is a multi-functional cytokine with anti - inflammatory activities and an important suppressor of macrophages, the production of which is induced after infection with T. gondii [26]. TGF-β is secreted by Intraepithelial lymphocytes (IELs), particularly by CD8 αβ and TCR αβ, regulates the inflammatory pathogenic responses elicited by lamina propria lymphocytes (LPLs) by down regulating the transcription of IFN-γ, IL-15, iNOS and TNF-α (pro - inflammatory cytokines) [1]. T. gondii can remain dormant in the CNS and the eye. In these sites, TGF-β and IL-10 cooperate together by first TGF-β conditioning antigen - presenting cells (APCs) to release IL-10 which in return will decrease NK- and CD4 Th1 - mediated pro - inflammatory responses suggesting that TGF-β is inefficient without IL-10 in immune - privileged sites in controlling the inflammation [1,27]. It also inhibits the production of IFN-γ by NK cells (Hunter et al., 1995-thesis), thus may down - regulate the effector functions of anti - Toxoplasma cellular immunity during acute toxoplasmosis. TGF-β is an important suppressor of macrophages [26], the production of which is induced after infection with T. gondii [28]. It also inhibits the production of IFN-γ by NK cells, thus may down - regulate the effector functions of anti - Toxoplasma cellular immunity during acute toxoplasmosis.

Role of Anti-inflammatory cytokines

Although IFN-γ-dependent pro - inflammatory cytokines are essential for resistance to T. gondii infection, an over -production of inflammatory cytokines and NO can result in serious tissue damage [13,29,30]. Thus, the host needs to balance the response in order to eliminate the parasite while minimizing tissue damage. Anti - inflammatory signals from the macrophages themselves or surrounding cells down - regulate macrophage activation and result in the production of anti - inflammatory cytokines such as IL-10, TGF-β and interleukin-27 [21].

Role of IL-10

The anti - inflammatory cytokine IL-10 plays an important role in reducing harmful pathological effects of inflammatory responses in T. gondii infection. IL-10 is a cytokine produced by DCs, macrophages, B-cells, Th2 cells and T - regulatory cells [31,32]. IL-10-deficient mice showed elevated IL-12 levels and consequently increased IFN-γ and TNF-α responses and intense hepatic inflammation and tissue necrosis [30]. During acute toxoplasmosis, IL-10 serves a dual role in the suppression of the host’s cellular immune response. First, it inhibits IFN-γ production and the proliferation of T-lymphocytes, thus preventing a potentially protective Th1 immune response. Such T-cell-dependent immune suppression exerted by IL-10 primarily appears to avoid overwhelming inflammation which eventually leads to death. Second, IL-10 may also deactivate macrophages, thus reducing IFN-γ-induced toxoplasmacidal activity and facilitating intracellular parasite survival. Hence, IL-10-induced immune suppression following infection with T. gondii is beneficial for both the parasite and the host and favors a stable host - parasite relationship [33,34].

Immunopathology in toxoplasmosis

Role of cell-mediated immunity in pathological changes: Although an early cell - mediated immune response is necessary to control T. gondii infection, an exacerbated response can also participate in tissue damage along with parasite - induced damage.

Toxoplasma infection rapidly overcomes hosts with impaired T - cell function and diminished ability to produce proinflammatory cytokines [35]. In recent years, it has become clear that pro-inflammatory and anti - inflammatory cytokine responses must be tightly regulated for optimal control of infection and that cytokine imbalances resulting from loss of control can play a role in the pathological changes associated with toxoplasmosis [24]. Nevertheless, it is difficult to experimentally separate pathological changes caused by parasite replication from more systemic damage caused by parasite-induced cytokines.

Acute infection and pathological changes in tissues: In most immune competent patients, acute toxoplasmosis results in post - cervical lymphadenopathy and mild fever [36], which occurs along with the activation of the immune system triggered by T. gondii and a simultaneous production of high levels of pro - inflammatory cytokines. In most patients, acute toxoplasmosis will progress to the asymptomatic stage within a few weeks of infection.

Intestinal pathology: Based on experimental studies on the production of inflammatory mediators during infection in mice, there is evidence that T-cell-derived cytokines may promote pathological changes during T. gondii infection. After peroral infection, the susceptible C57BL/6 mouse strain develops a severe intestinal inflammatory response, leading to severe necrosis of the villi and mucosal cells of the small intestine [37]. It was shown that the tissue damage was not parasite - induced, but caused mainly by the development of a strong pro -inflammatory immune response, characterized by overproduction of pro - inflammatory mediators including IL-12, IL-18, IFN-γ, TNF-α, and NO (‘cytokine storm’).The tissue damage was characterized by severe ileal necrosis with complete tissue destruction and intensive infiltration of neutrophilic granulocytes, macrophages, dendritic cells and lymphocytes within the lamina propria [37,38].

The role of cytokine - induced tissue damage was substantiated by the reversal of pathological changes when anti -IFN-γ or anti-CD4 monoclonal antibodies (MAb) were administered. In addition, the two MAb also delayed the death in terminally ill mice. It has also been demonstrated that IFN-γ triggers Fasdependent apoptosis of Peyer’s patch T-cells in perorally infected mice [37-39]. Similarly, the depletion of TNF, another inducer of Fas - dependent apoptosis, delayed the death of acutely infected mice with the highly virulent RH strain [40]. An uncontrolled pro -inflammatory cytokine response and the resulting pathological changes mediated by T-lymphocytes, was also confirmed in IL10 knockout mice [30]. Granulocytes have also been shown to contribute to the inflammatory pathological changes triggered by T. gondii infection [40]. Thus, several experimental studies suggest that Toxoplasma - induced inflammatory responses, and specifically CD4+ T-lymphocytes and granulocytes, contribute to the pathological damage associated with acute infection in mice.

Ocular pathology: Recently our group has reported that acute infection with T. gondii RH parasites, a mild Th1 pro - inflammatory response in the BALB/c mice with high IFN-γ and TNF-α and, low TGF-β 1 levels during the early stages of infection contributes to an effective cellular immune response leading to lower morbidity, mortality and less ocular tissue damage. However in the MF1 mice, a significantly high TGF-β1 level in the blood as well as in the aqueous humor during the acute intra - ocular toxoplasma infection adversely interferes with an effective cellular immune response leading to an increased mortality and extensive ocular tissue damage with parasite tachyzoites observed in the pigment epithelium layers (Figure 3,4) [14].

Chronic infection and pathological changes in tissues: The appearance of bradyzoites marks the beginning of the chronic phase of infection when parasite replication slows dramatically. Tissue cysts appear to be practically invisible to the host since there is little or no evidence of inflammation or immune cell infiltrates around them [41].

In reactivation of a latent T. gondii infection, cysts may occur in a variety of tissues, but the most important clinical site is the central nervous system, where uncontrolled parasite replication may lead to toxoplasmic encephalitis (TE). In the wake of low T-cell counts and declining local IFN-γ levels, bradyzoites revert to tachyzoites, which rapidly proliferate in astrocytes and microglia causing tissue necrosis [42]. Multiple lesions are frequently seen in TE patients, most commonly in the cerebral hemispheres and basal ganglia [41]. Tissue damage is not due to apoptosis since T. gondii actually induces an anti - apoptotic state in the infected cell [14].

Cytokines play a major role in the pathogenesis of Toxoplasma gondii. There is a strong experimental evidence that the manipulation of these cytokines can put forth a beneficial or damaging effect on the host and thus modulate the disease pathology. The importance of IFN-γ was clearly demonstrated when the neutralization of IL-12 and of IFN-γ using anti-IFN-γ & anti-IL-12 MAb resulted in reactivation and loss of control on the parasite’s multiplication leading to disease. Cytokine IL-27 was deemed as an endogenous suppresser on IL-17, the inflammatory cytokine that is capable of enhancing the inflammatory response in the brain. Although Toxoplasma is an intracellular pathogen thereby requiring a cell mediated immune response from the host, the cytokine IL-10 protects the infected mice from an exaggerated cellular immune response by inhibiting the production of pro - inflammatory cytokines: IL-12, IFN-γ, and TNF-β. Following Toxoplasma infection the host triggers a sequential balanced cytokine response to limit the infection and the disease pathology. However, cytokines can sometimes exert a negative effect on the host and augment the disease leading to severe irreversible tissue damage.

The financial support for this study was provided by the Research Sector, Kuwait University, Kuwait, project number YM 02/10.

1. Gaddi, PJ, Yap G S. Cytokine regulation of immune pathology in toxoplasmosis. Immunol Cell Biol. 2007; 85: 155-159.

2. Gelaye W, Kebede T, Hailu A. High prevalence of anti-toxoplasma antibodies and absence of Toxoplasma gondii infection risk factors among pregnant women attending routine antenatal care in two hospitals in Addis Ababa. Int J Infect Dis. 2015; 34: 41-45.

3. Munoz M, Liesenfeld O, Heimesaat MM. Immunology of Toxoplasma gondii. Immunol Rev. 2011; 240: 269-285.

4. Konishi E, Houki Y, Harano K, Mibawani RS, Marsudi D, Alibasah S, et al. High prevalence of antibody to Toxoplasma gondii among humans in Surabaya, Indonesia. Jpn J Infect Dis. 2000; 53: 238-241.

5. Hill RD, Dubey JP. Toxoplasma gondii: transmission, diagnosis and prevention. Clin Microbiol Infect. 2002; 8: 634-640.

6. Dubey JP, Ferreira LR, Martins J, Mcleod R. Oral oocyst-induced mouse model of toxoplasmosis: effect of infection with Toxoplasma gondii strains of different genotypes, dose, and mouse strains (transgenic, out-bred, in-bred) on pathogenesis and mortality. Parasitol. 2012; 139: 1-13.

7. Suzuki Y, Yang Q, Yang S, Nguyen N, Lim S, Liesenfeld O, et al. IL-4 is protective against development of toxoplasmic encephalitis. J Immunol. 1996; 157: 2564-2569.

8. Pappas G, Roussos N, Falagas ME. Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int J Parasitol. 2009: 39: 1385-1394.

9. Rogers NM, Peh C-A, Faull R, Pannell M, Cooper J, Russ GR. Transmission of toxoplasmosis in two renal allograft recipients receiving an organ from the same donor. Transpl Infect Dis. 2008; 10: 71-74.

10. Butler NJ, Furtado JM, Winthrop KL, Smith JR. Ocular toxoplasmosis. II. Clinical features, Pathology, and management. Clin Exp Ophthal. 2013; 41: 95-108.

11. Galvan-Ramirez Mde la L, Gutierrez-Maldonado AF, Verduzco-Grijalva F, Jimenez JM. The role of hormones on Toxoplasma gondii infection: a systematic review. Front Microbiol. 2014; 5: 503.

12. Robinson DP, Kliein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav. 2012; 62: 263-271.

13. Mordue DG, Monroy F, La Regina M, Dinarello CA, Sibley LD. Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. J Immunol. 2001; 167: 4574-4584.

14. Iqbal J, Al-Awadhi A, Raghupathy RG. TGF-β1 levels and intraocular tissue alterations in mice infected with a virulent type I RH Toxoplasma gondii strain. Exp Parasitol. 2016; 162: 57-63.

15. Rocha ACH, Calabrese Kda Silva, Tedesco RC, Campos WR, Neto MH, Vasconcelos AC, et al. Morphometric changes in C57BL/6 mice retina infected by Toxoplasma gondii ME 49 strain. Exp Parasitol. 2013; 136:1-4.

16. Hunter CA, Sibley LD. “Modulation of innate immunity by Toxoplasma gondii virulence effectors.” Nat Rev Microbiol. 2012; 10: 766-778.

17. Plattner F, Soldati-Favre D. Hijacking of host cellular functions by the Apicomplexa. Annu Rev Microbiol. 2008; 62: 471-487.

18. Peixoto L, Chen F, Harb OS, Davis PH, Beiting DP, Brownback CS, et al. Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses. Cell host Microbe. 2010; 8: 208- 218.

19. Gaddi PJ, Yap GS. Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol. 2007; 85: 155-159.

20. Sarciron ME, Gherardi A. Cytokines Involved in Toxoplasmic encephalitis. Scand J Immunol. 2000; 52: 534-543.

21. Miller CM, Boulter NR, Ikin RJ, Smith NC. The immunobiology of the innate response to Toxoplasma gondii. Int J Parasitol. 2009; 39: 23-39.

22. Martens S, Parvanova I, Zerrahn J, Griffiths G, Schell G, Reichmann G, et al. Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases. PLoS Pathog. 2005; 1: 24.

23. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, et al. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994; 153: 2533-2543.

24. DenkersE Y, Gazzinelli RT. Regulation and function of T-cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev. 1998; 11: 569-588.

25. Cai G, Kastelein R, Hunter, CA. Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii. Infect Immun. 2000; 68: 6932-6938.

26. Langermans JA, Nibbering PH, Van Vuren-Van der Hulst, MEB, Van Furth R. Transforming growth factor-β suppresses interferon-γ-induced toxoplasmastatic activity in murine macrophages by inhibition of tumour necrosis factor-α production. Parasite Immunol. 2001; 23: 169-175.

27. Lu F, Huang S, Kasper LH. Interleukin-10 and pathogenesis of murine ocular toxoplasmosis. Infect Immun. 2003; 71: 7159-7163.

28. Bermudez LE, Covaro G, Remington J. Infection of murine macrophages with Toxoplasma gondii is associated with release of transforming growth factor beta and down regulation of expression of tumor necrosis factor receptors. Infect Immun. 1993; 61: 4126-4130.

29. Gavrilescu LC, Denkers EY. IFN-γ overproduction and high level apoptosis are associated with high but not low virulence Toxoplasma gondii infection. J Immunol. 2001; 167: 902-909.

30. Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R, et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. J Immunol. 1996; 157: 798-805.

31. Levings MK, Bacchetta R, Schulz, U, Roncarolo MG. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol. 2002; 129: 263-276.

32. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001; 19: 683- 765.

33. Ellis-Neyer L, Grüning G, Fort M, Remington JS, Rennick D, Hunter CA. Role of interleukin-10 in regulation of T-cell-dependent and T-cell-independent mechanisms of resistance to Toxoplasma gondii. Infect Immun. 1997; 65: 1675-1682.

34. Khan I, Matsuura T, Kasper LH. IL-10 mediated immunosuppression following primary infection with Toxoplasma gondii in mice. Parasite Immunol. 1995; 17: 185-195.

35. Weiss LM, Dubey JP. Toxoplasmosis: A history of clinical observations. Int J Parasitol. 2009; 39: 895-901.

36. Frenkel JK. Pathophysiology of toxoplasmosis. Parasitol Today. 1988; 4: 273-278.

37. Liesenfeld O, Kosek JC, Remington JS, Suzuki Y. Association of CD41 T cell-dependent, IFN-γ-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii. J Exp Med. 1996; 184: 597-607.

38. Heimesaat MM, Bereswill S, Fischer A, Fuchs D, Struck D, Niebergall J. Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol. 2006; 177: 8785-8795.

39. 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: 4682-4689.

40. Marshall AJ, Denkers EY. Toxoplasma gondii triggers granulocyte-dependent, cytokine-mediated lethal shock in D-galactosamine sensitized mice. Infect Immun. 1998; 66: 1325-1333.

41. Strittmatter C, Lang W, Wiestler OD, Kleihues P. The changing pattern of human immunodeficiency virus-associated cerebral toxoplasmosis: a study of 46 postmortem cases. Acta Neuropathol. 1992; 83: 475-481.

42. Fagard R, Van Tan H, Creuzet C, Pelloux H. Differential development of Toxoplasma gondii in neural cells. Parasitol Today. 1999; 15: 504-507.