Search Results (20)

Proteinopathies, characterized by the misfolding, aggregation, and deposition of proteins, are hallmarks of various neurodegenerative and systemic diseases. Increasingly, research has highlighted the role of protein misfolding in parasitic infections, unveiling intricate interactions between host and parasite that exacerbate disease pathology and contribute to chronic outcomes. The life cycles of parasitic protozoa, including Plasmodium, Toxoplasmosis, and Leishmania species, are complicated and involve frequent changes between host and vector environments. Their proteomes are severely stressed during these transitions, which calls for highly specialized protein quality control systems. In order to survive harsh intracellular conditions during infection, these parasites have been demonstrated to display unique adaptations in the unfolded protein response, a crucial pathway controlling endoplasmic reticulum stress. In addition to improving parasite survival, these adaptations affect host cell signaling and metabolism, which may jeopardize cellular homeostasis. By causing oxidative stress, persistent inflammation, and disturbance of cellular proteostasis, host–parasite interactions also contribute to proteinopathy. For instance, Plasmodium falciparum disrupts normal protein homeostasis and encourages the accumulation of misfolded proteins by influencing host redox systems involved in protein folding. In addition to interfering with host chaperone systems, the parasitic secretion of effector proteins exacerbates protein misfolding and aggregate formation. Autophagy, apoptosis regulation, organelle integrity, and other vital cellular processes are all disrupted by these pathological protein aggregates. Long-term misfolding and aggregation can cause irreversible tissue damage, which can worsen the clinical course of illnesses like visceral leishmaniasis, cerebral malaria, and toxoplasmosis. Treating parasite-induced proteinopathies is a potentially fruitful area of therapy. According to recent research, autophagy modulators, proteasome enhancers, and small-molecule chaperones may be repurposed to lessen these effects. Pharmacological agents that target the UPR, for example, have demonstrated the ability to decrease parasite survival while also reestablishing host protein homeostasis. Targeting the proteins secreted by parasites that disrupt host proteostasis may also offer a novel way to stop tissue damage caused by proteinopathies. In conclusion, the intersection of protein misfolding and parasitic infections represents a rapidly advancing field of research. Dissecting the molecular pathways underpinning these processes offers unprecedented opportunities for developing innovative therapies. These insights could not only transform the management of parasitic diseases but also contribute to a broader understanding of proteinopathies in infectious and non-infectious diseases alike. Full article

North American beavers (Castor canadensis) are semi-aquatic rodents recognized as keystone species because they increase the diversity of freshwater ecosystems. This study aimed to characterize the mortality and pathological findings in free-ranging beavers in California and, based on these results, identify potential threats to freshwater ecosystems. This study included 18 beavers submitted for postmortem examination at the California Animal Health and Food Safety Laboratory, UC Davis, between 2008 and 2024. Gross and microscopic examinations, and bacteriological, parasitological, immunohistochemical, and molecular techniques, were used as tools to diagnose the cause of death/reason for euthanasia and comorbidities in the beavers. Baylisascaris spp.-associated or -suspected encephalitis was the most prevalent (9/18, 50%) cause of mortality/reason for euthanasia, followed by bacterial infections in six individuals. In these six animals, bacterial bronchopneumonia was diagnosed in two (Staphylococcus aureus and a mix of Gram-negative and -positive bacterial infection) and Listeria monocytogenes encephalitis, bacterial myofascitis (Aeromonas bestiarum and Pasteurella multocida), bacterial encephalitis (Acinetobacter towneri), and tularemia (Francisella tularensis) were diagnosed in one beaver each. Three animals died or were euthanized due to non-infectious causes, including motor vehicle trauma, squamous cell carcinoma, and capture cardiomyopathy. Endoparasitism was the main comorbidity, including granulomatous hepatitis caused by a suspected capillarid species, cerebral toxoplasmosis, Giardia infection, gastric nematodiasis, and cecal trematodiasis. In California, beavers are exposed to various pathogens that represent threats to humans, domestic animals, and wildlife. Since the interspecies transmission of these pathogens occurs in rivers, streams, lakes, and ponds, we suggest that studying beaver health can reflect freshwater ecosystem health. This study also indicates that the translocation of beavers to new areas without consideration and/or mitigation represents a potential risk of pathogen introduction. Full article

Toxoplasma gondii is an Apicomplexan parasite that is estimated to infect at least one-third of the global human population. T. gondii infection may be transmitted horizontally or vertically. The main risk factors for transmission to humans are related to diet, especially the consumption of undercooked meat, along with soil contact. In immunocompetent persons, the acute infection may go undetected as it typically produces minor, non-specific symptoms that are self-limited. After infection is established, recurrent retinochoroiditis is the most common clinical disease. In contrast, severe systemic or cerebral toxoplasmosis may be life-threatening for immunocompromised individuals. Furthermore, congenital toxoplasmosis acquired in utero may have devastating consequences if not recognized and promptly treated. A growing body of research has identified associations between latent T. gondii infection, and personality traits and risk-taking behaviors. Other studies have documented associations between latent infection and psychiatric conditions that include schizophrenia and bipolar affective disorder. With no current treatment regimens being curative of T. gondii infection, effective prevention measures at both the public health and individual levels are vitally important. Full article

Toxoplasmosis is a globally prevalent zoonotic disease with significant clinical implications, including neurotoxoplasmosis, a leading cause of cerebral lesions in AIDS patients. The current pharmacological treatments for toxoplasmosis face clinical limitations, necessitating the urgent development of new therapeutics. Natural sources have yielded diverse bioactive compounds, serving as the foundation for clinically used derivatives. The exploration of marine bacteria-derived natural products has led to marinoquinolines, which feature a pyrroloquinoline core and demonstrate in vitro and in vivo anti-Plasmodium activity. This study investigates the in vitro anti-Toxoplasma gondii potential of six marinoquinoline derivatives. Additionally, it conducts absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, and evaluates the in vivo efficacy of one selected compound. The compounds displayed half-maximal effective concentration (EC₅₀) values between 1.31 and 3.78 µM and half-maximal cytotoxic concentration (CC₅₀) values ranging from 4.16 to 30.51 µM, resulting in selectivity indices (SI) from 3.18 to 20.85. MQ-1 exhibiting the highest in vitro SI, significantly reduced tachyzoite numbers in the peritoneum of RH-infected Swiss mice when it was orally administered at 12.5 mg/kg/day for eight consecutive days. Also, MQ-1 significantly reduced the cerebral parasite burden in chronically ME49 infected C57BL/6 mice when it was orally administered at 25 mg/kg/day for 10 consecutive days. These findings underscore the promising anti-T. gondii activity of marinoquinolines and their potential as novel therapeutic agents against this disease. Full article

Toxoplasma gondii causes a global parasitic disease. Therapeutic options for eradicating toxoplasmosis are limited. In this study, ZnO and Mg-doped ZnO NPs were prepared, and their structural and morphological chrematistics were investigated. The XRD pattern revealed that Mg-doped ZnO NPs have weak crystallinity and a small crystallite size. FTIR and XPS analyses confirmed the integration of Mg ions into the ZnO framework, producing the high-purity Mg-doped ZnO nanocomposite. TEM micrographs determined the particle size of un-doped ZnO in the range of 29 nm, reduced to 23 nm with Mg²⁺ replacements. ZnO and Mg-doped ZnO NPs significantly decreased the number of brain cysts (p < 0.05) by 29.30% and 35.08%, respectively, compared to the infected untreated group. The administration of ZnO and Mg-doped ZnO NPs revealed a marked histopathological improvement in the brain, liver, and spleen. Furthermore, ZnO and Mg-doped ZnO NPs reduced P53 expression in the cerebral tissue while inducing CD31 expression, which indicated a protective effect against the infection-induced apoptosis and the restoration of balance between free radicals and antioxidant defense activity. In conclusion, the study proved these nanoparticles have antiparasitic, antiapoptotic, and angiogenetic effects. Being nontoxic compounds, these nanoparticles could be promising adjuvants in treating chronic toxoplasmosis. Full article

Introduction: Aicardi-Gouteres syndrome (AGS) is a monogenic interferonopathy characterized by early onset, dysregulation of skin (chilblain lesions), brain, and immune systems (fever, hepatomegaly, glaucoma, arthritis, myositis, and autoimmune activity). The disease looks like TORCH (Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes) infection with early-onset encephalopathy resulting in severe neuropsychological disability. Case description: A six-year-old girl has been suffering from generalized seizures, fever episodes, severe psychomotor development delay, and spastic tetraparesis since the first year of her life. Her two elder brothers died at a young age from suspected infantile cerebral palsy (ICP). Other siblings (younger brother and two elder sisters) are as healthy as their parents. The girl was diagnosed with juvenile dermatomyositis at 5.5 years. Basal ganglia, periventricular, and cerebellum calcifications; hypoplasia of the corpus callosum; and leukodystrophy were detected on CT. The IFN-I score was 12 times higher than normal. The previously not described nucleotide variant c.434G > C (chr 20:36935104C > G; NM_015474) was detected in exon 4 of the SAMHD1 gene in the homozygous state, leading to amino acid substitution p.R145P. Aicardi-Goutières syndrome 5 was diagnosed. Her treatment included corticosteroids, methotrexate, and tofacitinib 5 mg twice a day and it contributed to health improvements. The following brain CT depicted the previously discovered changes without the sign of calcification spreading. Conclusions: Early diagnosis of AGS is highly important as it allows starting treatment in a timely manner. Timely treatment, in return, can help avoid the development/progression of end-organ damage, including severe neurological complications and early death. It is necessary to spread information about AGS among neurologists, neonatologists, infectious disease specialists, and pediatricians. A multidisciplinary team approach is required. Full article

Apicomplexan parasites are the causal agents of different medically important diseases, such as toxoplasmosis, cryptosporidiosis, and malaria. Toxoplasmosis is considered a neglected parasitosis, even though it can cause severe cerebral complications and death in immunocompromised patients, including children and pregnant women. Drugs against Toxoplasma gondii, the etiological agent of toxoplasmosis, are highly toxic and lack efficacy in eradicating tissue cysts, promoting the establishment of latent infection and acute relapsing disease. Cryptosporidiosis has been recognized as the most frequent waterborne parasitosis in US outbreaks; anti-cryptosporidium drug discovery still faces a major obstacle: drugs that can act on the epicellular parasite. Severe malaria is most commonly caused by the progression of infection with Plasmodium falciparum. In recent years, great progress has been made in the field of antimalarial drugs and vaccines, although the resistance of P. falciparum to artemisinin has recently gained a foothold in Africa. As seen, the search for new drugs against these parasites remains a challenge. Peptide-based drugs seem to be attractive alternative therapeutic agents recently recognized by the pharmaceutical industry, as they can kill different infectious agents and modulate the immune response. A review of the experimental effects of bioactive peptides on these parasites follows, along with comments. In addition, some biological and metabolomic generalities of the parasites are reviewed to elucidate peptide mechanisms of action on Apicomplexan targets. Full article

Toxoplasmosis is one of the most common opportunistic infections, mainly reported in patients with acquired immunodeficiency syndrome (AIDS). Patients with rheumatoid arthritis (RA) have also been linked to reactivation of toxoplasmosis due to immunosuppressive treatment, although biologic drugs have seldom been implicated. We present a case of cerebral toxoplasmosis in a 62-year-old female patient with RA after initiation of biologic therapy (adalimumab). The patient had detectable serum IgG antibodies to toxoplasma gondii, was also on chronic treatment with other non-biologic drugs and presented with worsening disorientation, unsteady gait and left hemiparesis. Imaging studies showed a space-occupying lesion in the right basal ganglia with ring-enhancement. Brain biopsy confirmed the diagnosis of toxoplasmosis and the patient was treated with pyrimethamine and sulfadiazine for 6 weeks, showing complete recovery on follow-up. A review of the literature yielded other four case reports of cerebral toxoplasmosis implying biologic drugs; however, data concerning toxoplasmosis serologic testing, prophylaxis and treatment in these patients are lacking. Each case must be carefully evaluated prior to treatment and a high-index of suspicion in seropositive patients is warranted. Since the use of biologic drugs is increasing, further research is needed to establish practical guidelines for seropositive patients receiving immunosuppressive treatment. Full article

Management of cryptococcal infections among patients suffering from acquired immunodeficiency syndrome (AIDS) represents a medical challenge. This retrospective study aims to describe the disease management and outcomes among 24 AIDS patients who suffered from Cryptococcus neoformans meningitis. The parameters evaluated from our patients’ database records include epidemiological data, clinical manifestations, biochemical and microbiological analysis of patients’ cerebrospinal fluid (CSF), treatment profiles, and disease outcomes. All patients included in the study had a lymphocyte count of less than 200 CD4/mm³. Of the 24 patients included in this study, five had been diagnosed with HIV infection since childhood, after receiving HIV-infected blood transfusions. The most prominent symptom was fatigue in 62.5% of patients, followed by nausea/vomiting and headache. Seven patients had liver cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, while Kaposi sarcoma and cerebral toxoplasmosis were found in two patients. Six out of 24 patients died due to bacterial sepsis and acute respiratory distress syndrome (ARDS). High intracranial pressure was the strongest predictive factor for mortality (OR = 2.9), followed by ARDS (OR = 1.8), seizures at disease onset (OR = 1.4), and diabetes mellitus (OR = 1.2). Interestingly, patients younger than 40 years old had a significantly lower survival rate than that of the older patients. Before developing Cryptococcal meningitis, all patients had low adherence to the early ART treatment scheme and skipped the follow-up visits. All patients received a combination of amphotericin B and flucytosine as induction therapy, adding fluconazole for maintenance. Simultaneously, AIDS HAART was initiated at diagnosis of the cryptococcal infection. A combined regimen of antifungals and highly active antiretroviral therapy showed improved patient recovery with minor side effects. Full article

Stereotactic biopsy of posterior fossa lesions is often regarded as hazardous due to the critical structures in that area. Therefore, the aim of the study was to evaluate the diagnostic accuracy and safety of infratentorial stereotactic biopsy of brainstem or cerebellar lesions and its associations with other clinical, laboratory, and radiological parameters. From January 2000 to May 2021, 190 infratentorial stereotactic biopsies of posterior fossa tumors, including 108 biopsies of brainstem lesions, were performed. Moreover, 63 supratentorial biopsies of cerebral peduncle lesions were analyzed to compare the safety and efficacy of both approaches. Additionally, the presence of antibodies against Toxoplasma gondii and Epstein–Barr Virus (EBV) were documented in 67 and 66 patients, respectively, and magnetic resonance imaging (MRI) scans were evaluated in 114 patients. Only 4% of patients had minor complications and 1.5% had major complications, including one patient who died from intracranial bleeding. Nine (4.7%) biopsies were non-diagnostic. Isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status were assessed in 29 patients, and were non-diagnostic in only 3 (10.3%) cases. Patients with high-grade gliomas (HGG) were more frequently seropositive for T. gondii than individuals with low-grade gliomas (LGG; p < 0.001). A total of 27% of HGG and 41% of LGG were non-enhancing on MRI. The infratentorial approach is generally safe and reliable for biopsy of brainstem and cerebellar lesions. In our study, the safety and efficacy of supratentorial biopsy of the cerebral peduncle and infratentorial biopsy of lesions below the cerebral peduncle were comparably high. Moreover, patients with HGG were more frequently seropositive for T. gondii than patients with LGG, and the relationship between toxoplasmosis and gliomagenesis requires further investigation. Full article

Evidence of hearing impairment was identified in a harbour porpoise (Phocoena phocoena) on the basis of scanning electron microscopy. In addition, based on histopathology and immunohistochemistry, there were signs of unrelated cerebral toxoplasmosis. The six-year old individual live stranded on the Dutch coast at Domburg in 2016 and died a few hours later. The most significant gross lesion was multifocal necrosis and haemorrhage of the cerebrum. Histopathology of the brain revealed extensive necrosis and haemorrhage in the cerebrum with multifocal accumulations of degenerated neutrophils, lymphocytes and macrophages, and perivascular lymphocytic cuffing. The diagnosis of cerebral toxoplasmosis was confirmed by positive staining of protozoa with anti-Toxoplasma gondii antibodies. Tachyzoites were not observed histologically in any of the examined tissues. Ultrastructural evaluation of the inner ear revealed evidence of scattered loss of outer hair cells in a 290 µm long segment of the apical turn of the cochlea, and in a focal region of ~ 1.5 mm from the apex of the cochlea, which was compatible with noise-induced hearing loss. This is the first case of concurrent presumptive noise-induced hearing loss and toxoplasmosis in a free-ranging harbour porpoise from the North Sea. Full article

Toxoplasma gondii (T. gondii) is the causal agent of toxoplasmosis, which produces damage in the central nervous system (CNS). Toxoplasma–CNS interaction is critical for the development of disease symptoms. T. gondii can form cysts in the CNS; however, neurons are more resistant to this infection than astrocytes. The probable mechanism for neuron resistance is a permanent state of neurons in the interface, avoiding the replication of intracellular parasites. Steroids regulate the formation of Toxoplasma cysts in mice brains. 17β-estradiol and progesterone also participate in the control of Toxoplasma infection in glial cells in vitro. The aim of this study was to evaluate the effects of 17β-estradiol, progesterone, and their specific agonists–antagonists on Toxoplasma infection in neurons in vitro. Neurons cultured were pretreated for 48 h with 17β-estradiol or progesterone at 10, 20, 40, 80, or 160 nM/mL or tamoxifen 1 μM/mL plus 17β-estradiol at 10, 20, 40, 80, and 160 nM/mL. In other conditions, the neurons were pretreated during 48 h with 4,4′,4″-(4-propyl-[1H] pyrozole-1,3,5-triyl) trisphenol or 23-bis(4-hydroxyphenyl) propionitrile at 1 nM/mL, and mifepristone 1 µM/mL plus progesterone at 10, 20, 40, 80, and 160 nM/mL. Neurons were infected with 5000 tachyzoites of the T. gondii strain RH. The effect of 17β estradiol, progesterone, their agonists, or antagonists on Toxoplasma infection in neurons was evaluated at 24 and 48 h by immunocytochemistry. T. gondii replication was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. 17β-Estradiol alone or plus tamoxifen reduced infected neurons (50%) compared to the control at 48 h. Progesterone plus estradiol decreased the number of intracellular parasites at 48 h of treatment compared to the control (p < 0.001). 4,4′,4″-(4-propyl-[1H] pyrozole-1,3,5-triyl) trisphenol and 23-bis(4-hydroxyphenyl) propionitrile reduced infected neurons at 48 h of treatment significantly compared to the control (p < 0.05 and p < 0.001, respectively). The Toxoplasma infection process was decreased by the effect of 17β-estradiol alone or combined with tamoxifen or progesterone in neurons in vitro. These results suggest the essential participation of progesterone and estradiol and their classical receptors in the regulation of T. gondii neuron infection. Full article

Cerebral toxoplasmosis occurs mainly in immunocompromised hosts as a reactivation of latent Toxoplasma gondii infection. In the diagnostic process, magnetic resonance imaging (MRI), serum testing, and biopsy are used. We describe a case of a 43-year-old HIV-positive patient presenting with altered levels of consciousness, aphasia, and hemiparesis. The patient had a history of antiretroviral therapy discontinuation for about 3 years. MRI revealed lesions, suggesting cerebral toxoplasmosis and subacute hemorrhage, serum tests for Toxoplasma gondii were positive. Antiparasitics and glycocorticosteroids were administered. A decline in viral load and clinical improvement were observed, however CD4+ T-cell count continued to decrease. The patient’s state worsened, he developed CMV and bacterial pneumonia, which led to his death. What is crucial in the management of an HIV-infected patient is effective and continuous antiretroviral therapy. Discontinuation of the treatment may result in AIDS and lead to poor recovery of the CD4+ T-cell population, even after reimplementation of antiretroviral therapy and a decrease in viral load. Full article

Toxoplasma gondii is an obligate intracellular parasite considered one of the most successful pathogens in the world, owing to its ability to produce long-lasting infections and to persist in the central nervous system (CNS) in most warm-blooded animals, including humans. This parasite has a preference to invade neurons and affect the functioning of glial cells. This could lead to neurological and behavioral changes associated with cognitive impairment. Although several studies in humans and animal models have reported controversial results about the relationship between toxoplasmosis and the onset of dementia as a causal factor, two recent meta-analyses have shown a relative association with Alzheimer’s disease (AD). AD is characterized by amyloid-β (Aβ) peptide accumulation, neurofibrillary tangles, and neuroinflammation. Different authors have found that toxoplasmosis may affect Aβ production in brain areas linked with memory functioning, and can induce a central immune response and neurotransmitter imbalance, which in turn, affect the nervous system microenvironment. In contrast, other studies have revealed a reduction of Aβ plaques and hyperphosphorylated tau protein formation in animal models, which might cause some protective effects. The aim of this article is to summarize and review the newest data in regard to different pathophysiological mechanisms of cerebral toxoplasmosis and their relationship with the development of AD and cognitive impairment. All these associations should be investigated further through clinical and experimental studies. Full article

Central to the progression of cerebral toxoplasmosis is the interaction of Toxoplasma gondii with the blood-brain barrier (BBB) endothelial cells. In the present work, we tested the hypothesis that inhibition of Wnt pathway signalling by the monovalent ionophore monensin reduces the growth of T. gondii infecting human brain microvascular endothelial cells (hBMECs) or microglial cells. The anti-parasitic effect of monensin (a Wnt signalling inhibitor) on the in vitro growth of T. gondii tachyzoites was investigated using two methods (Sulforhodamine B staining and microscopic parasite counting). The monensin inhibited T. gondii growth (50% inhibitory concentration [IC₅₀] = 0.61 μM) with a selective index = 8.48 when tested against hBMECs (50% cytotoxic concentration [CC₅₀] = 5.17 μM). However, IC₅₀ of monensin was 4.13 μM with a SI = 13.82 when tested against microglia cells (CC₅₀ = 57.08 μM), suggesting less sensitivity of microglia cells to monensin treatment. The effect of T. gondii on the integrity of the BBB was assessed by the transendothelial electrical resistance (TEER) assay using an in vitro human BBB model. The results showed that T. gondii infection significantly decreased hBMECs’ TEER resistance, which was rescued when cells were treated with 0.1 µM monensin, probably due to the anti-parasitic activity of monensin. We also investigated the host-targeted effects of 0.1 µM monensin on global gene expression in hBMECs with or without T. gondii infection. Treatment of hBMECs with monensin did not significantly influence the expression of genes involved in the Wnt signalling pathway, suggesting that although inhibition of the Wnt signalling pathway did not play a significant role in T. gondii infection of hBMECs, monensin was still effective in limiting the growth of T. gondii. On the contrary, monensin treatment downregulated pathways related to steroids, cholesterol and protein biosynthesis and their transport between endoplasmic reticulum and Golgi apparatus, and deregulated pathways related to cell cycle and DNA synthesis and repair mechanisms. These results provide new insight into the host-modulatory effect of monensin during T. gondii infection, which merits further investigation. Full article