Vascular Endothelial Growth Factor-C Treatment Enhances Cerebrospinal Fluid Outflow during Toxoplasma gondii Brain Infection but Does Not Improve Cerebral Edema.

Cerebral edema frequently develops in the setting of brain infection and can contribute to elevated intracranial pressure, a medical emergency. How excess fluid is cleared from the brain is not well understood. Previous studies have shown that interstitial fluid is transported out of the brain along perivascular channels that collect into the cerebrospinal fluid (CSF)-filled subarachnoid space. CSF is then removed from the central nervous system through venous and lymphatic routes. The current study tested the hypothesis that increasing lymphatic drainage of CSF would promote clearance of cerebral edema fluid during infection with the neurotropic parasite Toxoplasma gondii. Fluorescent microscopy and magnetic resonance imaging was used to show that C57BL/6 mice develop vasogenic edema 4 to 5 weeks after infection with T. gondii. Tracer experiments were used to evaluate how brain infection affects meningeal lymphatic function, which demonstrated a decreased rate in CSF outflow in T. gondii-infected mice. Next, mice were treated with a vascular endothelial growth factor (VEGF)-C-expressing viral vector, which induced meningeal lymphangiogenesis and improved CSF outflow in chronically infected mice. No difference in cerebral edema was observed between mice that received VEGF-C and those that rececived sham treatment. Therefore, although VEGF-C treatment can improve lymphatic outflow in mice infected with T. gondii, this effect does not lead to increased clearance of edema fluid from the brains of these mice.

Immunological interaction between Giardia cyst extract and experimental toxoplasmosis.

Toxoplasmosis is mostly associated with other intestinal parasitic infections especially Giardia due to shared mode of peroral infection. Toxoplasma and Giardia induce a strong T-helper 1- immune response. Our aim was to induce a protective immune response that results in significant impact on intestinal and extra-intestinal phases of Toxoplasma infection. This study was conducted in experimental animals and assessment of Giardia cyst extract effect on Toxoplasma infection was investigated by histopathological examination of small intestine and brain, Toxoplasma cyst count and iNOS staining of the brain, measurement of IFN-γ and TGF-ß in intestinal tissues. Results showed that the brain Toxoplasma cyst number was decreased in mice infected with Toxoplasma then received Giardia cyst extract as compared to mice infected with Toxoplasma only. This effect was produced because Giardia cyst extract augmented the immune response to Toxoplasma infection as evidenced by severe inflammatory reaction in the intestinal and brain tissues, increased levels of IFN-γ and TGF-ß in intestinal tissues and strong iNOS staining of the brain. In conclusion, Giardia cyst extract generated a protective response against T. gondii infection. Therefore, Giardia antigen will be a suitable candidate for further researches as an immunomodulatory agent against Toxoplasma infection.

Intranasal immunization with recombinant Toxoplasma gondii actin depolymerizing factor confers protective efficacy against toxoplasmosis in mice.

BACKGROUND: Toxoplasma gondii is an opportunistic protozoan closely associated with AIDS and vertical transmission. T. gondii actin depolymerizing factor (TgADF) plays an important role in actin cytoskeleton remodeling, and it is required to invade host cells. TgADF was a promising vaccine candidate. To observe the immunological changes and protective efficacy of recombinant TgADF protein (rTgADF) against T. gondii infection, we optimized the intranasal immunization dose of rTgADF and analyzed the survival rate and tachyzoite loads in mouse tissues after oral challenge with T. gondii tachyzoites. RESULTS: rTgADF was prepared, purified, and combined with mouse anti-His antibody and rabbit anti-T. gondii serum. After intranasal immunization with 10 µg, 20 µg, 30 µg, or 40 µg of rTgADF, the 30-µg group elicited high levels of secretory IgA (sIgA) in nasal, intestinal, and vesical washes, raised IgG titres in the sera, strong proliferation of splenocytes, and increased secretion of IL-2 and IFN-γ when compared with the control group. When the mice were orally challenged with T. gondii, an increase in the survival rate (36.36 %) and a decrease in the tachyzoite loads in the liver (67.77 %) and brain (51.01 %) were observed. CONCLUSIONS: Our findings demonstrate that intranasal immunization with rTgADF can simultaneously trigger mucosal and systemic immune responses and protect the mice against T. gondii infection.

Analysis of structures and epitopes of a novel secreted protein MYR1 in Toxoplasma gondii.

Toxoplasma gondii (Nicolle et Manceaux, 1908) is an obligate intracellular apicomplexan parasite and can infect warmblooded animals and humans all over the world. Development of effective vaccines is considered the only ideal way to control infection with T. gondii. However, only one live vaccine is commercially available for use in sheep and goats. Thus more effective antigenic proteins are searched for. In the present study we report a novel protein by secreted T. gondii termed Myc regulation 1 (MYR1). The physical and chemical characteristics, epitopes, hydrophilicity and functional sites of MYR1 were analysed by multiple bioinformatic approaches. The 3D models of MYR1 proteins were constructed and analysed. Furthermore, liner B-cell epitopes and T-cell epitopes of MYR1 protein and SAG1 were predicted. Compared to SAG1, MYR1 with good B-cell epitopes and T-cell epitopes had a potentiality to become a more successful vaccine against T. gondii. The bioinformatics analysis of MYR1 proteins could laid the foundation for further studies of its biological function experimentally and provide valuable information necessary for a better prevention and treatment of toxoplasmosis.

Listeriosis and Toxoplasmosis in Pregnancy: Essentials for Healthcare Providers.

Listeriosis and toxoplasmosis are foodborne illnesses that can have long-term consequences when contracted during pregnancy. Listeriosis is implicated in stillbirth, preterm labor, newborn sepsis, and meningitis, among other complications. Toxoplasmosis is associated with blindness, cognitive delays, seizures, and hearing loss, among other significant disabilities. Healthcare providers who understand the fundamentals of Listeria and Toxoplasma infection will have the tools to identify symptoms and high-risk behaviors, educate women to make safer decisions, and provide anticipatory guidance if a pregnant woman would become infected with either of these foodborne illnesses.

Molecular target validation, antimicrobial delivery, and potential treatment of Toxoplasma gondii infections.

Toxoplasma gondii persistently infects over two billion people worldwide. It can cause substantial morbidity and mortality. Existing treatments have associated toxicities and hypersensitivity and do not eliminate encysted bradyzoites that recrudesce. New, improved medicines are needed. Transductive peptides carry small molecule cargos across multiple membranes to enter intracellular tachyzoites and encysted bradyzoites. They also carry cargos into retina when applied topically to eyes, and cross blood brain barrier when administered intravenously. Phosphorodiamidate morpholino oligomers (PMO) inhibit gene expression in a sequence-specific manner. Herein, effect of transductive peptide conjugated PMO (PPMO) on tachyzoite protein expression and replication in vitro and in vivo was studied. Initially, sequence-specific PPMO successfully reduced transfected T. gondii's fluorescence and luminescence. PPMO directed against T. gondii's dihydrofolate reductase (DHFR), an enzyme necessary for folate synthesis, limited tachyzoite replication. Rescue with exogenous folate demonstrated DHFR PPMO's specificity. PPMO directed against enoyl-ACP reductase (ENR), an enzyme of type II fatty acid synthesis that is structurally distinct in T. gondii from ENR in mammalian cells was investigated. PPMO directed against plant-like Apetela 2 (AP2) domain transcription factor XI-3 (AP2XI-3), not present in human cells, was characterized. ENR and AP2XI-3 PPMO each restricted intracellular parasite replication validating these molecular targets in tachyzoites. DHFR-specific PPMO administered to infected mice diminished parasite burden. Thus, these antisense oligomers are a versatile approach to validate T. gondii molecular targets, reduce essential T. gondii proteins in vitro and in vivo, and have potential for development as curative medicines.

Congenital Toxoplasmosis: A Review.

Acute infection of toxoplasmosis during pregnancy is detrimental to the developing fetus. In the United States, approximately 1 in 10,000 live births are affected by congenital toxoplasmosis. Although multifactorial in etiology, maternal infection is primarily attributed to the consumption of contaminated meat or water. Infection and transmission to the fetus may result in devastating neurologic impairment. Screening methods for all pregnant women should be implemented in routine prenatal care. This article will highlight the inherent dangers of congenital toxoplasmosis, while including general care of the fetus for prevention of transmission, medical management, and long-term outcomes.

[The issue of certain infectious diseases of pregnant women in everyday practice Part I. Bacterial and parasitic infections]. / Problematika niektorých infekcných ochorení tehotných zien v kazdodennej praxi Cast I. Bakteriálne a parazitárne ochorenia.

AIM OF STUDY: Authors in their text are bringing the latest published findings on the impact of some of the most common infectious diseases on the course and outcome of pregnancies. TYPE OF STUDY: Review. RESULTS: Proposals and recommendations for examination, treatment, and management of infected pregnant womans, especially from the view of a primary contact gynecologist.

Adoptive transfer of Treg cells counters adverse effects of Toxoplasma gondii infection on pregnancy.

Acute infection with Toxoplasma gondii (T. gondii) during pregnancy is associated with adverse outcomes. The mechanisms that cause this phenomenon are not clear. Regulatory T cells (Tregs) are involved in maternal tolerance, and here we observed a decrease in the absolute numbers of CTLA-4(+) Tregs and PD-1(+) Tregs in spleen and at the fetal-maternal interface in T. gondii-infected mice. Our results suggest that T. gondii induces apoptosis of Tregs. Additionally, we found that the expression of CTLA-4 and PD-1 on Tregs at fetal-maternal interface were higher than on spleen cells from normal pregnant mice. Therefore, we adoptively transferred Tregs from fetal-maternal interface or from spleens of normal pregnant mice into infected pregnant mice. Pregnancy outcomes were improved when Tregs were transferred from the fetal-maternal interface but not from the spleen. The mechanism appears to be through up-regulation of the number of CTLA-4(+) Tregs and PD-1(+) Tregs and correction of the imbalance between tolerant cytokines (IL-10, TGF-ß) and inflammatory cytokines (IFN-γ). Our data indicate that Tregs at fetal-maternal interface express high levels of inhibitory molecules that play a vital immuno-protective role during pregnancy.

Recommended management of Toxoplasma gondii infection in pregnant women and their children.

Aforesaid recommendations for the management of T.gondii infection, elaborated by the group of experts, are intended for physicians of various specialties in order to standardize and facilitate diagnostic and therapeutic management. Early diagnosis of congenital toxoplasmosis, both symptomatic and asymptomatic, in neonatal period, initiation of adequate treatment and long-term, multispecialist monitoring, including multi-organ rehabilitation of children may prevent or reduce the complications of congenital toxoplasmosis. Health education, whose role is often underestimated, should be targeted mainly on girls and women at reproductive age as to prevent from infection during pregnancy.

[Toxoplasmosis: Epidemiology, Diagnosis, Treatment].

The up-to-date literature and original data on the epidemiology, diagnosis and treatment of toxoplasmosis are presented. Particular attention is paid to the parasite infection during pregnancy. Spiramycin is the drug of choice for acute toxoplasmosis in pregnant women.

Recent advances in Toxoplasma gondii immunotherapeutics.

Toxoplasmosis is an opportunistic infection caused by the protozoan parasite Toxoplasma gondii. T. gondii is widespread globally and causes severe diseases in individuals with impaired immune defences as well as congenitally infected infants. The high prevalence rate in some parts of the world such as South America and Africa, coupled with the current drug treatments that trigger hypersensitivity reactions, makes the development of immunotherapeutics intervention a highly important research priority. Immunotherapeutics strategies could either be a vaccine which would confer a pre-emptive immunity to infection, or passive immunization in cases of disease recrudescence or recurrent clinical diseases. As the severity of clinical manifestations is often greater in developing nations, the development of well-tolerated and safe immunotherapeutics becomes not only a scientific pursuit, but a humanitarian enterprise. In the last few years, much progress has been made in vaccine research with new antigens, novel adjuvants, and innovative vaccine delivery such as nanoparticles and antigen encapsulations. A literature search over the past 5 years showed that most experimental studies were focused on DNA vaccination at 52%, followed by protein vaccination which formed 36% of the studies, live attenuated vaccinations at 9%, and heterologous vaccination at 3%; while there were few on passive immunization. Recent progress in studies on vaccination, passive immunization, as well as insights gained from these immunotherapeutics is highlighted in this review.

Clinical features and outcomes in patients with disseminated toxoplasmosis admitted to intensive care: a multicenter study.

BACKGROUND: Characteristics and outcomes of adult patients with disseminated toxoplasmosis admitted to the intensive care unit (ICU) have rarely been described. METHODS: We performed a retrospective study on consecutive adult patients with disseminated toxoplasmosis who were admitted from January 2002 through December 2012 to the ICUs of 14 university-affiliated hospitals in France. Disseminated toxoplasmosis was defined as microbiological or histological evidence of disease affecting >1 organ in immunosuppressed patients. Isolated cases of cerebral toxoplasmosis were excluded. Clinical data on admission and risk factors for 60-day mortality were collected. RESULTS: Thirty-eight patients were identified during the study period. Twenty-two (58%) had received an allogeneic hematopoietic stem cell transplant (median, 61 [interquartile range {IQR}, 43-175] days before ICU admission), 4 (10%) were solid organ transplant recipients, and 10 (27%) were infected with human immunodeficiency virus (median CD4 cell count, 14 [IQR, 6-33] cells/µL). The main indications for ICU admission were acute respiratory failure (89%) and shock (53%). The 60-day mortality rate was 82%. Allogeneic hematopoietic stem cell transplant (hazard ratio [HR] = 2.28; 95% confidence interval [CI], 1.05-5.35; P = .04) and systolic cardiac dysfunction (HR = 3.54; 95% CI, 1.60-8.10; P < .01) within 48 hours of ICU admission were associated with mortality. CONCLUSIONS: Severe disseminated toxoplasmosis leading to ICU admission has a poor prognosis. Recipients of allogeneic hematopoietic stem cell transplant appear to have the highest risk of mortality. We identified systolic cardiac dysfunction as a major determinant of outcome. Strategies aimed at preventing this fatal opportunistic infection may improve outcomes.

Toxoplasmosis in pregnancy: prevention, screening, and treatment.

BACKGROUND: One of the major consequences of pregnant women becoming infected by Toxoplasma gondii is vertical transmission to the fetus. Although rare, congenital toxoplasmosis can cause severe neurological or ocular disease (leading to blindness), as well as cardiac and cerebral anomalies. Prenatal care must include education about prevention of toxoplasmosis. The low prevalence of the disease in the Canadian population and limitations in diagnosis and therapy limit the effectiveness of screening strategies. Therefore, routine screening is not currently recommended. OBJECTIVE: To review the prevention, diagnosis, and management of toxoplasmosis in pregnancy. OUTCOMES: OUTCOMES evaluated include the effect of screening on diagnosis of congenital toxoplasmosis and the efficacy of prophylaxis and treatment. EVIDENCE: The Cochrane Library and Medline were searched for articles published in English from 1990 to the present related to toxoplasmosis and pregnancy. Additional articles were identified through references of these articles. VALUES: The quality of evidence is rated and recommendations made according to guidelines developed by the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: Guideline implementation should assist the practitioner in developing an approach to screening for and treatment of toxoplasmosis in pregnancy. Patients will benefit from appropriate management of this condition. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: 1. Routine universal screening should not be performed for pregnant women at low risk. Serologic screening should be offered only to pregnant women considered to be at risk for primary Toxoplasma gondii infection. (II-3E) 2. Suspected recent infection in a pregnant woman should be confirmed before intervention by having samples tested at a toxoplasmosis reference laboratory, using tests that are as accurate as possible and correctly interpreted. (II-2B) 3. If acute infection is suspected, repeat testing should be performed within 2 to 3 weeks, and consideration given to starting therapy with spiramycin immediately, without waiting for the repeat test results. (II-2B) 4. Amniocentesis should be offered to identify Toxoplasma gondii in the amniotic fluid by polymerase chain reaction (a) if maternal primary infection is diagnosed, (b) if serologic testing cannot confirm or exclude acute infection, or (c) in the presence of abnormal ultrasound findings (intracranial calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine growth restriction). (II-2B) 5. Amniocentesis should not be offered for the identification of Toxoplasma gondii infection at less than 18 weeks' gestation and should be offered no less than 4 weeks after suspected acute maternal infection to lower the occurrence of false-negative results. (II-2D) 6. Toxoplasma gondii infection should be suspected and screening should be offered to pregnant women with ultrasound findings consistent with possible TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes, and other) infection, including but not limited to intracranial calcification, microcephaly, hydrocephalus, ascites, hepatosplenomegaly, or severe intrauterine growth restriction. (II-2B) 7. Each case involving a pregnant woman suspected of having an acute Toxoplasma gondii infection acquired during gestation should be discussed with an expert in the management of toxoplasmosis. (III-B) 8. If maternal infection has been confirmed but the fetus is not yet known to be infected, spiramycin should be offered for fetal prophylaxis (to prevent spread of organisms across the placenta from mother to fetus). (I-B) 9. A combination of pyrimethamine, sulfadiazine, and folinic acid should be offered as treatment for women in whom fetal infection has been confirmed or is highly suspected (usually by a positive amniotic fluid polymerase chain reaction). (I-B) 10. Anti-toxoplasma treatment in immunocompetent pregnant women with previous infection with Toxoplasma gondii should not be necessary. (I-E) 11. Women who are immunosuppressed or HIV-positive should be offered screening because of the risk of reactivation and toxoplasmosis encephalitis. (I-A) 12. A non-pregnant woman who has been diagnosed with an acute Toxoplasma gondii infection should be counselled to wait 6 months before attempting to become pregnant. Each case should be considered separately in consultation with an expert. (III-B) 13. Information on prevention of Toxoplasma gondii infection in pregnancy should be made available to all women who are pregnant or planning a pregnancy. (III-C).

[Prevention of congenital toxoplasmosis in a Buenos Aires hospital]. / Prevención de la toxoplasmosis congénita en un hospital de Buenos Aires.

The prevention of congenital toxoplasmosis is based on providing information to women, serologic diagnosis and treatment of the infected mother and child. In this article we present the results of 12 years of implementation of a congenital toxoplasmosis prevention program in which we measured the mother's infection incidence rate, the transmission rate and the number and severity of infection in newborns. The study was performed on 12035 pregnant women in the period 2000-2011. The prevalence rate of antibodies against Toxoplasma gondii was 18.33% (2206/12035). Thirty-seven out of 9792 susceptible women presented acute infection and the mother's infection incidence rate was 3.78 per 1000 births. The transplacental transmission rate was 5.4% (2/37). Two newborns presented congenital toxoplasmosis infection, one had no clinical signs while the other presented strabismus and chorioretinitis. Thirty-five infected mothers and the two children with congenital infection were treated. The transmission rates obtained allow consider this prevention program as a valid resource to minimize the impact of congenital toxoplasmosis.

TORCH Infections.

Perinatal and neonatal infections are a significant cause of morbidity and mortality. As such, early recognition and workup when there is clinical concern is essential to supporting affected neonates. This article aims to focus specifically on the effects of toxoplasmosis, rubella, cytomegalovirus, herpes, and other agents (TORCH) infections, discussing epidemiology, diagnostics, and treatment if available. [Pediatr Ann. 2023;52(11):e400-e406.].