RESUMEN
Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. We hypothesised that recent findings of neurological features and parasite brain infiltration occurring at much earlier stages in HAT than previously thought could be explained by early activation of host genetic programmes controlling CNS disease. Accordingly, a transcriptomal analysis was performed on brain tissue at 0, 7, 14, 21 and 28dpi from the HAT CD1/GVR35 mouse model. Up to 21dpi, most parasites are restricted to the blood and lymphatic system. Thereafter the trypanosomes enter the brain initiating the encephalitic stage. Analysis of ten different time point Comparison pairings, revealed a dynamic transcriptome comprising four message populations. All 7dpi Comparisons had by far more differentially expressed genes compared to all others. Prior to invasion of the parenchyma, by 7dpi, ~2,000 genes were up-regulated, denoted [7dpi↑] in contrast to a down regulated population [7dpi↓] also numbering ~2,000. However, by 14dpi both patterns had returned to around the pre-infected levels. The third, [28dpi↑] featured over three hundred transcripts which had increased modestly up to14dpi, thereafter were significantly up-regulated and peaked at 28dpi. The fourth, a minor population, [7dpi↑-28dpi↑], had similar elevated levels at 7dpi and 28dpi. KEGG and GO enrichment analysis predicted a diverse phenotype by 7dpi with changes to innate and adaptive immunity, a Type I interferon response, neurotransmission, synaptic plasticity, pleiotropic signalling, circadian activity and vascular permeability without disruption of the blood brain barrier. This key observation is consistent with recent rodent model neuroinvasion studies and clinical reports of Stage 1 HAT patients exhibiting CNS symptoms. Together, these findings challenge the strict Stage1/Stage2 phenotypic demarcation in HAT and show that that significant neurological, and immune changes can be detected prior to the onset of CNS disease.
Asunto(s)
Encéfalo/parasitología , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/inmunología , Trypanosoma brucei brucei/fisiología , Tripanosomiasis Africana/genética , Tripanosomiasis Africana/inmunología , Animales , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/parasitología , Encéfalo/inmunología , Enfermedades del Sistema Nervioso Central/parasitología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Ratones , Fenotipo , Análisis por Matrices de Proteínas , Transcripción Genética , Tripanosomiasis Africana/parasitologíaRESUMEN
The infection by Trypanosoma brucei brucei (T.b.b.), a protozoan parasite, is characterized by an early-systemic stage followed by a late stage in which parasites invade the brain parenchyma in a T cell-dependent manner. Here we found that early after infection effector-memory T cells were predominant among brain T cells, whereas, during the encephalitic stage T cells acquired a tissue resident memory phenotype (TRM) and expressed PD1. Both CD4 and CD8 T cells were independently redundant for the penetration of T.b.b. and other leukocytes into the brain parenchyma. The role of lymphoid cells during the T.b.b. infection was studied by comparing T- and B-cell deficient rag1-/- and WT mice. Early after infection, parasites located in circumventricular organs, brain structures with increased vascular permeability, particularly in the median eminence (ME), paced closed to the sleep-wake regulatory arcuate nucleus of the hypothalamus (Arc). Whereas parasite levels in the ME were higher in rag1-/- than in WT mice, leukocytes were instead reduced. Rag1-/- infected mice showed increased levels of meca32 mRNA coding for a blood /hypothalamus endothelial molecule absent in the blood-brain-barrier (BBB). Both immune and metabolic transcripts were elevated in the ME/Arc of WT and rag1-/- mice early after infection, except for ifng mRNA, which levels were only increased in WT mice. Finally, using a non-invasive sleep-wake cycle assessment method we proposed a putative role of lymphocytes in mediating sleep alterations during the infection with T.b.b. Thus, the majority of T cells in the brain during the early stage of T.b.b. infection expressed an effector-memory phenotype while TRM cells developed in the late stage of infection. T cells and parasites invade the ME/Arc altering the metabolic and inflammatory responses during the early stage of infection and modulating sleep disturbances.
Asunto(s)
Enfermedades del Sistema Nervioso Central/inmunología , Enfermedades del Sistema Nervioso Central/parasitología , Subgrupos de Linfocitos T/fisiología , Trypanosoma brucei brucei , Tripanosomiasis Africana/inmunología , Tripanosomiasis Africana/patología , Animales , Encéfalo/parasitología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Memoria Inmunológica , Leucocitos , Ratones , Ratones Noqueados , SueñoRESUMEN
BACKGROUND: Parasitic infections affecting the central nervous system (CNS) present high morbidity and mortality rates and affect millions of people worldwide. The most important parasites affecting the CNS are protozoans (Plasmodium sp., Toxoplasma gondii, Trypanosoma brucei), cestodes (Taenia solium) and free-living amoebae (Acantamoeba spp., Balamuthia mandrillaris and Naegleria fowleri). Current therapeutic regimens include the use of traditional chemicals or natural compounds that have very limited access to the CNS, despite their elevated toxicity to the host. Improvements are needed in drug administration and formulations to treat these infections and to allow the drug to cross the blood-brain barrier (BBB). METHODS: This work aims to elucidate the recent advancements in the use of nanoparticles as nanoscaled drug delivery systems (NDDS) for treating and controlling the parasitic infections that affect the CNS, addressing not only the nature and composition of the polymer chosen, but also the mechanisms by which these nanoparticles may cross the BBB and reach the infected tissue. RESULTS: There is a strong evidence in the literature demonstrating the potential usefulness of polymeric nanoparticles as functional carriers of drugs to the CNS. Some of them demonstrated the mechanisms by which drugloaded nanoparticles access the CNS and control the infection by using in vivo models, while others only describe the pharmacological ability of these particles to be utilized in in vitro environments. CONCLUSION: The scarcity of the studies trying to elucidate the compatibility as well as the exact mechanisms by which NDDS might be entering the CNS infected by parasites reveals new possibilities for further exploratory projects. There is an urgent need for new investments and motivations for applying nanotechnology to control parasitic infectious diseases worldwide.
Asunto(s)
Barrera Hematoencefálica , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Nanopartículas , Enfermedades Parasitarias/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/parasitología , Humanos , NanotecnologíaRESUMEN
AIM: The rat lungworm, Angiostrongylus cantonensis, is well established in eastern Australia, where it is the almost exclusive cause of human eosinophilic meningoencephalitis (EME). While neuroangiostrongyliasis can result in severe morbidity or death, its diagnosis requires a high index of clinical suspicion among medical practitioners. Prevention requires a high level of public awareness. METHODS: We report two cases of EME in children from Queensland and summarise all reported Australian cases from the literature. We discuss the pathogenesis of neuroangiostrongyliasis, with particular reference to the timing of prophylaxis and treatment. RESULTS: A 5-year-old girl developed severe headache, eosinophilic meningitis and abnormal neuroimaging following a holiday to Bali. A 10-year-old boy with Rubinstein-Taybi syndrome, marked developmental delay and pica developed EME following ingestion of a snail, resulting in long-term morbidity. From 1971 to 2018, 28 Australian cases have been reported, with acquisition restricted to Southeast Queensland and New South Wales. Ages ranged from 10 months to 45 years; most were male and most likely acquired infection from consuming unwashed lettuce or vegetables. The mortality rate was 18%; most fatalities occurred in children <1 year old. Long-term neurological deficit was reported in 14% of cases and a full recovery in 57% of cases. CONCLUSIONS: Heightened medical and public awareness of the parasite is required to prevent infection and subsequent disease. A better understanding of the efficacy of prophylactic anthelmintic following ingestion or handling of molluscs and further studies of epidemiology of this parasite will inform and facilitate public health recommendations.
Asunto(s)
Angiostrongylus cantonensis/aislamiento & purificación , Infecciones por Strongylida/fisiopatología , Animales , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Enfermedades del Sistema Nervioso Central/parasitología , Niño , Preescolar , Femenino , Humanos , Masculino , Queensland/epidemiología , Enfermedades Raras , Infecciones por Strongylida/diagnóstico , Infecciones por Strongylida/tratamiento farmacológico , Infecciones por Strongylida/epidemiologíaRESUMEN
Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as "brain-eating amoebae". The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.
Asunto(s)
Amebiasis/tratamiento farmacológico , Amebiasis/parasitología , Amoeba/efectos de los fármacos , Encéfalo/parasitología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/parasitología , Naegleria fowleri/efectos de los fármacos , Naegleria fowleri/parasitología , Amebiasis/diagnóstico , Enfermedades del Sistema Nervioso Central/diagnóstico , HumanosRESUMEN
Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro The mechanism responsible for the NE suppression was found to be downregulation of dopamine ß-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine, with downregulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The downregulation was sex specific, with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection, as human cytomegalovirus did not downregulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels, which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioral effects of infection and associations with mental illness.
Asunto(s)
Catecolaminas/metabolismo , Enfermedades del Sistema Nervioso Central/parasitología , Dopamina beta-Hidroxilasa/metabolismo , Norepinefrina/metabolismo , Toxoplasmosis/metabolismo , Animales , Encéfalo/metabolismo , Enfermedades del Sistema Nervioso Central/metabolismo , Dopamina/metabolismo , Regulación hacia Abajo , Regulación de la Expresión Génica , Ratones , Neuronas/metabolismo , ARN Mensajero/metabolismo , RatasRESUMEN
Central nervous system (CNS) infections caused by free-living amoebae such as Acanthamoeba species and Naegleria fowleri are rare but fatal. A major challenge in the treatment against the infections caused by these amoebae is the discovery of novel compounds that can effectively cross the blood-brain barrier to penetrate the CNS. It is logical to test clinically approved drugs against CNS diseases for their potential antiamoebic effects since they are known for effective blood-brain barrier penetration and affect eukaryotic cell targets. The antiamoebic effects of clinically available drugs for seizures targeting gamma-amino butyric acid (GABA) receptor and ion channels were tested against Acanthamoeba castellanii belonging to the T4 genotype and N. fowleri. Three such drugs, namely, diazepam (Valium), phenobarbitone (Luminal), phenytoin (Dilantin), and their silver nanoparticles (AgNPs) were evaluated against both trophozoites and cysts stage. Drugs alone and drug conjugated silver nanoparticles were tested for amoebicidal, cysticidal, and host-cell cytotoxicity assays. Nanoparticles were synthesized by sodium borohydride reduction of silver nitrate with drugs as capping agents. Drug conjugated nanoconjugates were characterized by ultraviolet-visible (UV-vis) and Fourier transform infrared (FT-IR) spectroscopies and atomic force microscopy (AFM). In vitro moebicidal assay showed potent amoebicidal effects for diazepam, phenobarbitone, and phenytoin-conjugated AgNPs as compared to drugs alone against A. castellanii and N. fowleri. Furthermore, both drugs and drug conjugated AgNPs showed compelling cysticidal effects. Drugs conjugations with silver nanoparticles enhanced their antiacanthamoebic activity. Interestingly, amoeba-mediated host-cell cytotoxicity was also significantly reduced by drugs alone as well as their nanoconjugates. Since, these drugs are being used to target CNS diseases, their evaluation against brain-eating amoebae seems feasible due to advantages such as permeability of the blood-brain barrier, established pharmacokinetics and dynamics, and United States Food and Drug Administration (FDA) approval. Given the limited availability of effective drugs against brain-eating amoebae, the clinically available drugs tested here present potential for further in vivo studies.
Asunto(s)
Acanthamoeba castellanii/parasitología , Amebicidas/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Naegleria fowleri/efectos de los fármacos , Acanthamoeba castellanii/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/parasitología , Enfermedades del Sistema Nervioso Central/parasitología , Humanos , Nanopartículas del Metal/parasitología , Nanoconjugados , Espectroscopía Infrarroja por Transformada de Fourier/métodosRESUMEN
Zoonotic visceral leishmaniasis is caused by the protozoan Leishmania infantum and little is known about the occurrence and pathogenesis of this parasite in the CNS. The aims of this study were to evaluate the occurrence, viability and load of L. infantum in the CNS, and to identify the neurological histological alterations associated with this protozoan and its co-infections in naturally infected dogs. Forty-eight Leishmania-seropositive dogs from which L. infantum was isolated after necropsy were examined. Cerebrospinal fluid (CSF) samples were analyzed by parasitological culture, quantitative real-time PCR (qPCR) and the rapid immunochromatographic Dual Path Platform test. Brain, spinal cord and spleen samples were submitted to parasitological culture, qPCR, and histological techniques. Additionally, anti-Toxoplasma gondii and anti-Ehrlichia canis antibodies in serum and distemper virus antigens in CSF were investigated. None of the dogs showed neurological signs. All dogs tested positive for L. infantum in the CNS. Viable forms of L. infantum were isolated from CSF, brain and spinal cord in 25% of the dogs. Anti-L. infantum antibodies were detected in CSF in 61% of 36 dogs. Inflammatory histological alterations were observed in the CNS of 31% of the animals; of these, 66% were seropositive for E. canis and/or T. gondii. Amastigote forms were associated with granulomatous non-suppurative encephalomyelitis in a dog without evidence of co-infections. The highest frequency of L. infantum DNA was observed in the brain (98%), followed by the spinal cord (96%), spleen (95%), and CSF (50%). The highest L. infantum load in CNS was found in the spinal cord. These results demonstrate that L. infantum can cross the blood-brain barrier, spread through CSF, and cause active infection in the entire CNS of dogs. Additionally, L. infantum can cause inflammation in the CNS that can lead to neurological signs with progression of the disease.
Asunto(s)
Enfermedades del Sistema Nervioso Central/veterinaria , Enfermedades de los Perros/parasitología , Leishmania infantum/fisiología , Leishmaniasis Visceral/veterinaria , Animales , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Sistema Nervioso Central/parasitología , Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/parasitología , Coinfección/microbiología , Coinfección/parasitología , Coinfección/veterinaria , ADN Protozoario/genética , Enfermedades de los Perros/microbiología , Perros , Ehrlichia canis/inmunología , Ehrlichia canis/fisiología , Ehrlichiosis/microbiología , Ehrlichiosis/veterinaria , Interacciones Huésped-Parásitos , Interacciones Huésped-Patógeno , Hibridación in Situ , Leishmania infantum/genética , Leishmania infantum/inmunología , Leishmaniasis Visceral/líquido cefalorraquídeo , Leishmaniasis Visceral/parasitología , Carga de Parásitos , Reacción en Cadena en Tiempo Real de la Polimerasa , Toxoplasma/inmunología , Toxoplasma/fisiología , Toxoplasmosis/parasitologíaRESUMEN
Baylisascaris procyonis, predominantly found in raccoons, is a ubiquitous roundworm found throughout North America. Although raccoons are typically asymptomatic when infected with the parasite, the larval form of Baylisascaris procyonis can result in fatal human disease or severe neurologic outcomes if not treated rapidly. In the United States, Baylisascaris procyonis is more commonly enzootic in raccoons in the midwestern and northeastern regions and along the West Coast (1). However, since 2002, infections have been documented in other states (Florida and Georgia) and regions (2). Baylisascariasis is not a nationally notifiable disease in the United States, and little is known about how commonly it occurs or the range of clinical disease in humans. Case reports of seven human baylisascariasis cases in the United States diagnosed by Baylisascaris procyonis immunoblot testing at CDC are described, including review of clinical history and laboratory data. Although all seven patients survived, approximately half were left with severe neurologic deficits. Prevention through close monitoring of children at play, frequent handwashing, and clearing of raccoon latrines (communal sites where raccoons defecate) are critical interventions in curbing Baylisascaris infections. Early treatment of suspected cases is critical to prevent permanent sequelae.
Asunto(s)
Infecciones por Ascaridida/veterinaria , Ascaridoidea/aislamiento & purificación , Enfermedades del Sistema Nervioso Central/diagnóstico , Oftalmopatías/diagnóstico , Mapaches/parasitología , Adulto , Animales , Infecciones por Ascaridida/transmisión , Enfermedades del Sistema Nervioso Central/parasitología , Niño , Oftalmopatías/parasitología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estados UnidosRESUMEN
BACKGROUND: Information about the clinical and clinicopathologic aspects of cerebrospinal nematodiasis (CN) in camelids is limited. HYPOTHESIS: Clinical and therapeutic variables will be identified as factors predictive of survival. ANIMALS: Client-owned camelids suspected of having CN admitted to Purdue University between 1995 and 2015. METHODS: A retrospective study was performed. A diagnosis of CN was based on cerebrospinal fluid (CSF) eosinophilic pleocytosis or postmortem findings. RESULTS: Eleven alpacas and 9 llamas met the inclusion criteria. Seventy-five percent of the camelids were male (27% castrated and 73% intact). Common clinical abnormalities included proprioceptive deficits (100% of animals), recumbency (55%), tachypnea (55%), and ataxia (40%). Among the 85% of treated animals, 100% received PO fenbendazole, and 88% received a nonsteroidal anti-inflammatory drug. The survival rate to discharge was 45%. Plasma fibrinogen concentration, creatine kinase activity, and serum creatinine concentration were significantly higher in nonsurvivors. Blood eosinophil count, platelet count, and total CO2 were significantly lower in nonsurvivors. Factors associated with survival were species, sex, absence of treatment with corticosteroids, and clinical improvement. There was no association between recumbency at admission and survival. A plasma fibrinogen concentration above >266 mg/dL was an excellent diagnostic test to predict survival in the presence of neurological signs or CSF eosinophilia. CONCLUSIONS: Although prognosis for CN in camelids is guarded, presence of recumbency at admission is not predictive of nonsurvival. Male camelids and llamas appear more likely to die from CN. Corticosteroid treatment is contraindicated in animals diagnosed with CN.
Asunto(s)
Camélidos del Nuevo Mundo/parasitología , Enfermedades del Sistema Nervioso Central/veterinaria , Infecciones por Nematodos/veterinaria , Animales , Antihelmínticos/uso terapéutico , Enfermedades del Sistema Nervioso Central/parasitología , Enfermedades del Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Central/terapia , Femenino , Masculino , Infecciones por Nematodos/parasitología , Infecciones por Nematodos/patología , Infecciones por Nematodos/terapia , Estudios RetrospectivosRESUMEN
Paraffin-embedded blocks of brain of a nine months old bull calf that died of neurological signs in 1982 in Germany were restudied. Numerous schizonts and merozoites were found associated with extensive but focal necrosis and severe meningoencephalitis. Developing stages of schizonts as well as free merozoites were identified. The schizonts were primarily in perivascular areas. Ultrastructurally, schizonts were seen both in capillaries and in extravascular space. Merozoites were often concentrated in adventitial layers of capillaries. Schizonts divided by endopolygeny, the nucleus became multi-lobed, and at the terminal stage nuclear lobes were incorporated into budding merozoites. Individual merozoites were seen in neurons, astrocytes, oligodendrocytes, leukocytes, and vascular endothelial cells. Occasionally merozoites were present in the nucleus of mononuclear cells. Individual merozoites were ovoid, 3-5×2-3µm in size, and contained a prominent nucleus, numerous micronemes, a conoid, but no rhoptries. Schizonts and merozoites did not react to polyclonal rabbit Neospora caninum, Toxoplasma gondii, and Sarcocystis neurona antibodies but did react to Sarcocystis cruzi antibodies. Because of morphological characteristics and the type of lesions, the parasite was likely due to an unidentified Sarcocystis species, different from S. cruzi.
Asunto(s)
Enfermedades de los Bovinos/parasitología , Enfermedades del Sistema Nervioso Central/veterinaria , Sarcocistosis/veterinaria , Animales , Encéfalo/parasitología , Encéfalo/patología , Bovinos , Enfermedades del Sistema Nervioso Central/parasitología , Enfermedades del Sistema Nervioso Central/patología , Masculino , Adhesión en Parafina , Sarcocistosis/patologíaRESUMEN
Invasion of the central nervous system (CNS) by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-γ and TNF-α concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation.
Asunto(s)
Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Sistema Nervioso Central/parasitología , Factores Inmunológicos/administración & dosificación , Interleucina-10/administración & dosificación , Trypanosoma brucei brucei/crecimiento & desarrollo , Tripanosomiasis Africana/tratamiento farmacológico , Animales , Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Central/parasitología , Enfermedades del Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Femenino , Interferón gamma/sangre , Ratones , Plasma/química , Resultado del Tratamiento , Tripanosomiasis Africana/parasitología , Tripanosomiasis Africana/patología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Meningeal worms (Parelaphostrongylus tenuis) are a common malady of alpacas, often refractory to conventional treatments. Ivermectin is a very effective anthelmintic used against a variety of parasites but this drug is not consistently effective against alpaca meningeal worms once the parasite has gained access to the CNS, even if used in a protracted treatment protocol. Ivermectin is not effective against clinical cases of P. tenuis, raising the possibility that the drug is not sustained at therapeutic concentrations in the central nervous system (CNS). A specific protein (designated as p-glycoprotein (PGP)) effluxes ivermectin from the brain at the blood-brain barrier, thus hampering the maintenance of therapeutic concentrations of the drug in the CNS. Minocycline is a synthetic tetracycline antibiotic with an excellent safety profile in all animals tested to date. Minocycline has three unique characteristics that could be useful for treating meningeal worms in conjunction with ivermectin. First, minocycline is an inhibitor of PGP at the blood-brain barrier and this inhibition could maintain effective concentrations of ivermectin in the brain and meninges. Second, minocycline protects neurons in vivo through a number of different mechanisms and this neuroprotection could alleviate the potential untoward neurologic effects of meningeal worms. Third, minocycline is a highly lipid-soluble drug, thus facilitating efficient brain penetration. We thus hypothesized that minocycline will maintain ivermectin, or a related avermectin approved in ruminants (abamectin, doramectin, or eprinomectin), in the alpaca CNS. To test this hypothesis, we cloned the gene encoding the alpaca PGP, expressed the alpaca PGP in a heterologous expression system involving MDCK cells, and measured the ability of minocycline to inhibit the efflux of avermectins from the MDCK cells; doxycycline was used as a putative negative control (based on studies in other species). Our in vitro studies surprisingly revealed that doxycycline was effective at inhibiting the efflux of ivermectin and doramectin (minocycline had no effect). These two avermectins, in combination with doxycycline, should be considered when treating meningeal worms in alpacas.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Camélidos del Nuevo Mundo/metabolismo , Enfermedades del Sistema Nervioso Central/veterinaria , Doxiciclina/farmacología , Interacciones Farmacológicas , Ivermectina/análogos & derivados , Secuencia de Aminoácidos , Animales , Camélidos del Nuevo Mundo/genética , Línea Celular , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/parasitología , Perros , Regulación de la Expresión Génica/efectos de los fármacos , Ivermectina/metabolismo , Ivermectina/farmacología , Minociclina/farmacología , Datos de Secuencia MolecularRESUMEN
Toxocara canis and Toxocara cati are globally occurring intestinal nematodes of dogs and cats with a high zoonotic potential. Migrating larvae in the CNS of paratenic hosts, including humans, may cause neurotoxocarosis resulting in a variety of neurological symptoms. Toxocara canis exhibits a stronger affinity to the CNS than T. cati, causing more severe neurological symptoms in the mouse model. Pathomechanisms of neurotoxocarosis as well as host responses towards the respective parasite are mostly unknown. Therefore, the aim of this study was to characterise the pathogenesis at a transcriptional level using whole genome microarray expression analysis and identify differences and similarities between T. canis- and T. cati-infected brains. Microarray analysis was conducted in cerebra and cerebella of infected C57Bl/6J mice 42daysp.i. revealing more differentially transcribed genes for T. canis- than T. cati-infected brains. In cerebra and cerebella of T. canis-infected mice, a total of 2304 and 1954 differentially transcribed genes, respectively, were identified whereas 113 and 760 differentially transcribed genes were determined in cerebra and cerebella of T. cati-infected mice. Functional annotation analysis revealed major differences in host responses in terms of significantly enriched biological modules. Up-regulated genes were mainly associated with the terms "immune and defence response", "sensory perception" as well as "behaviour/taxis" retrieved from the Gene Ontology database. These observations indicate a strong immune response in both infection groups with T. cati-infected brains revealing less severe reactions. Down-regulated genes in T. canis-infected cerebra and cerebella revealed a significant enrichment for the Gene Ontology term "lipid/cholesterol biosynthetic process". Cholesterol is a highly abundant and important component in the brain, representing several functions. Disturbances of synthesis as well as concentration changes may lead to dysfunction in signal transduction and neurodegenerative disease. Overall, only a minor overlap of differentially transcribed genes was observed between the two infection groups in both brain parts. Most genes are regulated individually in each infection group, supporting the evident differences of both roundworm species observed in the paratenic host in previous studies. In summary the present study underlines the differences in pathogenicity of T. canis and T. cati. It furthermore provides a comprehensive basis for future analyses over the course of infection as well as functional tests to identify gene regulatory circuits that are crucial for pathogenesis of neurotoxocarosis. The results of this study provide a promising foundation for further specific research to evaluate the particular pathogenetic mechanisms and to identify possible therapeutic targets.
Asunto(s)
Enfermedades del Sistema Nervioso Central/parasitología , Lípidos/biosíntesis , Análisis por Matrices de Proteínas , Toxocara/clasificación , Toxocariasis/parasitología , Animales , Encéfalo/parasitología , Encéfalo/patología , Regulación de la Expresión Génica/fisiología , Ratones , ARN/genética , ARN/metabolismo , Especificidad de la EspecieRESUMEN
Pseudoloma neurophilia is a microsporidium of zebrafish (Danio rerio) that preferentially infects neural tissue. It is one of the most common pathogens of zebrafish in research laboratories based on diagnostic data from the Zebrafish International Resource Center diagnostic service (Eugene, OR). Five hundred fifty-nine zebrafish infected with P. neurophilia submitted to ZIRC from 86 laboratories between the years 2000 and 2013 were examined via histopathology to develop a retrospective study of the features of neural microsporidiosis. Parasite clusters (PCs) occurred in distinct axonal swellings, frequently with no associated inflammation. Inflammation was observed in viable cell bodies distant from PCs. Multiple PCs occasionally occurred within a single axon, suggesting axonal transport. PCs occurred most frequently in the spinal cord ventral white matter (40.3% of all PCs) and the spinal nerve roots (25.6%). Within the rhombencephalon, PCs were most common in the primary descending white matter tracts. Within the rhombencephalon gray matter, PCs occurred most frequently in the reticular formation and the griseum centrale (61% and 39%, respectively). High numbers of PCs within brain and spinal cord structures mediating startle responses and anxiety suggest that related behaviors could be altered by neural microsporidiosis. Infection could, therefore, introduce unacceptable variation in studies utilizing these behaviors.
Asunto(s)
Conducta Animal , Enfermedades del Sistema Nervioso Central/veterinaria , Enfermedades de los Peces/parasitología , Microsporidios/fisiología , Microsporidiosis/veterinaria , Pez Cebra/parasitología , Animales , Enfermedades del Sistema Nervioso Central/parasitología , Enfermedades del Sistema Nervioso Central/patología , Microsporidiosis/patologíaRESUMEN
Neosporosis is a polysystemic disease that can affect dogs of any age and can cause inflammation of the central nervous system. Antemortem diagnosis can be challenging, as clinical and conventional laboratory test findings are often nonspecific. A previous report described cerebellar lesions in brain MRI studies of seven dogs and proposed that these may be characteristic for central nervous system Neosporosis. The purpose of this retrospective study was to describe MRI characteristics in another group of dogs with confirmed central nervous system neosporosis and compare them with the previous report. The hospital's database was searched for dogs with confirmed central nervous system neosporosis and four observers recorded findings from each dog's MRI studies. A total of four dogs met inclusion criteria. Neurologic examination was indicative of a forebrain and cerebellar lesion in dog 2 and multifocal central nervous system disease in dogs 1, 3, and 4. Magnetic resonance imaging showed mild bilateral and symmetrical cerebellar atrophy in three of four dogs (dogs 2, 3, 4), intramedullary spinal cord changes in two dogs (dogs 3, 4) and a mesencephalic and metencephalic lesion in one dog (dog 2). Multifocal brain lesions were recognized in two dogs (dogs 1, 4) and were present in the thalamus, lentiform nucleus, centrum semiovale, internal capsule, brainstem and cortical gray matter of the frontal, parietal or temporal lobe. Findings indicated that central nervous system neosporosis may be characterized by multifocal MRI lesions as well as cerebellar involvement in dogs.
Asunto(s)
Encéfalo/diagnóstico por imagen , Enfermedades del Sistema Nervioso Central/veterinaria , Coccidiosis/veterinaria , Enfermedades de los Perros/diagnóstico por imagen , Imagen por Resonancia Magnética/veterinaria , Animales , Encéfalo/parasitología , Encéfalo/patología , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/parasitología , Coccidiosis/complicaciones , Coccidiosis/diagnóstico , Coccidiosis/parasitología , Enfermedades de los Perros/parasitología , Enfermedades de los Perros/patología , Perros , Femenino , Masculino , Neospora/fisiología , Radiografía , Estudios RetrospectivosRESUMEN
A total of 5 psittacine birds in an enclosed zoological exhibit, including 2 princess parrots and 3 cockatoos of 2 different species, developed severe central nervous system clinical signs over a 2-3-month period and died or were euthanized. Histologically, all birds had a lymphoplasmacytic and histiocytic encephalitis with intralesional protozoa consistent with a Sarcocystis species in addition to intramuscular tissue sarcocysts. By immunohistochemical staining, merozoites in brain and tissue cysts in muscle did not react with polyclonal antisera against Sarcocystis falcatula, Sarcocystis neurona, Toxoplasma gondii, and Neospora caninum, or with a monoclonal antibody to S. neurona. Transmission electron microscopy on sarcocyst tissue cyst walls from 2 birds was morphologically consistent with Sarcocystis calchasi. Polymerase chain reaction (PCR) amplification and sequencing of partial 18S ribosomal RNA from muscle tissue cysts and brain schizonts from 3 birds was consistent with a clade containing S. calchasi and Sarcocystis columbae but could not distinguish these closely related Sarcocystis species. However, PCR amplification and sequencing of the internal transcribed spacer 1 RNA segment in the brain from 2 birds and muscle from 2 birds specifically identified the isolates as S. calchasi. The current report documents that multiple psittacine species are susceptible intermediate hosts of S. calchasi, and that infection can cause encephalitis resulting in significant morbidity and mortality in psittacine aviaries.
Asunto(s)
Enfermedades de las Aves/parasitología , Enfermedades del Sistema Nervioso Central/veterinaria , Loros , Filogenia , Sarcocystis/aislamiento & purificación , Sarcocistosis/veterinaria , Animales , Animales de Zoológico , Secuencia de Bases , Enfermedades de las Aves/patología , Enfermedades del Sistema Nervioso Central/parasitología , Enfermedades del Sistema Nervioso Central/patología , ADN Protozoario/química , ADN Protozoario/genética , Brotes de Enfermedades/veterinaria , Resultado Fatal , Inmunohistoquímica/veterinaria , Microscopía Electrónica de Transmisión , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/veterinaria , ARN Ribosómico 18S/química , ARN Ribosómico 18S/genética , Sarcocystis/genética , Sarcocystis/ultraestructura , Sarcocistosis/parasitología , Sarcocistosis/patología , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
Toxoplasma gondii, an Apicomplexan, is a pathogic protozoan that can infect the central nervous system. Infection during pregnancy can result in a congenial infection with severe neurological sequelae. In immunocompromised individuals reactivation of latent neurological foci can result in encephalitis. Immunocompetent individuals infected with T. gondii are typically asymptomatic and maintain this infection for life. However, recent studies suggest that these asymptomatic infections may have effects on behavior and other physiological processes. Toxoplasma gondii infects approximately one-third of the world population, making it one of the most successful parasitic organisms. Cats and other felidae serve as the definite host producing oocysts, an environmentally resistant life cycle stage found in cat feces, which can transmit the infection when ingested orally. A wide variety of warm-blooded animals, including humans, can serve as the intermediate host in which tissue cysts (containing bradyzoites) develop. Transmission also occurs due to ingestion of the tissue cysts. There are three predominant clonal lineages, termed Types I, II and III, and an association with higher pathogenicity with the Type I strains in humans has emerged. This chapter presents a review of the biology of this infection including the life cycle, transmission, epidemiology, parasite strains, and the host immune response. The major clinical outcomes of congenital infection, chorioretinitis and encephalitis, and the possible association of infection of toxoplasmosis with neuropsychiatric disorders such as schizophrenia, are reviewed.
Asunto(s)
Enfermedades del Sistema Nervioso Central/etiología , Enfermedades del Sistema Nervioso Central/parasitología , Toxoplasma/patogenicidad , Toxoplasmosis , Animales , Humanos , Toxoplasmosis/complicaciones , Toxoplasmosis/epidemiología , Toxoplasmosis/parasitologíaRESUMEN
Strongyloides stercoralis is a nematode endemic in humid tropical regions. The life cycle of this parasite is complex and unique due to its capacity to cause autoinfection, resulting in chronic infections. Innate and adaptive immune responses are responsible for clearing the parasite. Many risk factors have been described, but the most important is living in or having visited an endemic area. The clinical presentation of strongyloidiasis is varied and ranges from asymptomatic chronic infection to hyperinfection syndrome. Hyperinfection syndrome is more common in patients with immunosuppresion due to therapy with corticosteroids, coinfection with human T-lymphotropic virus type I (HTLV-1), transplant patients, or patients receiving chemotherapy. Multiplication and migration of large parasite numbers cause worsening of the initial symptoms and leads to a high mortality rate. CNS involvement in strongyloidiasis has only been seen in patients with hyperinfection syndrome. Meningitis is the most common form of CNS involvement and gram-negative bacteria are the more frequent etiology. Repeated stool samples with concentration methods have a good sensitivity and specificity. In patients that are not from endemic areas serum antibody tests may be useful in the diagnosis. Treatment with a single dose of ivermectin is recommended for most patients. In severe or hyperinfection cases repeated doses may be needed.
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Enfermedades del Sistema Nervioso Central/etiología , Enfermedades del Sistema Nervioso Central/parasitología , Strongyloides stercoralis/patogenicidad , Estrongiloidiasis/complicaciones , Animales , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/terapia , Humanos , Estrongiloidiasis/diagnóstico , Estrongiloidiasis/inmunología , Estrongiloidiasis/terapiaRESUMEN
Isolated cerebellar mass lesion is an uncommon presentation of toxoplasmosis. The authors report one rare case in a 50-year-old HIV-infected male patient who presented with clipped speech, gait ataxia and incoordination. The cerebellar toxoplasmosis was suspected based on imaging findings, despite the atypical location. This case highlights the need for a high index of clinical suspicion among HIV-infected patients with neurological manifestations and suspicious neuroimaging findings.