Neofunctionalization of an ancient domain allows parasites to avoid intraspecific competition by manipulating host behaviour.

Intraspecific competition is a major force in mediating population dynamics, fuelling adaptation, and potentially leading to evolutionary diversification. Among the evolutionary arms races between parasites, one of the most fundamental and intriguing behavioural adaptations and counter-adaptations are superparasitism and superparasitism avoidance. However, the underlying mechanisms and ecological contexts of these phenomena remain underexplored. Here, we apply the Drosophila parasite Leptopilina boulardi as a study system and find that this solitary endoparasitic wasp provokes a host escape response for superparasitism avoidance. We combine multi-omics and in vivo functional studies to characterize a small set of RhoGAP domain-containing genes that mediate the parasite's manipulation of host escape behaviour by inducing reactive oxygen species in the host central nervous system. We further uncover an evolutionary scenario in which neofunctionalization and specialization gave rise to the novel role of RhoGAP domain in avoiding superparasitism, with an ancestral origin prior to the divergence between Leptopilina specialist and generalist species. Our study suggests that superparasitism avoidance is adaptive for a parasite and adds to our understanding of how the molecular manipulation of host behaviour has evolved in this system.

Didelphis albiventris as a carrier of Leptospira sp. in the central nervous tissue in the semiarid region of Northeast, Brazil.

Leptospirosis has been investigated in several species of wild animals. The white-eared opossum (Didelphis albiventris) is a mammal common in the brazilian semi-arid, so, this study aimed to investigate its role in the occurrence of the leptospirosis in the region Northeast of Brazil. 12 animals were used, from which samples were collected for the attempt of isolation, molecular detection and serological examination. There was no microbial growth, nor were any anti-Leptospira sp. antibodies found in the serological samples. The PCR detected leptospiric DNA in the central nervous system (CNS) of five animals (41.7 %). The gene in one of the samples was sequenced and showed identity with Leptospira interrogans. The presence of Leptospira sp. in the CNS of Didelphis albiventris does not allow the characterization of the studied animals as reservoirs with potential for transmission of the pathogen in the region, however it represents a site that needs to be further investigated.

Nitric oxide debilitates the neuropathogenic schistosome Trichobilharzia regenti in mice, partly by inhibiting its vital peptidases.

BACKGROUND: Avian schistosomes, the causative agents of human cercarial dermatitis (or swimmer's itch), die in mammals but the mechanisms responsible for parasite elimination are unknown. Here we examined the role of reactive nitrogen species, nitric oxide (NO) and peroxynitrite, in the immune response of mice experimentally infected with Trichobilharzia regenti, a model species of avian schistosomes remarkable for its neuropathogenicity. METHODS: Inducible NO synthase (iNOS) was localized by immunohistochemistry in the skin and the spinal cord of mice infected by T. regenti. The impact of iNOS inhibition by aminoguanidine on parasite burden and growth was then evaluated in vivo. The vulnerability of T. regenti schistosomula to NO and peroxynitrite was assessed in vitro by viability assays and electron microscopy. Additionally, the effect of NO on the activity of T. regenti peptidases was tested using a fluorogenic substrate. RESULTS: iNOS was detected around the parasites in the epidermis 8 h post-infection and also in the spinal cord 3 days post-infection (dpi). Inhibition of iNOS resulted in slower parasite growth 3 dpi, but the opposite effect was observed 7 dpi. At the latter time point, moderately increased parasite burden was also noticed in the spinal cord. In vitro, NO did not impair the parasites, but inhibited the activity of T. regenti cathepsins B1.1 and B2, the peptidases essential for parasite migration and digestion. Peroxynitrite severely damaged the surface tegument of the parasites and decreased their viability in vitro, but rather did not participate in parasite clearance in vivo. CONCLUSIONS: Reactive nitrogen species, specifically NO, do not directly kill T. regenti in mice. NO promotes the parasite growth soon after penetration (3 dpi), but prevents it later (7 dpi) when also suspends the parasite migration in the CNS. NO-related disruption of the parasite proteolytic machinery is partly responsible for this effect.

Neurochagas: atualização clínica / Neurochagas: clinical update

A doença de Chagas ainda é uma doença tropical muito prevalente no Brasil. Pode apresentar duas fases (aguda e crônica) e exibe grandes repercussões, sobretudo as que envolvem o sistema nervoso periférico e/ou central. Com o aumento do número de pessoas vivendo em estado (transitório ou permanente) de imunossupressão, os casos de manifestações neurológicas por neurochagas aumentaram, e este tornou-se um importante diagnóstico diferencial com outras doenças oportunistas. Este artigo teve como objetivo revisar os principais aspectos clínicos e terapêuticos da doença de Chagas no sistema nervoso central.

Chagas disease is still a very prevalent tropical disease in Brazil. It can have two phases - acute and chronic ­ and shows major repercussions, especially those involving the peripheral and/ or central nervous system. With the increase in the number of people living in the (transient or permanent) state of immunosuppression the cases of neurological manifestations of Chagas disease increased and this became an important differential diagnosis with other opportunistic diseases. This article aimed to review the main clinical and therapeutic aspects of central nervous system Chagas disease

The ROP16III-dependent early immune response determines the subacute CNS immune response and type III Toxoplasma gondii survival.

Toxoplasma gondii is an intracellular parasite that persistently infects the CNS and that has genetically distinct strains which provoke different acute immune responses. How differences in the acute immune response affect the CNS immune response is unknown. To address this question, we used two persistent Toxoplasma strains (type II and type III) and examined the CNS immune response at 21 days post infection (dpi). Contrary to acute infection studies, type III-infected mice had higher numbers of total CNS T cells and macrophages/microglia but fewer alternatively activated macrophages (M2s) and regulatory T cells (Tregs) than type II-infected mice. By profiling splenocytes at 5, 10, and 21 dpi, we determined that at 5 dpi type III-infected mice had more M2s while type II-infected mice had more pro-inflammatory macrophages and that these responses flipped over time. To test how these early differences influence the CNS immune response, we engineered the type III strain to lack ROP16 (IIIΔrop16), the polymorphic effector protein that drives the early type III-associated M2 response. IIIΔrop16-infected mice showed a type II-like neuroinflammatory response with fewer infiltrating T cells and macrophages/microglia and more M2s and an unexpectedly low CNS parasite burden. At 5 dpi, IIIΔrop16-infected mice showed a mixed inflammatory response with more pro-inflammatory macrophages, M2s, T effector cells, and Tregs, and decreased rates of infection of peritoneal exudative cells (PECs). These data suggested that type III parasites need the early ROP16-associated M2 response to avoid clearance, possibly by the Immunity-Related GTPases (IRGs), which are IFN-γ- dependent proteins essential for murine defenses against Toxoplasma. To test this possibility, we infected IRG-deficient mice and found that IIIΔrop16 parasites now maintained parental levels of PECs infection. Collectively, these studies suggest that, for the type III strain, rop16III plays a key role in parasite persistence and influences the subacute CNS immune response.

Impact of Interleukin-27p28 on T and B Cell Responses during Toxoplasmosis.

Interleukin-27 (IL-27) is a heterodimeric cytokine composed of the subunits IL-27p28 and EBi3, and while the IL-27 heterodimer influences T cell activities, there is evidence that IL-27p28 can have EBi3-independent activities; however, their relevance to infection is unclear. Therefore, the studies presented here compared how IL-27p28 transgenics and IL-27p28-/- mice responded to the intracellular parasite Toxoplasma gondii While the loss of IL-27p28 and its overexpression both result in increased susceptibility to T. gondii, the basis for this phenotype reveals distinct roles for IL-27p28. As a component of IL-27, IL-27p28 is critical to limit infection-induced T cell-mediated pathology, whereas the ectopic expression of IL-27p28 reduced the effector T cell population and had a major inhibitory effect on parasite-specific antibody titers and a failure to control parasite replication in the central nervous system. Indeed, transfer of immune serum to infected IL-27p28 transgenics resulted in reduced parasite burden and pathology. Thus, IL-27p28, independent of its role as a component of IL-27, can act as a negative regulator of humoral and cellular responses during toxoplasmosis.

[Infections of the central nervous system by protozoa, helminths and fungi]. / Infektionen des zentralen Nervensystems durch Protozoen, Würmer und Pilze.

A plethora of different parasites and fungi can lead to infections of the central nervous system (CNS) and cause different clinical symptoms and outcomes depending on the pathogen and the anatomic location of the infection. The diagnosis and treatment of these eukaryotic infections is challenging. The prevalence of CNS infections depends on many factors, including geographical location, living conditions, genetic background and the immune status of the individual. In Germany, infections of the CNS by fungi and parasites are rare but can lead to considerable morbidity. Some parasitic and fungal CNS infections are becoming increasingly more prevalent and clinically relevant due to the increasing number of immunocompromised people. Case fatality rates of these infections, which are difficult to diagnose and to treat, are high. This article provides an overview of a subjective selection of parasitic and fungal infections of the CNS relevant to clinical practice in Germany and presents the diagnostic and therapeutic options.

Toxoplasmosis: A pathway to neuropsychiatric disorders.

Toxoplasma gondii is an obligate intracellular parasite that resides, in a latent form, in the human central nervous system. Infection with Toxoplasma drastically alters the behaviour of rodents and is associated with the incidence of specific neuropsychiatric conditions in humans. But the question remains: how does this pervasive human pathogen alter behaviour of the mammalian host? This fundamental question is receiving increasing attention as it has far reaching public health implications for a parasite that is very common in human populations. Our current understanding centres on neuronal changes that are elicited directly by this intracellular parasite versus indirect changes that occur due to activation of the immune system within the CNS, or a combination of both. In this review, we explore the interactions between Toxoplasma and its host, the proposed mechanisms and consequences on neuronal function and mental health, and discuss Toxoplasma infection as a public health issue.

Case Report: Central Nervous System Strongyloidiasis: Two Cases Diagnosed Antemortem.

Central nervous system (CNS) strongyloidiasis is a known but rare form of disseminated infection. The diagnosis is often made postmortem, with only five published cases of an antemortem diagnosis. We report two fatal cases of CNS strongyloidiasis diagnosed antemortem, with Strongyloides stercoralis larvae visualized in the CNS sample in one case. Risk factors for disseminated strongyloidiasis common to both cases included origination from the Caribbean, underlying human T-lymphotropic virus-1 infection, and recent prednisone use. Both cases occurred in Canada, where the occurrence of Strongyloides is uncommon, and serve as a reminder to maintain a high index of suspicion in patients with epidemiologic or clinical risk factors for dissemination.

Detection of Taenia solium DNA in the Urine of Neurocysticercosis Patients.

Neurocysticercosis (NCC), caused by Taenia solium larvae that reside in the central nervous system, results in serious public health and medical issues in many regions of the world. Current diagnosis of NCC is complex requiring both serology and costly neuroimaging of parasitic cysts in the brain. This diagnostic pipeline can be problematic in resource-constrained settings. There is an unmet need for a highly sensitive and clinically informative diagnostic test to complement the present diagnostic approaches. Here, we report that T. solium-derived cell-free DNA is readily detectable in the urine of patients with the subarachnoid and parenchymal forms of NCC, and discuss the potential utility of this approach in enhancing and refining T. solium diagnostics.

Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies.

Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.

Helminthic Infections of the Central Nervous System.

PURPOSE OF REVIEW: This article discusses select helminthic parasitic infections that may affect the central nervous system and reviews the epidemiology, neurologic presentation, recommended diagnostic testing, and treatment approach to these infections. RECENT FINDINGS: Emigration from and travel to areas endemic for helminthic infections that affect the nervous system has led to increased incidence of parasitic neurologic disease in developed countries, necessitating that neurologists be familiar with the diagnostic and therapeutic approach to these diseases. Evidence is emerging on the optimal treatment for neurocysticercosis, which varies based on the form of the disease in the nervous system. SUMMARY: Parenchymal neurocysticercosis is a leading cause of acquired epilepsy worldwide, and extraparenchymal neurocysticercosis is responsible for many cases of hydrocephalus. Recognition of the different stages and locations of neurocysticercosis is essential for proper management. Similarly, schistosomiasis constitutes a major cause of myelopathy in endemic areas and requires prompt diagnosis and treatment to avoid permanent deficits.

Morphological changes, nitric oxide production, and phagocytosis are triggered in vitro in microglia by bloodstream forms of Trypanosoma brucei.

The flagellated parasite Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (HAT). By a mechanism not well understood yet, trypanosomes enter the central nervous system (CNS), invade the brain parenchyma, and cause a fatal encephalopathy if is not treated. Trypanosomes are fast dividing organisms that, without any immune response, would kill the host in a short time. However, infected individuals survive either 6-12 months or more than 3 years for the acute and chronic forms, respectively. Thus, only when the brain defense collapses a lethal encephalopathy will occur. Here, we evaluated interactions between trypanosomes and microglial cells, which are the primary immune effector cells within the CNS. Using co-cultures of primary microglia and parasites, we found clear evidences of trypanosome phagocytosis by microglial cells. Microglia activation was also evident; analysis of its ultrastructure showed changes that have been reported in activated microglia undergoing oxidative stress caused by infections or degenerative diseases. Accordingly, an increase of the nitric oxide production was detected in supernatants of microglia/parasite co-cultures. Altogether, our results demonstrate that microglial cells respond to the presence of the parasite, leading to parasite's engulfment and elimination.

A gel-free proteomic analysis of Taenia solium and Taenia crassiceps cysticerci vesicular extracts.

The taeniasis/cysticercosis complex is a zoonosis caused by the presence of the parasite Taenia solium in humans. It is considered a neglected disease that causes serious public health and economic problems in developing countries. In humans, the most common locations for the larval form are the skeletal muscles, ocular system, and the central nervous system, which is the most clinically important. Several glycoproteins of T. solium and Taenia crassiceps cysticerci have been characterized and studied for their use in the immunodiagnosis of neurocysticercosis and/or the development of synthetic or recombinant vaccines against cysticercosis. The aim of this study was to perform a gel-free shotgun proteomic analysis to identify saline vesicular extract (SVE) proteins of T. solium and T. crassiceps cysticerci. After solubilization of the SVE with and without surfactant reagent and in-solution digestion, the proteins were analyzed by LC-MS/MS. Use of a surfactant resulted in a significantly higher number of proteins that were able to be identified by LC-MS/MS. Novel proteins were identified in T. solium and T. crassiceps SVE. The qualitative analysis revealed a total of 79 proteins in the Taenia species: 29 in T. solium alone, 11 in T. crassiceps alone, and 39 in both. These results are an important contribution to support future investigations and for establishing a Taenia proteomic profile to study candidate biomarkers involved in the diagnosis or pathogenesis of neurocysticercosis.

No association of IL2, IL4, IL6, TNF, and IFNG gene polymorphisms was found with Taenia solium human infection or neurocysticercosis severity in a family-based study.

Neurocysticercosis (NC) is caused by the establishment of the metacestode stage of Taenia solium in the human central nervous system. A great heterogeneity in the susceptibility to the infection and to the disease has been reported. While the factors involved in this heterogeneity are not completely understood, clearly different immune-inflammatory profiles have been associated to each condition. This study evaluated the association of cytokine single nucleotide polymorphisms (SNPs) with susceptibility to infection and disease severity in NC patients. Blood samples from 92 NC cases and their parents (trios) were genotyped for SNPs in five cytokines relevant for the immune response: IL4 (-589C/T), IL6 (-174C/G), IFNG (+874T/A), TNF (-238G/A), and IL2 (-330G/T). Specific DNA fragments were amplified by the polymerase chain reaction, using the 5'-nuclease Taqman assay on a 7500 platform, allowing the detection of the polymorphism genotypes. No association between the polymorphisms evaluated neither with susceptibility to infection nor with disease severity was found, although previous studies reported variations in the levels of these cytokines among different NC clinical pictures. These results, nevertheless, add new elements to our understanding of the complex pathogenic mechanisms involved in susceptibility to infection by T. solium cysticerci and the severity of the ensuing disease.

Paciente puérpera diagnosticada de neurocisticercosis. A propósito de un caso y revisión de la literatura / Puerperal patient diagnosed with neurocysticercosis. About a case and review of the literature

La neurocisticercosis es una enfermedad infecciosa parasitaria rara en nuestro medio producida por la Taenia solium. En los últimos años, la incidencia de la neurocisticercosis ha sufrido un repunte por el aumento de inmigrantes procedentes de países endémicos. Los cisticercos presentan una especial predisposición para afectar al sistema nervioso central con la formación de nódulos quísticos que provocan inflamación de las zonas adyacentes pudiendo producir crisis comiciales. Presentamos el caso de una paciente puérpera de 3 días con un episodio de crisis comicial acompañada de fiebre. Se diagnostica por resonancia magnética nuclear cerebral de neurocisticercosis (AU)

Neurocysticercosis is a parasitic infectious disease rare in our Midst produced by Taenia solium. In recent years, the incidence of neurocysticercosis has been rebounded by an increase in immigrants from endemic countries. The cysticerci have a special predisposition to affect the central nervous system with the formation of cystic nodules that causes inflammation of the adjacent areas, these could produce comitial crises. We present the case of a puerperal patient of 3 days of evolution who presented an episode of comitial crisis accompanied by fever who was diagnosed by cerebral magnetic resonance imaging of neurocysticercosis (AU)

Infection by the nematode Angiostrongylus cantonensis induces differential expression of miRNAs in mouse brain.

BACKGROUND: The parasitic nematode Angiostrongylus cantonensis is the primary pathogen causing eosinophilic meningitis and meningoencephalitis in nonpermissive hosts. The larval parasites are eliminated by the host's immune responses in the central nervous system (CNS) through infiltration of eosinophils and lymphocytes. This study aimed to determine primary alterations of microRNA (miRNA) during A. cantonensis infection in mice. METHODS: miRNA array was used to analyze the expression of miRNA in uninfected and A. cantonensis-infected mouse brains at 21 days postinfection (dpi). Target genes were predicted by miRDB software, and protein-protein interaction network was analyzed using STRING v9.1. Expression levels of selected miRNAs and cytokine production were verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Twenty-five mature miRNAs showed differential expression in infected mouse brains, of which 24 were upregulated and one was downregulated compared to the uninfected control. These 25 miRNAs were divided into five clusters, and the first upregulated cluster was selected for further bioinformatics analysis. Target gene prediction and gene ontology (GO) enrichment analysis revealed that the miRNAs were mainly related to the immune response. Furthermore, six target genes of mmu-miR-146a-5p were predicted to interact with tumor necrosis factor alpha (TNF-α). The in vitro study suggested that transfected mmu-miR-146a-5p inhibitor upregulated TNF-α and its target gene Traf6 in microglia following stimulation with A. cantonensis larval antigen. CONCLUSION: This study suggested a critical role of miRNAs in the host defense during A. cantonensis infection, providing new insights into the molecular mechanisms underlying the interaction between mmu-miR-146a-5p and TNF-α in angiostrongyliasis in nonpermissive hosts.

Understanding host-parasite relationship: the immune central nervous system microenvironment and its effect on brain infections.

The central nervous system (CNS) has been recognized as an immunologically specialized microenvironment, where immune surveillance takes a distinctive character, and where delicate neuronal networks are sustained by anti-inflammatory factors that maintain local homeostasis. However, when a foreign agent such as a parasite establishes in the CNS, a set of immune defences is mounted and several immune molecules are released to promote an array of responses, which ultimately would control the infection and associated damage. Instead, a host-parasite relationship is established, in the context of which a close biochemical coevolution and communication at all organization levels between two complex organisms have developed. The ability of the parasite to establish in its host is associated with several evasion mechanisms to the immune response and its capacity for exploiting host-derived molecules. In this context, the CNS is deeply involved in modulating immune functions, either protective or pathogenic, and possibly in parasitic activity as well, via interactions with evolutionarily conserved molecules such as growth factors, neuropeptides and hormones. This review presents available evidence on some examples of CNS parasitic infections inducing different morbi-mortality grades in low- or middle-income countries, to illustrate how the CNS microenvironment affect pathogen establishment, growth, survival and reproduction in immunocompetent hosts. A better understanding of the influence of the CNS microenvironment on neuroinfections may provide relevant insights into the mechanisms underlying these pathologies.