Chronic Toxoplasma Gondii Infection Research Articles

Lentinan has a beneficial effect on cognitive deficits induced by chronic Toxoplasma gondii infection in mice

BackgroundToxoplasma gondii (T. gondii) is increasingly considered a risk factor for neurodegenerative diseases. However, there is only limited information on the development of drugs for T. gondii infection. Lentinan from Lentinula edodes is a bioactive ingredient with the potential to enhance anti-infective immunity. The present study aimed to investigate the neuroprotective effect of lentinan on T. gondii-associated cognitive deficits in mice.MethodsA chronic T. gondii infection mouse model was established by administering 10 cysts of T. gondii by gavage. Lentinan was intraperitoneally administered 2 weeks before infection. Behavioral tests, RNA sequencing, immunofluorescence, transmission electron microscopy and Golgi-Cox staining were performed to assess the effect of lentinan on cognitive deficits and neuropathology in vivo. In vitro, the direct and indirect effects of lentinan on the proliferation of T. gondii tachyzoites were evaluated in the absence and presence of BV-2 cells, respectively.ResultsLentinan prevented T. gondii-induced cognitive deficits and altered the transcriptome profile of genes related to neuroinflammation, microglial activation, synaptic function, neural development and cognitive behavior in the hippocampus of infected mice. Moreover, lentinan reduced the infection-induced accumulation of microglia and downregulated the mRNA expression of proinflammatory cytokines. In addition, the neurite and synaptic ultrastructural damage in the hippocampal CA1 region due to infection was ameliorated by lentinan administration. Lentinan decreased the cyst burden in the brains of infected mice, which was correlated with behavioral performance. In line with this finding, lentinan could significantly inhibit the proliferation of T. gondii tachyzoites in the microglial cell line BV2, although lentinan had no direct inhibitory effect on parasite growth.ConclusionsLentinan prevents cognitive deficits via the improvement of neurite impairment and synaptic loss induced by T. gondii infection, which may be associated with decreased cyst burden in the brain. Overall, our findings indicate that lentinan can ameliorate T. gondii-related neurodegenerative diseases.Graphical

Immunomodulatory, Antioxidant, and Anti-Inflammatory Activities of Green Synthesized Copper Nanoparticles for Treatment of Chronic Toxoplasma gondii Infection.

Nowadays, interest in the use of nanotechnology for medical purposes is increasing. The current experimental investigation is planned for the green synthesis, characterization, and efficacy of copper nanoparticles (CLN) against chronic Toxoplasma gondii infection. Green synthesis of CNP was performed using the Lupinus arcticus extract via the precipitation method. The effects of CNP on tachyzoites, infectivity rate, parasites inside THP-1 cells, nitric oxide (NO) triggering, iNOS, and IFN-γ expression genes were evaluated. Following toxoplasmosis in BALB/c mice via the T. gondii ME49 strain, mice received CNP at 5 and 10 mg/kg/day alone and combined with pyrimethamine (PYM) at 5 mg/kg for two weeks. CNP's in vivo effects were evaluated by analyzing the load and size of cysts, oxidant/antioxidant enzymes, and bradyzoite surface antigen 1 (BAG1) expression gene levels. CNP displayed a circular shape ranging from 10 to 85 nm. The IC50 value of CNP and PYM against tachyzoites was 37.2 and 25.7 µg/mL, respectively, whereas the CC50 value of CNP and pyrimethamine against THP-1 cells was 491.4 μg/mL and 269.5 μg/mL, respectively. The rate of infectivity and parasite load among THP-1 cells exposed to CNP was obviously reduced (p < 0.05). CNP at the doses of 5 and 10 mg/kg predominantly along with PYM evidently (p < 0.05) reduced the number and size of the T. gondii cysts in the infected mice. The levels of NO, iNOS, and IFN-γ genes were remarkably (p < 0.001) boosted compared with the cells without treatment. CNP at the doses of 10 and 20 mg/kg drastically (p < 0.05) reduced the oxidative stress markers in the infected mice, whereas CNP significantly elevated the level of antioxidant factors. CNP also revealed no toxicity in the liver and kidney at the tested doses in healthy mice. Our experimental study reported the beneficial effects of CNP principally along with existing chemical drugs against latent toxoplasmosis in mice, whereas the possible action mechanisms of CNP are controlling oxidative stress, refining antioxidant enzymes, and increasing the production of immunomodulatory cytokines with no toxicity to the function of vital organs. But, additional trials are required to confirm these results, as well as to clarify the accurate mechanisms and their toxicity.

Tryptophan metabolism and immune alterations in pregnant Hispanic women with chronic Toxoplasma gondii infection.

Pregnancy markedly modifies women's metabolism and immune functions. We hypothesized that pregnancy might alter the immune and metabolic responses to chronic Toxoplasma gondii infection in pregnancy. A population of 690 pregnant Hispanic women were screened for antibodies to T. gondii and 158 women were positive (23% positivity) with 83% showing high avidity indices. These seropositive women were followed through their pregnancies with four data collection time points and a postpartum collection at two clinics in Tampa, Florida. A T. gondii seronegative group (N=128) was randomly selected to serve as a control group and measured along pregnancy in the same way. Serum levels of tryptophan, kynurenine, and their ratio, phenylalanine, tyrosine and their ratio, neopterin, and nitrite were measured through pregnancy and the postpartum. A plasma cytokine panel (IFN-γ, TNFα, IL-2, IL-10, IL-12, IL-6, IL-17) was analyzed in parallel. The major findings suggest that indoleamine 2,3-dioxygenase (IDO-1) was less activated in T. gondii seropositive pregnant Hispanic women with chronic infection. Evidence for IDO-1 suppression was that tryptophan catabolism was less pronounced and there were lower levels of multiple inflammatory cytokines including IFN-γ, which is the major inducer of IDO-1, and higher nitrite concentration, a surrogate marker for nitric oxide, an inhibitor of IDO. Latent T. gondii infection was associated with higher plasma tryptophan levels, and lower inflammatory cytokines across pregnancy, suggesting suppression of the IDO-1 enzyme, and possible T cell exhaustion during pregnancy.

Efficacy of clofazimine against acute and chronic Toxoplasma gondii infection in mice

Toxoplasmosis is a zoonotic protozoal disease affecting approximately one-third of the world's population. The lack of current treatment options necessitates the development of drugs with good tolerance and effectiveness on the active and cystic stages of the parasite. The present study was established to investigate, for the first time, the potential potency of clofazimine (CFZ) against acute and chronic experimental toxoplasmosis. For this purpose, the type II T. gondii (Me49 strain) was used for induction acute (20 cysts in each mouse) and chronic (10 cysts in each mouse) experimental toxoplasmosis. The mice were treated with 20 mg/kg of CFZ intraperitoneally and orally. The histopathological changes, brain cyst count, total Antioxidant Capacity (TAC), malondialdehyde (MDA) assay, and the level of INF-γ were also evaluated. In the acute toxoplasmosis, both IP and oral administration of CFZ induced a significant reduction in brain parasite burden by 90.2 and 89%, respectively, and increased the survival rate to 100% compared with 60% in untreated controls. In the chronic infection, cyst burden decreased at 85.71 and 76.18% in CFZ-treated subgroups in comparison to infected untreated controls. In addition, 87.5% and 100% of CFZ-treated subgroups survived versus untreated control 62.5%. Moreover, CFZ significantly increased INF-γ levels in acute and chronic toxoplasmosis. Tissue inflammatory lesions were considerably reduced in the CFZ-treated chronic subgroups. CFZ treatment significantly reduced MDA levels and elevated TAC in both acute and chronic infections. In conclusion, CFZ showed a promising finding regarding the ability to reduce cyst burden in acute and chronic infection. Further studies are needed to investigate the therapeutic role of CFZ on toxoplasmosis using the long-term treatment and more advanced approaches. In addition, clofazimine may need to be accompanied by another drug to augment its effect and prevent the regrowth of parasites.

Association of Chronic Toxoplasma gondii Infection with Pro-Inflamatory Cytokine Interleukin (IL)-12 Responses in Type-2 Diabetes Mellitus Patients of Bangladesh.

Toxoplasma gondii is an intracellular protozoan parasite that causes toxoplasmosis in around one-third of the world population, particularly in pregnant women and immunocompromised individuals. Diabetes mellitus (DM) is one of the most severe global health challenges in the 21st century, and especially, type-2 diabetes mellitus (T2DM) accounts for 90% of the diabetes cases diagnosed globally. In Bangladesh, the rate of T2DM is rising gradually with the improvement in living standards. The aim of this study is to find out the correlation between latent toxoplasmosis and T2DM, emphasizing the pro-inflammatory cytokine immunity. For this, 100 (N = 100) patients with T2DM and 100 (N = 100) healthy controls were enrolled to determine the seroprevalence of toxoplasmosis using enzyme-linked immunosorbent assay (ELISA). In addition, ELISA was also performed to determine the level of pro-inflammatory cytokine, interleukin (IL)-12, to understand its role in the development of toxoplasmosis. In our study, 39.39% of the T2DM patients were positive with anti-T. gondii Immunoglobulin G by ELISA, whereas the rate of seropositivity in healthy controls was 39.73%. We did not find significant association between T. gondii infection and T2DM, but our data confirmed a high prevalence of chronic toxoplasmosis in Bangladeshi population. From hematology tests, it was found that the T2DM patients had significantly lower levels of total white blood cells (P = 0.0015), circulating eosinophils (P = 0.0026), and neutrophils (P = 0.0128) than the healthy controls. On the other hand, the levels of lymphocytes (P = 0.0204) and monocytes (P = 0.0067) were significantly higher in patients. Furthermore, T. gondii infected T2DM patients had significantly higher levels of IL-12 than the healthy controls (P = 0.026), suggesting a link between parasitic infection and IL-12 secretion. Further studies are to be performed to find out the exact cause of high prevalence of chronic T. gondii infection in Bangladeshi population.

Dynamic changes in TIGIT expression on the T-cell surface and TIGIT-mediated T-cell dysfunction in the brains of mice with chronic Toxoplasma gondii infection

The immunosuppressive receptor TIGIT plays a vital role in the regulation of the immune system's response to pathogens. However, the expression pattern of this receptor in mouse brains during infection with Toxoplasma gondii cysts is not known. Here, we provide evidence of immunological changes and TIGIT expression in infected mouse brains through flow cytometry and QPCR. The obtained results show that TIGIT expression on brain T cells rose considerably after infection. T. gondii infection triggered the conversion of TIGIT+ TCM cells to TIGIT+ TEM cells and reduced their cytotoxicity. During the whole period of T. gondii infection, high intensity and persistent expression of IFN-γ and TNF-α in brain and serum of mice. This study shows that chronic T. gondii infection increases TIGIT expression on brain T cells and affects their immune function.

Chronic Toxoplasma gondii infection contributes to perineuronal nets impairment in the primary somatosensory cortex

Toxoplasma gondii is able to manipulate the host immune system to establish a persistent and efficient infection, contributing to the development of brain abnormalities with behavioral repercussions. In this context, this work aimed to evaluate the effects of T. gondii infection on the systemic inflammatory response and structure of the primary somatosensory cortex (PSC). C57BL/6 and BALB/c mice were infected with T. gondii ME49 strain tissue cysts and accompanied for 30 days. After this period, levels of cytokines IFN-γ, IL-12, TNF-α and TGF-β were measured. After blood collection, mice were perfused and the brains were submitted to immunohistochemistry for perineuronal net (PNN) evaluation and cyst quantification. The results showed that C57BL/6 mice presented higher levels of TNF-α and IL-12, while the levels of TGF-β were similar between the two mouse lineages, associated with the elevated number of tissue cysts, with a higher occurrence of cysts in the posterior area of the PSC when compared to BALB/c mice, which presented a more homogeneous cyst distribution. Immunohistochemistry analysis revealed a greater loss of PNN labeling in C57BL/6 animals compared to BALB/c. These data raised a discussion about the ability of T. gondii to stimulate a systemic inflammatory response capable of indirectly interfering in the brain structure and function.Graphical

Adverse pregnancy outcomes in Toxoplasma gondii seropositive Hispanic women.

Chronic Toxoplasma gondii infection is not thought to affect pregnancy or birth outcomes, but there are few prospective studies. The study aims were T. gondii immunoglobulin G measurement and relationship of chronic T. gondii infection with gestational age at birth and adverse pregnancy outcomes in 690 Hispanic women in Tampa, Florida. Hispanic women, born either in the United States or in Latin America or the Caribbean had a venous blood sample drawn to measure T. gondii IgG and T. gondii serotype at the first prenatal visit, along with collection of demographic and health-related measures. Seropositive and seronegative women were followed throughout their pregnancy. Gestational age, infant weights, and adverse pregnancy outcomes (miscarriages, preterm births) were compared in the two groups. There were 740 women of self-reported Hispanic ethnicity screened and enrolled in Tampa, Florida, with 690 having birth data extracted from the electronic health record (538 T. gondii negative and 152 T. gondii seropositive). T. gondii seropositivity was 22.4% and the majority (83%) had high avidity titers, indicating chronic infection. Compared to T. gondii seronegative Hispanic women, seroseropositive women had more smaller for gestational age infants and higher prevalences of miscarriages and preterm birth. This is one of the largest longitudinal cohort studies of women with chronic T. gondii infection followed through pregnancy. There was a higher percentages of adverse pregnancy outcomes in this group compared to T. gondii seronegative controls. The mechanism for this is unknown and warrants reexamination of the dogma that chronic T. gondii infection in pregnant women has no significant clinical consequences.

β-Glucan ameliorates anxiety-like behavior in mice chronically infected with the Toxoplasma gondii Wh6 strain.

Chronic Toxoplasma gondii (T. gondii) infection has been revealed to be a risk factor for neuropsychiatric diseases, including anxiety. However, there is no intervention strategy. The present study aimed to investigate the protective effect of β-glucan on T. gondii Wh6 strain-induced anxiety-like behavior in mice. The anxiety mouse model was established by infection with 10 cysts of the T. gondii Wh6 strain. β-Glucan was intraperitoneally administered 2weeks before infection. Open field and elevated plus maze tests were performed to assess anxiety-like behavior. In the open field test, Wh6-infected mice spent less time in the central zone and had fewer entries into the central zone. In the elevated plus maze test, the infection reduced the frequency and time of head entries in the open arms. These results showed that Wh6 causes anxiety-like behavior in mice. Interestingly, the administration of β-glucan significantly ameliorated anxiety-like behavioral performance. The present study shows that β-glucan can alleviate the anxiety-like behavior induced by chronic T. gondii infection in mice, which indicates that β-glucan may be a potential drug candidate for treating T. gondii-related mental disorders, including anxiety.

Cluster analysis of splenocyte microRNAs in the pig reveals key signal regulators of immunomodulation in the host during acute and chronic Toxoplasma gondii infection

BackgroundToxoplasma gondii is an obligate intracellular protozoan parasite that can cause a geographically widespread zoonosis. Our previous splenocyte microRNA profile analyses of pig infected with T. gondii revealed that the coordination of a large number of miRNAs regulates the host immune response during infection. However, the functions of other miRNAs involved in the immune regulation during T. gondii infection are not yet known.MethodsClustering analysis was performed by K-means, self-organizing map (SOM), and hierarchical clustering to obtain miRNA groups with the similar expression patterns. Then, the target genes of the miRNA group in each subcluster were further analyzed for functional enrichment by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway to recognize the key signaling molecules and the regulatory signatures of the innate and adaptive immune responses of the host during T. gondii infection.ResultsA total of 252 miRNAs were successfully divided into 22 subclusters by K-means clustering (designated as K1–K22), 29 subclusters by SOM clustering (designated as SOM1–SOM29), and six subclusters by hierarchical clustering (designated as H1–H6) based on their dynamic expression levels in the different infection stages. A total of 634, 660, and 477 GO terms, 15, 26, and 14 KEGG pathways, and 16, 15, and 7 Reactome pathways were significantly enriched by K-means, SOM, and hierarchical clustering, respectively. Of note, up to 22 miRNAs mainly showing downregulated expression at 50 days post-infection (dpi) were grouped into one subcluster (namely subcluster H3-K17-SOM1) through the three algorithms. Functional analysis revealed that a large group of immunomodulatory signaling molecules were controlled by the different miRNA groups to regulate multiple immune processes, for instance, IL-1-mediated cellular response and Th1/Th2 cell differentiation partly depending on Notch signaling transduction for subclusters K1 and K2, innate immune response involved in neutrophil degranulation and TLR4 cascade signaling for subcluster K15, B cell activation for subclusters SOM17, SOM1, and SOM25, leukocyte migration, and chemokine activity for subcluster SOM9, cytokine–cytokine receptor interaction for subcluster H2, and interleukin production, chemotaxis of immune cells, chemokine signaling pathway, and C-type lectin receptor signaling pathway for subcluster H3-K17-SOM1.ConclusionsCluster analysis of splenocyte microRNAs in the pig revealed key regulatory properties of subcluster miRNA molecules and important features in the immune regulation induced by acute and chronic T. gondii infection. These results contribute new insight into the identification of physiological immune responses and maintenance of tolerance in pig spleen tissues during T. gondii infection.Graphical

Detection of Acute and Chronic Toxoplasma gondii Infection among Women with History of Abortion in the Southwest of Iran.

Background Toxoplasma gondii (T. gondii) is one of the most common intracellular protozoan parasites, which can infect humans and a wide range of mammals and birds. The current study is aimed at investigating the occurrence of T. gondii infection in women with a history of abortion in Khuzestan, Iran. Materials and Methods A total of 480 women with an abortion history, as well as 200 pregnant women with a normal delivery, were examined in this study. The blood, placenta, and umbilical cord blood samples were assessed by the enzyme-linked immunosorbent assay (ELISA) and nested-polymerase chain reaction (PCR) assay. Results Based on the results of ELISA assay, the prevalence of toxoplasmosis was 30.83% in women with a history of abortion (25.62% with T. gondii IgG and 5.20% with T. gondii IgM). According to the IgG avidity test, 60.16% of IgG-positive samples showed high avidity, while 27.64% showed low avidity. On the other hand, the prevalence of toxoplasmosis in women with a normal delivery was 23% (21.5% with T. gondii IgG and 1.5% with T. gondii IgM). According to the IgG avidity test, 81.39% of these women showed high avidity, while only 4.65% showed low avidity. Based on the nested-PCR method, T. gondii DNA was detected in 14.18% of blood samples, 4.69% of placental samples, and 1.34% of umbilical cord samples, collected from 148 seropositive women with a history of abortion. Besides, using this method, the parasite DNA was identified in 4.34% of blood samples, collected from 46 seropositive women with a normal delivery, but not in any of the umbilical cord or placenta samples. Conclusion The present results showed that T. gondii infection contributes to abortion in Khuzestan Province, Iran. Therefore, it is essential to investigate toxoplasmosis in pregnant women, especially in those who are seronegative, using molecular and serological methods and inform them about their disease and the associated risks.

Dynamic Expressions of TIGIT on Splenic T Cells and TIGIT-Mediated Splenic T Cell Dysfunction of Mice With Chronic Toxoplasma gondii Infection.

As an immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) play a critical part in cellular immune regulation mediated by pathogen infection. Whereas, TIGIT expression on splenic T cells in hosts infected with Toxoplasma gondii cysts has not been studied. In this study, we detected TIGIT expression and the changes of immune function in the spleen by flow cytometry and real-time PCR (RT-PCR). We found that TIGIT expression on splenic T cells increased significantly post infection. At the same time, splenic TIGIT+TCM cells were activated and transformed into TIGIT+TEM cells during the infection, and the cytotoxicity of TIGIT+ T cells was reduced in the later stage of infection. This study shows that chronic T. gondii infection can upregulate TIGIT expression on the surface of T cells and affect immune cell function.

Impact of chronic toxoplasma gondii infection on serum dopamine and adrenaline levels in patients with neuropsychiatric disorders compared to healthy individuals

Background: Toxoplasma gondii is an intracellular parasite whose life cycle is completed in felids especially cats, the definitive host. Humans and many other animals can also be infected and serve as intermediate hosts. This study aimed to assess the role of chronic toxoplasmosis in changes of neurotransmitters levels in human serum. Methods: This case control study was conducted on 41 patients by examining the serofrequency of T. gondii among IgG and IgM antibodies patients with neuropsychiatric disorders and cross-matched 41 healthy individuals without any known neuropsychiatric disorders were included as a control group. All patients were subjected to full history taking, general examination, laboratory investigation, renal function test analysis, Psychiatric diagnosis and measurement of serum concentrations of three neurotransmitters (dopamine, adrenaline, and noradrenaline). Results: T. gondii IgG was significantly higher in group A compared to group B (58.5% vs. 31.7%, P=0.026). The mean dopamine level was significantly higher in group A compared to group B (92.7 ± 17.94 pg/ml vs. 45.4 ± 22.48 pg/ml, P&lt;0.001). The mean adrenaline level was significantly higher in group A compared to group B (272.5 ± 135.04 pg/ml vs. 147.4 ± 71.44 pg/ml, P&lt;0.001).

Detection of Anti-Toxoplasma gondii IgG and IgM Antibodies and Associated Risk Factors during Pregnancy in Southwest Iran.

Background This research was aimed at evaluating the seroprevalence of acute and chronic Toxoplasma gondii (T. gondii) infection in pregnant women and related risk factors in southwest Iran. Methods In this cross-sectional study, eighty-eight pregnant women were included from October 2019 to December 2019. The presence of anti-T. gondii IgM and IgG antibodies was measured using the enzyme-linked immunosorbent assay (ELISA). In addition, a questionnaire consisting of demographic information was completed for each subject. Results The overall seroprevalence of T. gondii infection was estimated to be 34.09% (30/88). Of these, 1 (1.13%) and 29 (32.95%) samples were found positive for IgM and IgG, respectively. Regarding the risk factors, the consumption of raw/undercooked meat (P value = 0.007) and history of abortion (P value = 0.017) were significantly associated with IgG seroprevalence in pregnant women. Conclusion The results showed that the pregnant women of southwest Iran might be moderately exposed to T. gondii. Since the risk of acute T. gondii infection in this susceptible group is very important, regular screening tests to diagnose the infection are recommended before pregnancy.

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution.

Toxoplasma gondii is a resilient parasite that infects a multitude of warm-blooded hosts and results in a lifelong chronic infection requiring continuous responses by the host. Chronic infection is characterized by a balanced immune response and neuropathology that are driven by changes in gene expression. Previous research pertaining to these processes has been conducted in various mouse models, and much knowledge of infection-induced gene expression changes has been acquired through the use of high throughput sequencing techniques in different mouse strains and post-mortem human studies. However, lack of infection time course data poses a prominent missing link in the understanding of chronic infection, and there is still much that is unknown regarding changes in genes specifically relating to neuropathology and resulting repair mechanisms as infection progresses throughout the different stages of chronicity. In this paper, we present a targeted approach to gene expression analysis during T. gondii infection through the use of NanoString nCounter gene expression assays. Wild type C57BL/6 and BALB/c background mice were infected, and transcriptional changes in the brain were evaluated at 14, 28, and 56 days post infection. Results demonstrate a dramatic shift in both previously demonstrated and novel gene expression relating to neuropathology and resolution in C57BL/6 mice. In addition, comparison between BALB/c and C57BL/6 mice demonstrate initial differences in gene expression that evolve over the course of infection and indicate decreased neuropathology and enhanced repair in BALB/c mice. In conclusion, these studies provide a targeted approach to gene expression analysis in the brain during infection and provide elaboration on previously identified transcriptional changes and also offer insights into further understanding the complexities of chronic T. gondii infection.

Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer's Disease Model Mice.

In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer’s disease (AD) worsens with the accumulation of amyloid β (Aβ) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and Aβ plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed Aβ plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating Aβ plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.

Synergistic effect of GRA7 and profilin proteins in vaccination against chronic Toxoplasma gondii infection

Toxoplasmosis is a zoonotic disease with worldwide prevalence in humans and warm-blooded animal populations. In livestock Toxoplasma gondii is the causal agent of significant economic losses since it can cause abortions in goats and sheep. It is estimated that one third of the world population is infected. Although there are effective therapies for acute infection, these are sometimes poorly tolerated, teratogenic, and have a long administration time. Considering the deficiencies that exist related to the prevention and treatment of toxoplasmosis, the development of a safe and effective vaccine would be extremely valuable in fighting against this infection. In the present work, we characterize for the first time the adjuvant and immunogenic potential of a recombinant profilin protein (rTgPF), in a vaccine formulation alone or in combination with the well-known GRA7 antigen candidate in a murine toxoplasmosis model. Since TgPF acts as a ligand for TLR11 and 12 inducing innate immune responses that promote type 1 adaptive responses, we first study the capacity of the mix rGRA7 + rTgPF to initiate an immune response by evaluating dendritic cell activation. Both rTgPF and rGRA7 induces activation of mouse BMDCs more efficiently than the single proteins, evidenced by increased expression of CD80 and CD86 co-stimulatory proteins and secretion of IL-6, IL-10 and IL-12 cytokines after in vitro stimulation. The sum of the effects of rGRA7 and rTgPF on BMDCs maturation led us to assay them in a vaccination protocol. BALB/c mice vaccinated with this mix elicited a Th1-biased immunity via the induction of lymphocyte proliferation, activation of CD4+T cells and increased IFN-γ production that resulted in enhanced protection against chronic Toxoplama gondii infection. Profilin per se induce only cellular immunity but augments the effect of rGRA7 immune responses when used together, thus allowing us to postulate rTgPF as a potential adjuvant in a protein vaccine.

Chronic Toxoplasma gondii Infection Alleviates Experimental Autoimmune Encephalomyelitis by the Immune Regulation Inducing Reduction in IL-17A/Th17 Via Upregulation of SOCS3

Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), a demyelinating autoimmune disease caused by the infiltration of a harmful autoreactive Th1 and Th17 cells. To mitigate MS, which is impossible to cure with medication only, immunomodulatory interventions that prevent Th17 cell activation are ideal. The objective of the present study was to analyze the effect of Toxoplasma gondii infection on the onset of EAE. Our results found that Toxoplasma gondii infection in the brain increases SOCS3 expression and decreases the phosphorylation of STAT3, resulting in reducing IL-17A and IL-23, which suppress the differentiation and expansion of pathogenic Th17 cells, an important factor in MS development. These immune responses resulted in a reduction in the clinical scoring of EAE induced by myelin oligodendrocyte glycoprotein 35–55 immunization. In the EAE group with T. gondii infection (Tg + EAE group), Th17-related immune responses that exacerbate the onset of EAE were reduced compared to those in the EAE group. This study suggests that the alleviation of EAE after T. gondii infection is regulated in a SOCS3/STAT3/IL-17A/blood–brain barrier integrity-dependent manner. Although parasite infection would not be permitted for MS treatment, this study using T. gondii infection identified potential targets that contribute to disease attenuation.

Gasdermin-D-dependent IL-1\u03b1 release from microglia promotes protective immunity during chronic Toxoplasma gondii infection

Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF-κB and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1β in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1β, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, we show that ex vivo IL-1α release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in brain inflammation and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.

EFFECT OF NITRIC OXIDE IN CHRONIC EXPERIMENTAL TOXOPLASMA GONDII INFECTION: HISTOPATHOLOGICAL AND HISTOCHEMICAL STUDY

Aim of the work: To evaluate the histopathological alterations and immuno-histochemical pattern in chronic Toxoplasma gondii infection, and to evaluate the role aminoguanidine in experimental toxoplasmosis. Subjects and methods: This study was carried out on 48 laboratory-bred male Swiss albino mice which were divided into 4 groups (non-infected control; infected control; infected and treated with spiramycin; infected and treated with aminoguanidine). The effect of the used drugs was assessed using parasitological, histopathological and immunohistochemical approaches. Results: There was highly significant (P