NMDA Receptor and L-Type Calcium Channel Modulate Prion Formation.

Transmissible neurodegenerative prion diseases are characterized by the conversion of the cellular prion protein (PrP) to misfolded isoforms denoted as prions or PrP. Although the conversion can occur in the test tube containing recombinant prion protein or cell lysates, efficient prion formation depends on the integrity of intact cell functions. Since neurons are main targets for prion replication, we asked whether their most specialized function, i.

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.

Human African trypanosomiasis: How do the parasites enter and cause dysfunctions of the nervous system in murine models?

In this review we describe how Trypanosoma brucei brucei, a rodent pathogenic strain of African trypanosomes, can invade the nervous system, first by localization to the choroid plexus, the circumventricular organs (CVOs) and peripheral ganglia, which have fenestrated vessels, followed by crossing of the blood-brain barrier (BBB) into the white matter, hypothalamus, thalamus and basal ganglia. White blood cells (WBCs) pave the way for the trypanosome neuroinvasion. Experiments with immune deficient mice show that the invasion of WBCs is initiated by the toll-like receptor 9, followed by an augmentation phase that depends on the cytokine IFN-γ and the chemokine CXCL10.

Emerging Viral Infections in Sub-Saharan Africa and the Developing Nervous System: A Mini Review.

The global public health concern is heightened over the increasing number of emerging viruses, i.e., newly discovered or previously known that have expanded into new geographical zones.

Nitric Oxide Protects against Infection-Induced Neuroinflammation by Preserving the Stability of the Blood-Brain Barrier.

Nitric oxide (NO) generated by inducible NO synthase (iNOS) is critical for defense against intracellular pathogens but may mediate inflammatory tissue damage. To elucidate the role of iNOS in neuroinflammation, infections with encephalitogenic Trypanosoma brucei parasites were compared in inos(-/-) and wild-type mice. Inos(-/-) mice showed enhanced brain invasion by parasites and T cells, and elevated protein permeability of cerebral vessels, but similar parasitemia levels.

H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice.

An increased incidence in the sleep-disorder narcolepsy has been associated with the 2009-2010 pandemic of H1N1 influenza virus in China and with mass vaccination campaigns against influenza during the pandemic in Finland and Sweden. Pathogenetic mechanisms of narcolepsy have so far mainly focused on autoimmunity. We here tested an alternative working hypothesis involving a direct role of influenza virus infection in the pathogenesis of narcolepsy in susceptible subjects.

Tryps and trips: cell trafficking across the 100-year-old blood-brain barrier.

One hundred years ago, Edwin E. Goldmann discovered the blood-brain barrier (BBB) using trypan dyes. These dyes were developed and named by Paul Ehrlich during his search for drugs to kill African trypanosomes (extracellular parasites that cause sleeping sickness) while sparing host cells.

Live imaging of prions reveals nascent PrPSc in cell-surface, raft-associated amyloid strings and webs.

Mammalian prions refold host glycosylphosphatidylinositol-anchored PrP(C) into β-sheet-rich PrP(Sc). PrP(Sc) is rapidly truncated into a C-terminal PrP27-30 core that is stable for days in endolysosomes. The nature of cell-associated prions, their attachment to membranes and rafts, and their subcellular locations are poorly understood; live prion visualization has not previously been achieved.

Role of the Listeria monocytogenes 2-Cys peroxiredoxin homologue in protection against oxidative and nitrosative stress and in virulence.

Peroxiredoxins contribute to protection of some bacteria against reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs). Listeria monocytogenes, a facultative intracellular bacterial pathogen, interacts with ROIs and RNIs during infection. In this study, we investigated the involvement of the 2-Cys peroxiredoxin (Prx) homologue in L.

Mechanisms of CNS invasion and damage by parasites.

Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.

Prion formation correlates with activation of translation-regulating protein 4E-BP and neuronal transcription factor Elk1.

Cellular mechanisms play a role in conversion of the normal prion protein PrP(C) to the disease-associated protein PrP(Sc). The cells provide not only PrP(C), but also still largely undefined factors required for efficient prion replication. Previously, we have observed that interference with ERK and p38-JNK MAP kinase pathways has opposing effects on the formation of prions indicating that the process is regulated by a balance in intracellualar signaling pathways.

Neopterin is a cerebrospinal fluid marker for treatment outcome evaluation in patients affected by Trypanosoma brucei gambiense sleeping sickness.

Background: Post-therapeutic follow-up is essential to confirm cure and to detect early treatment failures in patients affected by sleeping sickness (HAT). Current methods, based on finding of parasites in blood and cerebrospinal fluid (CSF) and counting of white blood cells (WBC) in CSF, are imperfect. New markers for treatment outcome evaluation are needed.

New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients.

Accurate stage determination is crucial in the choice of treatment for patients suffering from sleeping sickness, also known as human African trypanosomiasis (HAT). Current staging methods, based on the counting of white blood cells (WBC) and the detection of parasites in the cerebrospinal fluid (CSF) have limited accuracy. We hypothesized that immune mediators reliable for staging T.

Passage of parasites across the blood-brain barrier.

The blood-brain barrier (BBB) is a structural and functional barrier that protects the central nervous system (CNS) from invasion by blood-borne pathogens including parasites. However, some intracellular and extracellular parasites can traverse the BBB during the course of infection and cause neurological disturbances and/or damage which are at times fatal. The means by which parasites cross the BBB and how the immune system controls the parasites within the brain are still unclear.

Actigraphy in human African trypanosomiasis as a tool for objective clinical evaluation and monitoring: a pilot study.

Background: Human African trypanosomiasis (HAT) or sleeping sickness leads to a complex neuropsychiatric syndrome with characteristic sleep alterations. Current division into a first, hemolymphatic stage and second, meningoencephalitic stage is primarily based on the detection of white blood cells and/or trypanosomes in the cerebrospinal fluid. The validity of this criterion is, however, debated, and novel laboratory biomarkers are under study.

Distinct Toll-like receptor signals regulate cerebral parasite load and interferon α/β and tumor necrosis factor α-dependent T-cell infiltration in the brains of Trypanosoma brucei-infected mice.

Background: The penetration of T cells and trypanosomes into the brain parenchyma is a major pathogenetic event in African trypanosomiasis.

Methods: The role of innate immune responses in the penetration of T cells and Trypanosoma brucei brucei into the brain was studied in knockout mice by using double immunofluorescent staining and real-time polymerase chain reaction.

Results: We demonstrate that Toll-like receptor (TLR)-MyD88-mediated signaling is required for T-cell and parasite penetration into the brain and microglial activation, besides controlling parasitemia and antigen-specific T-cell activation.

Microbes' roadmap to neurons.

The nervous system is protected by barriers that restrict the invasion of pathogens. Nevertheless, mechanisms have evolved by which microbes can pass these barriers, enter and exit neurons and target various regions of the nervous system. In the brain, immune responses to pathogens are generally not robust, so microbes can hide and survive or, conversely, cause severe uncontrolled infections.

Identification of stage biomarkers for human African trypanosomiasis.

Human African trypanosomiasis (HAT), caused by infection with sub-species of Trypanosoma brucei (T. b.), manifests as a hemolymphatic stage followed by an encephalitic stage.

Clock gene expression during chronic inflammation induced by infection with Trypanosoma brucei brucei in rats.

African sleeping sickness is characterized by alterations in rhythmic functions. It is not known if the disease affects the expression of clock genes, which are the molecular basis for rhythm generation. We used a chronic rat model of experimental sleeping sickness, caused by the extracellular parasite Trypanosoma brucei brucei (Tb brucei), to study the effects on clock gene expression.

African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions.

The extracellular parasite Trypanosoma brucei causes human African trypanosomiasis (HAT), also known as sleeping sickness. Trypanosomes are transmitted by tsetse flies and HAT occurs in foci in sub-Saharan Africa. The disease, which is invariably lethal if untreated, evolves in a first hemo-lymphatic stage, progressing to a second meningo-encephalitic stage when the parasites cross the blood-brain barrier.

Expression and role of CXCL10 during the encephalitic stage of experimental and clinical African trypanosomiasis.

Background: Human African trypanosomiasis, caused by Trypanosoma brucei, involves an early hemolymphatic stage followed by a late encephalitic stage.

Methods: We studied the expression of chemokines with use of microarray and enzyme-linked immunosorbent assay in T. brucei brucei-infected mice and in patients with human African trypanosomiasis and examined their role in controlling brain accumulation of T cells and parasites.