Manipulative neuroparasites: uncovering the intricacies of neurological host control.

Manipulative neuroparasites are a fascinating group of organisms that possess the ability to hijack the nervous systems of their hosts, manipulating their behavior in order to enhance their own survival and reproductive success. This review provides an overview of the different strategies employed by manipulative neuroparasites, ranging from viruses to parasitic worms and fungi. By examining specific examples, such as Toxoplasma gondii, Leucochloridium paradoxum, and Ophiocordyceps unilateralis, we highlight the complex mechanisms employed by these parasites to manipulate their hosts' behavior. We explore the mechanisms through which these parasites alter the neural processes and behavior of their hosts, including the modulation of neurotransmitters, hormonal pathways, and neural circuits. This review focuses less on the diseases that neuroparasites induce and more on the process of their neurological manipulation. We also investigate the fundamental mechanisms of host manipulation in the developing field of neuroparasitology, which blends neuroscience and parasitology. Finally, understanding the complex interaction between manipulative neuroparasites and their hosts may help us to better understand the fundamentals of behavior, neurology, and host-parasite relationships.

Biochemical and apoptotic changes in the nervous and ovotestis tissues of Biomphalaria alexandrina following infection with Schistosoma mansoni.

Infection with trematodes produces physiological and behavioural changes in intermediate snail hosts. One response to infection is parasitic castration, in which energy required for reproduction of the host is thought to be redirected to promote development and multiplication of the parasite. This study investigated some reproductive and biochemical parameters in the nervous (CNS) and ovotestis (OT) tissues of Biomphalaria alexandrina during the course of Schistosoma mansoni infection. Antioxidant and oxidative stress parameters including catalase (CAT), nitric oxide (NO) and lipid peroxidation (MDA) were measured. Levels of steroid hormones, including testosterone, progesterone and estradiol, were also assessed. Finally, flow cytometry was used to compare measures of apoptosis between control snails and those shedding cercariae by examining mitochondrial membrane potential with the stain 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1) and poly(ADP-ribose) polymerase (PARP). Infection with S. mansoni caused a 47.7% reduction in the net reproductive rate (Ro) of B. alexandrina. CAT activity was increased in the CNS at 21 days post infection (dpi) but by 28 dpi it was reduced below control values. Also, CAT activity increased significantly in the OT at 14, 21 and 28 dpi. In CNS tissues, NO levels were reduced at 7 dpi, increased at 14 and 21 dpi, and reduced again at 28 dpi. The overall level of lipid peroxidation gradually increased during the course of infection to reach its highest levels at 28 dpi. Steroid hormone measurements showed that concentrations of testosterone and estradiol were reduced in the CNS tissues at 28 dpi, while those of progesterone were slightly increased in the CNS and OT tissues. The percentage of cells that positively stained with JC-1was significantly increased in CNS and OT tissues of infected snails while the percentage of cells positively stained with PARP was decreased compared to controls. Together, these findings indicate that infection initiates diverse biochemical and hormonal changes leading to loss of cells responsible for egg laying and reproduction in B. alexandrina.

Neuroparasitology of Parasite-Insect Associations.

Insect behavior can be manipulated by parasites, and in many cases, such manipulation involves the central and peripheral nervous system. Neuroparasitology is an emerging branch of biology that deals with parasites that can control the nervous system of their host. The diversity of parasites that can manipulate insect behavior ranges from viruses to macroscopic worms and also includes other insects that have evolved to become parasites (notably, parasitic wasps). It is remarkable that the precise manipulation observed does not require direct entry into the insect brain and can even occur when the parasite is outside the body. We suggest that a spatial view of manipulation provides a holistic approach to examining such interactions. Integration across approaches from natural history to advanced imaging techniques, omics, and experiments will provide new vistas in neuroparasitology. We also suggest that for researchers interested in the proximate mechanisms of insect behaviors, studies of parasites that have evolved to control such behavior is of significant value.

Circumventricular Organs and Parasite Neurotropism: Neglected Gates to the Brain?

Circumventricular organs (CVOs), neural structures located around the third and fourth ventricles, harbor, similarly to the choroid plexus, vessels devoid of a blood-brain barrier (BBB). This enables them to sense immune-stimulatory molecules in the blood circulation, but may also increase chances of exposure to microbes. In spite of this, attacks to CVOs by microbes are rarely described. It is here highlighted that CVOs and choroid plexus can be infected by pathogens circulating in the bloodstream, providing a route for brain penetration, as shown by infections with the parasites Trypanosoma brucei. Immune responses elicited by pathogens or systemic infections in the choroid plexus and CVOs are briefly outlined. From the choroid plexus trypanosomes can seed into the ventricles and initiate accelerated infiltration of T cells and parasites in periventricular areas. The highly motile trypanosomes may also enter the brain parenchyma from the median eminence, a CVO located at the base of the third ventricle, by crossing the border into the BBB-protected hypothalamic arcuate nuclei. A gate may, thus, be provided for trypanosomes to move into brain areas connected to networks of regulation of circadian rhythms and sleep-wakefulness, to which other CVOs are also connected. Functional imbalances in these networks characterize human African trypanosomiasis, also called sleeping sickness. They are distinct from the sickness response to bacterial infections, but can occur in common neuropsychiatric diseases. Altogether the findings lead to the question: does the neglect in reporting microbe attacks to CVOs reflect lack of awareness in investigations or of gate-opening capability by microbes?

[Neuroendocrine effects of helminthiases (A review)].

Nowadays the number of patients diagnosed with helminthiases shows tendency for steady growth around the world. During last few years, researches in the field of immunology have again turned their attention towards the question of parasitological immunity and tissue response. Helminthiases and other parasitic diseases in some instances can induce central nervous system disorders and violate human behavioral reactions. Studies have suggested an association between epilepsy and helminth infection, but a causal relationship is not established in many helminths, except perhaps with neurocysticercosis. The aim of this review is to reveal details of specific mechanisms of the general helminths' impact on the nervous system and the endocrine control level of physiological functions of the host organism. Finally, we discuss the current gaps in knowledge about the interaction between helminths, immunity, and human endocrine system. Key words: helminths, immunity, hormones, cytokines.

Having bird schistosomes in mind-the first detection of Bilharziella polonica (Kowalewski 1895) in the bird neural system.

Nasal bird schistosomes can cause bilharziosis in birds and have the potential to cause swimmer's itch in humans. We determined the prevalence of bird schistosomes in 106 mallards (Anas plathyrhynchos) from 11 water sources in Germany from 2014. Dissections were performed focusing on parasitic infections of the neural system. Infections with Trichobilharzia regenti (Horák et al. 1998) were found in 21% of the birds (n = 22), whereas Bilharziella polonica (Kowalewski 1895) were found between the brain membranes (meninges) and the brain, in the spinal cord or in the intestine of 12% of the mallards (n = 13). No significant influence of sex, age, and body condition between infected and non-infected animals was observed. Our study provides the first description of B. polonica from the neural system of birds and provides an epidemiological understanding of a parasite of human health concern.

Involvement of the nervous system following experimental infection with Pasteurella multocida B:2 in buffalo (Bubalus bubalis): A clinicopathological study.

Haemorrhagic septicaemia (HS) is an acute, fatal, septicaemic disease of cattle and buffaloes caused by one of two specific serotypes of Pasteurella multocida B:2 and E:2 in Asian and African, respectively. It is well known that HS affect mainly the respiratory and digestive tracts. However, involvement of the nervous system in pathogenesis of HS has been reported in previous studies without details. In this study, nine buffalo calves of 8 months old were distributed into three groups. Animals of Group 1 and 2 were inoculated orally and subcutaneously with 10 ml of 1 × 10(12) cfu/ml of P. multocida B:2, respectively, while animals of Group 3 were inoculated orally with 10 ml of phosphate buffer saline as a control. All calves in Group 1 and Group 3 were euthanised after 504 h (21 day) post-infection, while calves in Group 2 had to euthanise after 12 h post-infection as they develop sever clinical signs of HS. Significant differences were found in Group 2 in the mean scores of clinical signs, gross and histopathological changes which mainly affect different anatomic regions of the nervous system. In addition, successful bacterial isolation of P. multocida B:2 were obtained from different sites of the nervous system. On the other hand, less sever, clinical, gross and histopathological changes were found in Group 1. These results provide for the first time strong evidence of involving of the nervous system in pathogenesis of HS, especially in the peracute stage of the disease.

Pathogenesis of Taenia solium taeniasis and cysticercosis.

Taenia solium infections (taeniasis/cysticercosis) are a major scourge to most developing countries. Neurocysticercosis, the infection of the human nervous system by the cystic larvae of this parasite, has a protean array of clinical manifestations varying from entirely asymptomatic infections to aggressive, lethal courses. The diversity of clinical manifestations reflects a series of contributing factors which include the number, size and location of the invading parasites, and particularly the inflammatory response of the host. This manuscript reviews the different presentations of T. solium infections in the human host with a focus on the mechanisms or processes responsible for their clinical expression.

In vitro infection of human nervous cells by two strains of Toxoplasma gondii: a kinetic analysis of immune mediators and parasite multiplication.

The severity of toxoplasmic infection depends mainly on the immune status of the host, but also on the Toxoplasma gondii strains, which differ by their virulence profile. The relationship between the human host and T. gondii has not yet been elucidated because few studies have been conducted on human models. The immune mechanisms involved in the persistence of T. gondii in the brains of immunocompetent subjects and during the reactivation of latent infections are still unclear. In this study, we analyzed the kinetics of immune mediators in human nervous cells in vitro, infected with two strains of T. gondii. Human neuroblast cell line (SH SY5Y), microglial (CMH5) and endothelial cells (Hbmec) were infected separately by RH (type I) or PRU (type II) strains for 8 h, 14 h, 24 h and 48 h (ratio 1 cell: 2 tachyzoites). Pro-inflammatory protein expression was different between the two strains and among different human nervous cells. The cytokines IL-6, IL-8 and the chemokines MCP-1 and GROα, and SERPIN E1 were significantly increased in CMH5 and SH SY5Y at 24 h pi. At this point of infection, the parasite burden declined in microglial cells and neurons, but remained high in endothelial cells. This differential effect on the early parasite multiplication may be correlated with a higher production of immune mediators by neurons and microglial cells compared to endothelial cells. Regarding strain differences, PRU strain, but not RH strain, stimulates all cells to produce pro-inflammatory growth factors, G-CSF and GM-CSF. These proteins could increase the inflammatory effect of this type II strain. These results suggest that the different protein expression profiles depend on the parasitic strain and on the human nervous cell type, and that this could be at the origin of diverse brain lesions caused by T. gondii.

Comparing mechanisms of host manipulation across host and parasite taxa.

Parasites affect host behavior in several ways. They can alter activity, microhabitats or both. For trophically transmitted parasites (the focus of our study), decreased activity might impair the ability of hosts to respond to final-host predators, and increased activity and altered microhabitat choice might increase contact rates between hosts and final-host predators. In an analysis of trophically transmitted parasites, more parasite groups altered activity than altered microhabitat choice. Parasites that infected vertebrates were more likely to impair the host's reaction to predators, whereas parasites that infected invertebrates were more likely to increase the host's contact with predators. The site of infection might affect how parasites manipulate their hosts. For instance, parasites in the central nervous system seem particularly suited to manipulating host behavior. Manipulative parasites commonly occupy the body cavity, muscles and central nervous systems of their hosts. Acanthocephalans in the data set differed from other taxa in that they occurred exclusively in the body cavity of invertebrates. In addition, they were more likely to alter microhabitat choice than activity. Parasites in the body cavity (across parasite types) were more likely to be associated with increased host contact with predators. Parasites can manipulate the host through energetic drain, but most parasites use more sophisticated means. For instance, parasites target four physiological systems that shape behavior in both invertebrates and vertebrates: neural, endocrine, neuromodulatory and immunomodulatory. The interconnections between these systems make it difficult to isolate specific mechanisms of host behavioral manipulation.

The Chagas' disease parasite Trypanosoma cruzi exploits nerve growth factor receptor TrkA to infect mammalian hosts.

Trypanosoma cruzi, the agent of Chagas' disease, is an obligate intracellular parasite that invades various organs including several cell types in the nervous system that express the Trk receptor tyrosine kinase. Activation of Trk is a major cell-survival and repair mechanism, and parasites could use Trks to invade cells as a strategy to protect their habitat and prolong parasitism of vertebrate hosts. We show that T. cruzi binds to TrkA specifically and activates TrkA-dependent survival mechanisms. This interaction facilitates parasite adherence and promotes efficient invasion of neuronal, epithelial, and phagocytic cells via a process that requires TrkA kinase activity. Diffusible TrkA and TrkA-blocking agents neutralized infection in cellular and animal models of acute Chagas' disease, suggesting cellular receptors as therapeutic targets against parasitic diseases. Thus, TrkA, the nerve growth factor receptor commonly associated with neural survival and protection, may also underlie clinical progression of an important human parasitic disease.

Comparison of Sarcocystis neurona isolates derived from horse neural tissue.

Sarcocystis neurona is a protozoan parasite that can cause neurological deficits in infected horses. The route of transmission is by fecal-oral transfer of sporocysts from opossums. However, the species identity and the lifecycle are not completely known. In this study, Sarcocystis merozoites from eight isolates obtained from Michigan horses were compared to S. neurona from a California horse (UCD1), Sarcocystis from a grackle (Cornell), and five Sarcocystis isolates from feral opossums from Michigan. Comparisons were made using several techniques. SDS-PAGE analysis with silver staining showed that Sarcocystis spp. from the eight horses appeared the same, but different from the grackle isolate. One Michigan horse isolate (MIH6) had two bands at 72 and 25kDa that were more prominent than the UCD1 isolate and other Michigan horse isolates. Western blot analysis showed that merozoites of eight of eight equine-derived isolates, and the UCD1 S. neurona isolate had similar bands when developed with serum or CSF of an infected horse. Major bands were seen at 60, 44, 30, and 16kDa. In the grackle (Cornell) isolate, bands were seen at 60, 44, 29, and 16kDa. DNA from merozoites of each of the eight equine-derived isolates and the grackle-derived isolate produced a 334bp PCR product (Tanhauser et al., 1999). Restriction fragment length polymorphism (RFLP) analysis of these horse isolates showed banding patterns characteristic for S. neurona. The grackle (Cornell) isolate had an RFLP banding pattern characteristic of other S. falcatula species. Finally, electron microscopy examining multiple merozoites of each of these eight horse isolates showed similar morphology, which differed from the grackle (Cornell) isolate. We conclude that the eight Michigan horse isolates are S. neurona species and the grackle isolate is an S. falcatula species.

The range and biological activity of FMRFamide-related peptides and classical neurotransmitters in nematodes.

Nematodes include both major parasites of humans, livestock and plants in addition to free-living species such as Caenorhabditis elegans. The nematode nervous system (especially in C. elegans) is exceptionally well defined in terms of the number, location and projections of the small number of neurons in the nervous system and their integration into circuits involved in regulatory behaviours vital to their survival. This review will summarize what is known about the biological activity of neurotransmitters in nematodes: the biosynthetic pathways and genes involved, their receptors, inactivation mechanisms and secondary messenger signalling systems. It will cover the 'classical' transmitters, such as acetylcholine (ACh), GABA, glutamate, serotonin, dopamine, octopamine, noradrenaline and nitric oxide. The localization of peptides throughout the nematode nervous system is summarized, in addition to the isolation of nematode neuropeptides by both traditional biochemical techniques and more modern genetic means. The major contribution of the completion of the C. elegans genome-sequencing program is highlighted throughout. Efforts to unravel neurotransmitter action in various physiological actions such as locomotion, feeding and reproduction are detailed as well as the various inactivation mechanisms for the current complement of nematode transmitters.

Tissue migration of Elaphostrongylus spp. in guinea pigs (Cavia porcellus).

Third-stage larvae of Elaphostrongylus cervi, originating from red deer (Cervus elaphus), first reached the central nervous system (CNS) of guinea pigs (Cavia porcellus) 11 days postinfection (DPI). Neurologic signs were seen between 11 and 62 DPI in 4 of a total of 18 infected guinea pigs killed up to 112 DPI. Animals showing signs had 3 or more larvae in the CNS. Only 1, of a total of 1,114 larvae recovered, had developed to the fourth stage at 40 DPI. A direct tissue migration by third-stage larvae to the CNS was revealed by pressing and digesting almost all body tissues and by histological examination. Larvae penetrated through the stomach wall into the peritoneal cavity and then through the diaphragm into the pleural cavity. Many became encapsulated by inflammatory cells in the omentum, abdominal mesentery, mediastinum, and just beneath the liver capsule and lung pleura. A total of 44 larvae succeeded in reaching the CNS, apparently by migrating from the body cavities into muscles of the lateral body wall and entering the vertebral canal, likely along spinal nerves. Data were not consistent with a hematogenous migratory route that has been proposed previously. Few third-stage larvae of E. alces, originating from moose (Alces alces), were able to penetrate the gut of guinea pigs and none reached the CNS.

Neurobiology of cerebral malaria and African sleeping sickness.

This review is aimed at emphasizing the need for basic neuroscience research on two tropical diseases, malaria and sleeping sickness (African trypanosomiasis), that still represent major health problems and in which severe involvement of the nervous system is frequently the direct cause of death. The life cycles of the two parasites, the protozoan Plasmodium and Trypanosoma brucei, which are the causative agents of malaria and sleeping sickness, respectively, are briefly reviewed. The historical contribution to the pathogenesis and therapy of malaria by a renowned pioneer in neuroscience, Camillo Golgi, is pointed out. The different strategies for survival in the host by the intracellular Plasmodium and the extracellular African trypanosomes are summarized; such strategies include sites favorable for hiding or replication of the parasites in the host, antigenic variation, and interactions with the cytokine network of the host. In particular, tumor necrosis factor-alpha and interferon-gamma may play a role in these infections. The parasites may paradoxically interact with cytokines to their benefit. However, cytokine receptors are expressed on neuronal subsets sensitive to cytokine action, and stimulation of these subsets may cause neuronal dysfunctions during the infections. Finally, the clinical symptoms of cerebral malaria and African trypanosomiasis and research aiming at deciphering their pathogenetic mechanisms that could affect the nervous system at a molecular level are described. The need for neuroscientists in this endeavor is emphasized.

Current research on Sarcocystis species of domestic animals.

The genus Sarcocystis is composed of about 130 species of heteroxenous cyst-forming coccidia with differences in life cycle and pathogenicity. Pathogenic Sarcocystis spp. can cause disease in their intermediate hosts, in particular in ruminants. Research on Sarcocystis infections has been impeded by several facets of the parasites. Intermediate as well as definitive hosts can be parasitized by several different species with similarities in biology and morphology. Antigen preparations derived from pathogenic Sarcocystis spp. are highly cross-reactive with antibodies directed against non-pathogenic species. As a consequence, none of the currently available immunological tests is species-specific and can differentiate between pathogenic and non-pathogenic Sarcocystis spp. Over the last decade, new techniques in immunology, protein chemistry and molecular biology have facilitated more advanced studies on the molecular composition and molecular biology of Sarcocystis spp. in various laboratories. The development of species-specific monoclonal antibodies and analyses of the molecular composition of some life-cycle stages of Sarcocystis spp. of cattle and sheep showed that species-specific proteins and antigens exist in these species, although they are not highly abundant. In addition, comparisons of rRNA genes of different Sarcocystis spp. identified unique sequences in the rRNA of pathogenic Sarcocystis spp. that are suitable targets for species-specific identification. Thus, tools have become available that facilitate the development of methods for species-specific identification and differentiation of Sarcocystis spp. as well as the identification and study of molecules that are associated with pathogenicity of some of these parasites.