Neospora caninum e toxoplasma gondii: revisão de literatura / Neospora caninum and toxoplasma gondii: review of literature / Neospora caninum y toxoplasma gondii: revisión de literatura

A Neospora caninum e a Toxoplasma gondii são os agentes etiológicos que causam a Neosporose e a Toxoplasmose, respectivamente. Estas duas doenças são consideradas de grande importância econômica e de distribuição mundial, que acometem tanto animais de produção quanto animais domésticos. Apresentam sinais clínicos inespecíficos, sendo a Neosporose frequentemente associada ao abortamento em fêmeas. Ambas enfermidades costumavam ser confundidas, dificultando o diagnóstico. São causadas por protozoários cosmopolitas de ciclos biológicos heteróxenos. O Toxoplasma gondii é responsável por doença clínica em cães e gatos, enquanto o Neospora caninum acomete somente cães. Além disso, não há, até o momento, relatos de Neosporose em humanos, diferente da Toxoplasmose. Ocasionalmente esta pode ocorrer em coiotes, suínos, ovinos, caprinos, equinos, cervídeos e bubalinos. Anticorpos contra Neospora tem sido descrito em raposas, camelos e felídeos. O objetivo da presente revisão, é elucidar a forma de transmissão, sinais clínicos, diagnóstico, tratamento e controle de ambas as doenças, mostrando suas semelhanças, afim de que se possa diagnosticá-las corretamente.(AU)

Neospora caninum and toxoplasma gondii are agents of great economic importance and worldwide distribution that affect production and domestic animals. They present nonspecific clinical signs, and neosporosis is a disease that frequently causes abortion in females, which is considered current, because both used to be confused, making diagnosis difficult. They are protozoan, cosmopolitan, of heterogeneous biological cycles. Toxoplasma gondii is responsible for clinical disease in dogs and cats, while Neospora caninum affects only dogs. Furthermore, there are no reports to date of neosporosis in humans, other than toxoplasmosis. Occasionally it may occur in coyotes, pigs, sheep, goats, horses, deer, and bubaline. Antibodies to Neospora have been described in foxes, camels, and felids. This review aims to elucidate the transmission, clinical signs, diagnosis, treatment, and control of both diseases, showing their similarities, so that they can be correctly diagnosed.(AU)

Neospora caninum y Toxoplasma gondii son los agentes etiológicos que causan Neosporosis y Toxoplasmosis, respectivamente. Estas dos enfermedades se consideran de gran importancia económica y de distribución mundial, afectando tanto al ganado como a los animales domésticos. Presentan signos clínicos inespecíficos y la neosporosis se asocia con frecuencia al aborto en mujeres. Ambas dolencias solían ser erróneas, lo que hacía difícil el diagnóstico. Son causados por protozoos cosmopolitas de ciclos biológicos heterogéneos. Toxoplasma gondii es responsable de enfermedades clínicas en perros y gatos, mientras que Neospora caninum sólo ataca a perros. Además, no se han notificado casos de Neosporosis en humanos hasta el momento, diferente de Toxoplasmosis. Ocasionalmente esto puede ocurrir en coyotes, cerdos, ovejas, cabras, caballos, ciervos y bubalinos. Se han notificado anticuerpos contra la Neospora en zorros, camellos y felinos. El propósito de esta revisión es dilucidar la forma de transmisión, los signos clínicos, el diagnóstico, el tratamiento y el control de ambas enfermedades, mostrando sus similitudes, de manera que puedan ser diagnosticadas correctamente.(AU)

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-ß 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-ß 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.

Virulence-related gene wx2 of Toxoplasma gondii regulated host immune response via classic pyroptosis pathway.

BACKGROUND: Toxoplasma gondii is known as the most successful parasite, which can regulate the host immune response through a variety of ways to achieve immune escape. We previously reported that a novel gene wx2 of T. gondii may be a virulence-related molecule. The objective of this study was to explore the mechanism of wx2 regulating host immune response. METHODS: The wx2 knockout strain (RHwx2-/- strain) and complementary strain (RHwx2+/+ strain) were constructed by the CRISPR/Cas9 technique, and the virulence of the wx2 gene was detected and changes in pyroptosis-related molecules were observed. RESULTS: Compared with the wild RH and RHwx2+/+ strain groups, the survival time for mice infected with the RHwx2-/- strain was prolonged to a certain extent. The mRNA levels of pyroptosis-related molecules of caspase-1, NLRP3, and GSDMD and et al. in mouse lymphocytes in vivo and RAW267.4 cells in vitro infected with RHwx2-/- strain increased to different degrees, compared with infected with wild RH strain and RHwx2+/+ strain. As with the mRNA level, the protein level of caspase-1, caspase-1 p20, IL-1ß, NLRP3, GSDMD-FL, GSDMD-N, and phosphorylation level of NF-κB (p65) were also significantly increased. These data suggest that wx2 may regulate the host immune response through the pyroptosis pathway. In infected RAW264.7 cells at 48 h post-infection, the levels of Th1-type cytokines of IFN-γ, Th2-type cytokines such as IL-13, Th17-type cytokine of IL-17 in cells infected with RHwx2-/- were significantly higher than those of RH and RHwx2+/+ strains, suggesting that the wx2 may inhibit the host's immune response. CONCLUSION: wx2 is a virulence related gene of T. gondii, and may be involved in host immune regulation by inhibiting the pyroptosis pathway.

Tylvalosin demonstrates anti-parasitic activity and protects mice from acute toxoplasmosis.

AIMS: Toxoplasmosis, caused by Toxoplasma gondii (Tg), is one of the most prevalent zoonotic diseases worldwide. Currently, safe and efficient therapeutic options for this disease are still being developed, and are urgently needed. Tylvalosin (Tyl), a broad-spectrum third-generation macrolide, exhibits anti-bacterial, anti-viral, and anti-inflammatory properties. The present study aims to explore the anti-parasitic and immunomodulation activities of Tyl against Tg, and the underlying mechanism. MAIN METHODS: Adhesion, invasion, replication, proliferation, plaque, reversibility, immunofluorescence assays and transmission electron microscopy were utilized to determine the anti-Toxoplasma effect of Tyl. With acute toxoplasmosis model and rabies virus-induced brain inflammation model, the anti-toxoplasmosis and immunomodulation activities of Tyl were assessed by colorimetric assay, histopathological and Oil red O staining, and real-time quantitative PCR. The involved molecular mechanisms were investigated by western blotting and immunohistochemical staining. KEY FINDINGS: Tyl (5 and 10 µg/ml) can inhibit Tg propagation, and damage its ultrastructure irreversibly. The combination of Tyl and Pyrimethamine (Pyr) exhibits a better synergistic effect. Tyl (50 and 100 mg/kg) treatment intraperitoneally can delay mice death and improve survival rate, accompanying the reduced histopathological score and parasite load in the indicated tissues, espically for ileum, liver, spleen, lung and brain. Furthermore, Tg can modulate host phospho-p38 MAPK (pp38), subtilisin/kexin-isozyme-1 (SKI-1)-sterol regulatory element binding protein-1 (SREBP-1) (SKI-1-SREBP-1) pathway and peroxisome proliferators-activated receptor δ (PPARδ), while Tyl is able to reverse these signal pathways close to normal levels. SIGNIFICANCE: Our findings indicate that Tyl exhibits anti-Toxoplasma activity and protects mice from acute toxoplasmosis.

Toxoplasmosis impact on prematurity and low birth weight.

BACKGROUND: Toxoplasma gondii, one of the most common parasites, causes toxoplasmosis, one of the most frequent zoonotic diseases worldwide. T. gondii infects about one-third of the world's population. T. gondii infection is generally considered a major risk for spontaneous abortion, prematurity and low birth weight in the animal sphere. Less commonly, a toxoplasma serological profile is correlated with the particular data of delivery. Acute T. gondii infection during pregnancy often leads to spontaneous abortion and/or a severe injury of the eyes, brain, and other structures of the foetus. Latent T. gondii infection of pregnant women could lead to less obvious but important changes during pregnancy, including the end product of pregnancy and the timing of labour. This study aimed to contribute to the current knowledge by comparing serological T. gondii profiles of pregnant women with prematurity and low birth weights of newborns. MATERIAL AND METHODS: A retrospective study design was adopted. The study participants included a cohort of 1733 pregnant women who consecutively gave birth to their children and underwent regular antenatal biochemical screening between the 14th and 16th weeks of pregnancy. Prematurity was defined as the liveborn preterm delivery in gestational age of pregnancy <37 weeks. Low birth weight was defined as weight at birth of ≤2499 grams. The complement-fixation test (CFT) provided serological profiles for toxoplasmosis that expresses the overall levels of toxoplasma immunoglobulins of all classes. Enzyme-linked immunosorbent assay (ELISA) tests for IgG and IgM were used simultaneously. IgM positivity helped to differentiate acute from the latent stage of toxoplasmosis. Birth data, especially the week of delivery and fetal weight, were evaluated accordingly. RESULTS: Of the 1733 pregnant women, 25% were diagnosed as latent toxoplasma positive, and 75% as toxoplasma negative. There were 87 premature deliveries versus 1646 timely births. We observed 88 low birth weights and 1645 normal fetal weights. We found a statistically significant association between latent toxoplasmosis and prematurity, χ2(1) = 5.471, p = .019 and between latent toxoplasmosis and low birth weight of newborns, χ2(1) = 7.663, p = .006. There was a 1.707 times higher risk of prematurity for toxoplasma-positive women, while the risk for low birth weight was 1.861 times higher. The strength of both tests of association was mild. We tested the correlation between the levels of CFT titres and week of delivery and weight of newborns. No association was found between the level of latent toxoplasmosis and the week of delivery and fetal weight. CONCLUSION: Latent toxoplasmosis was associated with premature birth rate and lower birth weight of newborns. The odds of premature delivery was 1.7 and low birth weight 1.9 times higher in women with latent toxoplasmosis compared to toxoplasma negative women. Even though the strength of the association in our large sample is relatively mild, the combination of latent toxoplasmosis with other adverse factors could cause serious harm. Whole CFT and specific IgG levels of latent toxoplasmosis are not linked to the severity of prematurity or low birth weight in newborns.

Pantothenate biosynthesis is critical for chronic infection by the neurotropic parasite Toxoplasma gondii.

Coenzyme A (CoA) is an essential molecule acting in metabolism, post-translational modification, and regulation of gene expression. While all organisms synthesize CoA, many, including humans, are unable to produce its precursor, pantothenate. Intriguingly, like most plants, fungi and bacteria, parasites of the coccidian subgroup of Apicomplexa, including the human pathogen Toxoplasma gondii, possess all the enzymes required for de novo synthesis of pantothenate. Here, the importance of CoA and pantothenate biosynthesis for the acute and chronic stages of T. gondii infection is dissected through genetic, biochemical and metabolomic approaches, revealing that CoA synthesis is essential for T. gondii tachyzoites, due to the parasite's inability to salvage CoA or intermediates of the pathway. In contrast, pantothenate synthesis is only partially active in T. gondii tachyzoites, making the parasite reliant on its uptake. However, pantothenate synthesis is crucial for the establishment of chronic infection, offering a promising target for intervention against the persistent stage of T. gondii.

Impact of IFN-y and CD40 signalling on Toxoplasma gondii cyst formation in differentiated Neuro-2a neuroblastoma cells.

Signalling by IFN-y and CD40 is known to trigger anti-microbial activity in macrophages infected with Toxoplasma gondii, but their effects on infected neurons are less well known. Here, we compared how stimulation with IFN-y and an agonistic anti-CD40 mAb impacts infection and cyst formation in the mouse neuroblastoma cell line Neuro-2a relative to bone marrow-derived macrophages. Both IFN-y and CD40 mAb decreased cyst emergence in Neuro-2a cells. In macrophages, these stimuli decreased infection, but had no impact on infection in the neuroblastoma cell line. Resistance to killing in Neuro-2a cells may explain why neurons preferentially harbour parasites during chronic infection in the brain.

Pathogenic role of mitogen activated protein kinases in protozoan parasites.

Protozoan parasites with complex life cycles have high mortality rates affecting billions of human lives. Available anti-parasitic drugs are inadequate due to variable efficacy, toxicity, poor patient compliance and drug-resistance. Hence, there is an urgent need for the development of safer and better chemotherapeutics. Mitogen Activated Protein Kinases (MAPKs) have drawn much attention as potential drug targets. This review summarizes unique structural and functional features of MAP kinases and their possible role in pathogenesis of obligate intracellular protozoan parasites namely, Leishmania, Trypanosoma, Plasmodium and Toxoplasma. It also provides an overview of available knowledge concerning the target proteins of parasite MAPKs and the need to understand and unravel unknown interaction network(s) of MAPK(s).

Infections at the maternal-fetal interface: an overview of pathogenesis and defence.

Infections are a major threat to human reproductive health, and infections in pregnancy can cause prematurity or stillbirth, or can be vertically transmitted to the fetus leading to congenital infection and severe disease. The acronym 'TORCH' (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) refers to pathogens directly associated with the development of congenital disease and includes diverse bacteria, viruses and parasites. The placenta restricts vertical transmission during pregnancy and has evolved robust mechanisms of microbial defence. However, microorganisms that cause congenital disease have likely evolved diverse mechanisms to bypass these defences. In this Review, we discuss how TORCH pathogens access the intra-amniotic space and overcome the placental defences that protect against microbial vertical transmission.

Toxoplasma gondii virulence prediction using hierarchical cluster analysis based on coding sequences (CDS) of sag1, gra7 and rop18.

Toxoplasma gondii consists of three genotypes, namely genotype I, II and III. Based on its virulence, T. gondii can be divided into virulent and avirulent strains. This study intends to evaluate an alternative method for predicting T. gondii virulence using hierarchical cluster analysis based on complete coding sequences (CDS) of sag1, gra7 and rop18 genes. Dendrogram was constructed using UPGMA with a Kimura 80 nucleotide distance measurement. The results showed that the prediction errors of T. gondii virulence using sag1, gra7 and rop18 were 7.41%, 6.89% and 9.1%, respectively. Analysis based on CDS of gra7 and rop18 was able to differentiate avirulent strains into genotypes II and III, whereas sag1 failed to differentiate.

Alkyl Hydroperoxide Reductase as a Determinant of Parasite Antiperoxide Response in Toxoplasma gondii.

Toxoplasma gondii is a protozoan parasite that is widely parasitic in the nucleated cells of warm-blooded animals. Bioinformatic analysis of alkyl hydroperoxide reductase 1 (AHP1) of T. gondii is a member of the Prxs family and exhibits peroxidase activity. Cys166 was certified to be a key enzyme active site of TgAHP1, indicating that the enzyme follows a cysteine-dependent redox process. TgAHP1 was present in a punctate staining pattern anterior to the T. gondii nucleus. Oxidative stress experiments showed that the ∆Ahp1 strain was more sensitive to tert-butyl hydroperoxide (tBOOH) than hydrogen peroxide (H2O2), indicating that tBOOH may be a sensitive substrate for TgAHP1. Under tBOOH culture conditions, the ∆Ahp1 strain was significantly less invasive, proliferative, and pathogenic in mice. This was mainly due to the induction of tBOOH, which increased the level of reactive oxygen species in the parasites and eventually led to apoptosis. This study shows that TgAHP1 is a peroxisomes protein with cysteine-dependent peroxidase activity and sensitive to tBOOH.

Primary brain cell infection by Toxoplasma gondii reveals the extent and dynamics of parasite differentiation and its impact on neuron biology.

Toxoplasma gondii is a eukaryotic parasite that forms latent cysts in the brain of immunocompetent individuals. The latent parasite infection of the immune-privileged central nervous system is linked to most complications. With no drug currently available to eliminate the latent cysts in the brain of infected hosts, the consequences of neurons' long-term infection are unknown. It has long been known that T. gondii specifically differentiates into a latent form (bradyzoite) in neurons, but how the infected neuron responds to the infection remains to be elucidated. We have established a new in vitro model resulting in the production of mature bradyzoite cysts in brain cells. Using dual, host and parasite RNA-seq, we characterized the dynamics of differentiation of the parasite, revealing the involvement of key pathways in this process. Moreover, we identified how the infected brain cells responded to the parasite infection revealing the drastic changes that take place. We showed that neuronal-specific pathways are strongly affected, with synapse signalling being particularly affected, especially glutamatergic synapse signalling. The establishment of this new in vitro model allows investigating both the dynamics of parasite differentiation and the specific response of neurons to long-term infection by this parasite.

Toxoplasmosis is a risk factor for acquiring SARS-CoV-2 infection and a severe course of COVID-19 in the Czech and Slovak population: a preregistered exploratory internet cross-sectional study.

BACKGROUND: Latent toxoplasmosis, i.e. a lifelong infection with the protozoan parasite Toxoplasma gondii, affects about a third of the human population worldwide. In the past 10 years, numerous studies have shown that infected individuals have a significantly higher incidence of mental and physical health problems and are more prone to exhibiting the adverse effects of various diseases. METHODS: A cross-sectional internet study was performed on a population of 4499 (786 Toxoplasma-infected) participants and looked for factors which positively or negatively affect the risk of SARS-CoV-2 infection and likelihood of a severe course of COVID-19. RESULTS: Logistic regression and partial Kendall correlation controlling for sex, age, and size of the place of residence showed that latent toxoplasmosis had the strongest effect on the risk of infection (OR = 1.50) before sport (OR = 1.30) and borreliosis (1.27). It also had the strongest effect on the risk of severe course of infection (Tau = 0.146), before autoimmunity, immunodeficiency, male sex, keeping a cat, being overweight, borreliosis, higher age, or chronic obstructive pulmonary disease. Toxoplasmosis augmented the adverse effects of other risk factors but was not the proximal cause of the effect of cat-keeping on higher likelihood of COVID infection and higher severity of the course of infection because the effect of cat-keeping was also observed (and in particular) in a subset of Toxoplasma-infected respondents (Tau = 0.153). Effects of keeping a cat were detected only in respondents from multi-member families, suggesting that a cat could be a vector for the transmission of SARS-CoV-2 within a family. CONCLUSIONS: Toxoplasmosis is currently not considered a risk factor for COVID-19, and Toxoplasma-infected individuals are neither informed about their higher risk nor prioritised in vaccination programs. Because toxoplasmosis affects a large segment of the human population, its impact on COVID-19-associated effects on public health could be considerable.

Expression of immunoproteasome subunits in the brains of Toxoplasma gondii-infected mice.

The immunoproteasomes are specific proteasomes that clear oxidant-damaged proteins under inflammatory conditions in various diseases. Toxoplasma gondii (T. gondii) infects the central nervous system and causeencephalitis. However, the relationship between the immunoproteasomes and brain inflammation during T. gondii infection is not well characterized. In this study, we established an in vivo mouse model of T. gondii PLK strain infection via intraperitoneal injection and evaluated the expression of immunoproteasome subunits in the brains of infected mice. The results demonstrated that first, pathological changes in the brains of infected mice increase in severity over time. Second, following T. gondii infection, activated microglia and astrocytes undergo a series of functional alterations and morphological transformations, including proliferation and migration. Third, T. gondii infection induces expression of inflammatory cytokines, including IFN-γ, IL-1ß, TNF-α, and IL-6. Fourth, the immunoproteasome subunits low-molecular-weight polypeptide 2 (LMP2), LMP7, and LMP10 mRNA and protein levels are significantly upregulated in T. gondii-infected mouse brains, as shown by RT-qPCR and western blot analysis, compared with that in vehicle-treated brains, and their expression is localized in the microglia, astrocytes, and neurons of T. gondii-infected brains, as determined via immunofluorescence staining. Furthermore, the western blot mean gray value for the immunoproteasome subunits and the positive microglia and astrocyte immunohistochemical signals in the brains of T. gondii-infected mice were positively correlated, indicating that the observed relationships were highly significant. Therefore, it was concluded that the induction of the immunoproteasomes is a pathogenic mechanism underlying T. gondii infection-induced inflammation.

Risk of dementia in patients with toxoplasmosis: a nationwide, population-based cohort study in Taiwan.

BACKGROUND: Approximately 25-30% of individuals worldwide are infected with Toxoplasma gondii (T. gondii), which is difficult to detect in its latent state. We aimed to evaluate the association between toxoplasmosis, the risk of dementia, and the effects of antibiotics in Taiwan. METHODS: This nationwide, population-based, retrospective cohort study was conducted using the Longitudinal Health Insurance Database containing the records of 2 million individuals retrieved from Taiwan's National Health Insurance Research Database. Fine-Gray competing risk analysis was used to determine the risk for the development of dementia in the toxoplasmosis cohort relative to the non-toxoplasmosis cohort. A sensitivity analysis was also conducted. The effects of antibiotics (sulfadiazine or clindamycin) on the risk of dementia were also analyzed. RESULTS: We enrolled a total of 800 subjects, and identified 200 patients with toxoplasmosis and 600 sex- and age-matched controls without toxoplasmosis infection in a ratio of 1:3, selected between 2000 and 2015. The crude hazard ratio (HR) of the risk of developing dementia was 2.570 [95% confidence interval (CI) = 1.511-4.347, P < 0.001]. After adjusting for sex, age, monthly insurance premiums, urbanization level, geographical region, and comorbidities, the adjusted HR was 2.878 (95% CI = 1.709-4.968, P < 0.001). Sensitivity analysis revealed that toxoplasmosis was associated with the risk of dementia even after excluding diagnosis in the first year and the first 5 years. The usage of sulfadiazine or clindamycin in the treatment of toxoplasmosis was associated with a decreased risk of dementia. CONCLUSIONS: This finding supports the evidence that toxoplasmosis is associated with dementia and that antibiotic treatment against toxoplasmosis is associated with a reduced risk of dementia. Further studies are necessary to explore the underlying mechanisms of these associations.

Toxoplasma gondii UBL-UBA Shuttle Protein DSK2s Are Important for Parasite Intracellular Replication.

Toxoplasma gondii (T. gondii) is an important human and veterinary pathogen causing life-threatening disease in immunocompromised patients. The UBL-UBA shuttle protein family are important components of the ubiquitin-proteasome system. Here, we identified a novel UBL-UBA shuttle protein DSK2b that is charactered by an N-terminal ubiquitin-like domain (UBL) and a C-terminal ubiquitin-associated domain (UBA). DSK2b was localized in the cytoplasm and nucleus. The deletion of dsk2b did not affect the degradation of ubiquitinated proteins, parasite growth in vitro or virulence in mice. The double-gene knockout of dsk2b and its paralogs dsk2a (ΔΔdsk2adsk2b) results in a significant accumulation of ubiquitinated proteins and the asynchronous division of T. gondii. The growth of ΔΔdsk2adsk2b was significantly inhibited in vitro, while virulence in mice was not attenuated. In addition, autophagy occurred in the ΔΔdsk2adsk2b, which was speculated to degrade the accumulated ubiquitinated proteins in the parasites. Overall, DSK2b is a novel UBL-UBA shuttle protein contributing to the degradation of ubiquitinated proteins and is important for the synchronous cell division of T. gondii.

Establishment and validation of a guinea pig model for human congenital toxoplasmosis.

BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite with a worldwide distribution. Congenital infection in humans and animals may lead to severe symptoms in the offspring, especially in the brain. A suitable animal model for human congenital toxoplasmosis is currently lacking. The aim of this study is to establish and validate the guinea pig as a model for human congenital toxoplasmosis by investigating the impact of the T. gondii infection dose, the duration of infection and the gestational stage at infection on the seroconversion, survival rate of dams, fate of the offspring, T. gondii DNA loads in various offspring tissues and organs and the integrity of the offspring brain. METHODS: Pregnant guinea pigs were infected with three different doses (10, 100, 500 oocysts) of T. gondii strain ME49 at three different time points during gestation (15, 30, 48 days post-conception). Serum of dams was tested for the presence of T. gondii antibodies using immunoblotting. T. gondii DNA levels in the dam and offspring were determined by qPCR. Offspring brains were examined histologically. RESULTS: We found the survival rate of dams and fate of the offspring to be highly dependent on the T. gondii infection dose with an inoculation of 500 oocysts ending lethally for all respective offspring. Moreover, both parameters differ depending on the gestational stage at infection with infection in the first and third trimester of gestation resulting in a high offspring mortality rate. The duration of infection was found to substantially impact the seroconversion rate of dams with the probability of seroconversion exceeding 50% after day 20 post-infection. Furthermore, the infection duration of dams influenced the T. gondii DNA loads in the offspring and the integrity of offspring brain. Highest DNA levels were found in the offspring brain of dams infected for ≥ 34 days. CONCLUSION: This study contributes to establishing the guinea pig as a suitable model for human congenital toxoplasmosis and thus lays the foundation for using the guinea pig as a suitable animal model to study scientific questions of high topicality and clinical significance, which address the pathogenesis, diagnosis, therapy and prognosis of congenital toxoplasmosis.

Cutting Edge: CD36 Mediates Phagocyte Tropism and Avirulence of Toxoplasma gondii.

Resistance and tolerance are vital for survivability of the host-pathogen relationship. Virulence during Toxoplasma infection in mice is mediated by parasite kinase-dependent antagonism of IFN-γ-induced host resistance. Whether avirulence requires expression of parasite factors that induce host tolerance mechanisms or is a default status reflecting the absence of resistance-interfering factors is not known. In this study, we present evidence that avirulence in Toxoplasma requires parasite engagement of the scavenger receptor CD36. CD36 promotes macrophage tropism but is dispensable for the development of resistance mechanisms. Instead CD36 is critical for re-establishing tissue homeostasis and survival following the acute phase of infection. The CD36-binding capacity of T. gondii strains is negatively controlled by the virulence factor, ROP18. Thus, the absence of resistance-interfering virulence factors and the presence of tolerance-inducing avirulence factors are both required for long-term host-pathogen survival.