Neurologic Manifestations of<i>Leishmania spp.</i>Infection

Petersen, Christine A.; Greenlee, M. Heather West

doi:10.4303/jnp/n110401

Cited by 25 publications

(22 citation statements)

References 42 publications

(52 reference statements)

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“…The ␤-amyloid peptide and brevican, both found in the brain, bound to all the stationary-phase promastigotes tested and to most procyclic promastigotes. The ability of Leishmania strains to interact with molecules specifically expressed in the brain might be related to reported instances of central or peripheral neurologic manifestations during Leishmania infection both in humans and in animals (51) and to the detection of amastigotes in the central nervous systems of Leishmania-infected hamsters (52). The presence of brain proteins in the interaction repertoire of Leishmania parasites might ease their interaction with the brain environment.…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

et al. 2014

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We have set up an assay to study the interactions of live pathogens with their hosts by using protein and glycosaminoglycan arrays probed by surface plasmon resonance imaging. We have used this assay to characterize the interactions of Leishmania promastigotes with ϳ70 mammalian host biomolecules (extracellular proteins, glycosaminoglycans, growth factors, cell surface receptors). We have identified, in total, 27 new partners (23 proteins, 4 glycosaminoglycans) of procyclic promastigotes of six Leishmania species and 18 partners (15 proteins, 3 glycosaminoglycans) of three species of stationary-phase promastigotes for all the strains tested. The diversity of the interaction repertoires of Leishmania parasites reflects their dynamic and complex interplay with their mammalian hosts, which depends mostly on the species and strains of Leishmania. Stationary-phase Leishmania parasites target extracellular matrix proteins and glycosaminoglycans, which are highly connected in the extracellular interaction network. Heparin and heparan sulfate bind to most Leishmania strains tested, and 6-O-sulfate groups play a crucial role in these interactions. Numerous Leishmania strains bind to tropoelastin, and some strains are even able to degrade it. Several strains interact with collagen VI, which is expressed by macrophages. Most Leishmania promastigotes interact with several regulators of angiogenesis, including antiangiogenic factors (endostatin, anastellin) and proangiogenic factors (ECM-1, VEGF, and TEM8 [also known as anthrax toxin receptor 1]), which are regulated by hypoxia. Since hypoxia modulates the infection of macrophages by the parasites, these interactions might influence the infection of host cells by Leishmania.

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Section: Discussionmentioning

confidence: 99%

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

et al. 2014

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“…This suggests that the L. major parasites managed to cross the immunological blood-brain barrier, which has only rarely been reported for this cutaneous strain with very low levels of parasites detected [63]. However, dissemination of parasites to the central nervous system (CNS) has been frequently observed in visceral Leishmaniasis in both humans and dogs [64]–[67]. It has been suggested that parasites arrive in the CNS via infected leukocytes [65] and/or disruption to the blood brain barrier caused by inflammation [67].…”

Section: Discussionmentioning

confidence: 99%

Deletion of IL-4 Receptor Alpha on Dendritic Cells Renders BALB/c Mice Hypersusceptible to Leishmania major Infection

et al. 2013

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In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11ccreIL-4Rα-/lox) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/lox mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11ccreIL-4Rα-/lox mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions.

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“…The trypanosome Leishmania amazonensis is another parasite that can live in the brain of vertebrates (including humans) and has been associated with behavioral changes in its host (Petersen and Greenlee, 2011;Maia et al, 2015). Recently a study found that experimentally infected mice consistently had several key cytokines (IFN-y, IL-1,4,6,10) down regulated, while tumor necrosis factor alpha (TNF-α) was upregulated in the prefrontal cortex (Portes et al, 2016).…”

Section: Immunological Host Manipulation Immunological Manipulation Omentioning

confidence: 99%

“…However, this idea appears conflicting, as much of the evidence for the neuroimmune hypothesis in vertebrates, comes from cerebral parasites (Hemachudha et al, 2002;Klein, 2003;Bentivoglio and Kristensson, 2007;Sciutto et al, 2007;Hamilton et al, 2008;Henriquez et al, 2009;Petersen and Greenlee, 2011;Holland and Hamilton, 2013;Portes et al, 2016). Logic suggests that a parasite already present in the brain of a host will not have to by-pass the brains defenses in order to manipulate host behavior.…”

Section: Immunological Host Manipulation Immunological Manipulation Omentioning

confidence: 99%

Lessons in Mind Control: Trends in Research on the Molecular Mechanisms behind Parasite-Host Behavioral Manipulation

Herbison

2017

Front. Ecol. Evol.

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Scientific and public interest in host manipulation by parasites has surged over the past few decades, resulting in an exponential growth of cases where potential behavioral manipulation has been identified. However, these studies dwarf the number of genuine attempts to elucidate the mechanistic processes behind this behavioral manipulation. Ultimately, this imbalance has slowed progress in the study of the mechanisms underlying host manipulation. As it stands, research suggests that the mechanisms of host manipulation fall into three categories: immunological, genomic/proteomic and neuropharmacological, and forth potential category: symbioant-mediated manipulation. After exploration of the literature pertaining to these four pathways, four major trends become evident. First and foremost, there is a severe disconnect between the observed molecular and behavioral shifts in a parasitized host. Indeed, very rarely a study demonstrates that molecular changes observed in a host are the result of active manipulation by the resident parasite, or that these molecular changes directly result in behavioral manipulation that increases the parasite's fitness. Secondly, parasites may often employ multiple pathways in unison to achieve control over their hosts. Despite this, current scientific approaches usually focus on each manipulation pathway in isolation rather than integrating them. Thirdly, the relative amount of host-parasite systems yet to be investigated in terms of molecular manipulation is staggering. Finally, as a result of the aforementioned trends, guiding mechanisms or principles for the multiple types of behavioral manipulation are yet to be found. Researchers should look to identify the manipulative factors required to generate the molecular changes seen in hosts, while also considering the "multi-pronged" approach parasites are taking to manipulate behavior. Assessing gene expression and its products during transitional periods in parasites may be a key methodological approach for tackling these recent trends in the host manipulation literature.

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Neurologic Manifestations ofLeishmania spp.Infection

Cited by 25 publications

References 42 publications

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

Deletion of IL-4 Receptor Alpha on Dendritic Cells Renders BALB/c Mice Hypersusceptible to Leishmania major Infection

Lessons in Mind Control: Trends in Research on the Molecular Mechanisms behind Parasite-Host Behavioral Manipulation

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