Bacteria-induced BBB breakdown.

Bacterial LPS disrupts the blood-brain barrier by inducing endothelial cell pyroptosis.

Gingipains may be one of the key virulence factors of Porphyromonas gingivalis to impair cognition and enhance blood-brain barrier permeability: An animal study.

AIM: Blood-brain barrier (BBB) disorder is one of the early findings in cognitive impairments. We have recently found that Porphyromonas gingivalis bacteraemia can cause cognitive impairment and increased BBB permeability. This study aimed to find out the possible key virulence factors of P. gingivalis contributing to the pathological process. MATERIALS AND METHODS: C57/BL6 mice were infected with P. gingivalis or gingipains or P. gingivalis lipopolysaccharide (P. gingivalis LPS group) by tail vein injection for 8 weeks. The cognitive behaviour changes in mice, the histopathological changes in the hippocampus and cerebral cortex, the alternations of BBB permeability, and the changes in Mfsd2a and Cav-1 levels were measured. The mechanisms of Ddx3x-induced regulation on Mfsd2a by arginine-specific gingipain A (RgpA) in BMECs were explored. RESULTS: P. gingivalis and gingipains significantly promoted mice cognitive impairment, pathological changes in the hippocampus and cerebral cortex, increased BBB permeability, inhibited Mfsd2a expression and up-regulated Cav-1 expression. After RgpA stimulation, the permeability of the BBB model in vitro increased, and the Ddx3x/Mfsd2a/Cav-1 regulatory axis was activated. CONCLUSIONS: Gingipains may be one of the key virulence factors of P. gingivalis to impair cognition and enhance BBB permeability by the Ddx3x/Mfsd2a/Cav-1 axis.

TGFß1-induced hedgehog signaling suppresses the immune response of brain microvascular endothelial cells elicited by meningitic Escherichia coli.

BACKGROUND: Meningitic Escherichia coli (E. coli) is the major etiological agent of bacterial meningitis, a life-threatening infectious disease with severe neurological sequelae and high mortality. The major cause of central nervous system (CNS) damage and sequelae is the bacterial-induced inflammatory storm, where the immune response of the blood-brain barrier (BBB) is crucial. METHODS: Western blot, real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and dual-luciferase reporter assay were used to investigate the suppressor role of transforming growth factor beta 1 (TGFß1) in the immune response of brain microvascular endothelial cells elicited by meningitic E. coli. RESULT: In this work, we showed that exogenous TGFß1 and induced noncanonical Hedgehog (HH) signaling suppressed the endothelial immune response to meningitic E. coli infection via upregulation of intracellular miR-155. Consequently, the increased miR-155 suppressed ERK1/2 activation by negatively regulating KRAS, thereby decreasing IL-6, MIP-2, and E-selectin expression. In addition, the exogenous HH signaling agonist SAG demonstrated promising protection against meningitic E. coli-induced neuroinflammation. CONCLUSION: Our work revealed the effect of TGFß1 antagonism on E. coli-induced BBB immune response and suggested that activation of HH signaling may be a potential protective strategy for future bacterial meningitis therapy. Video Abstract.

Egr-1 is a key regulator of the blood-brain barrier damage induced by meningitic Escherichia coli.

Bacterial meningitis remains a leading cause of infection-related mortality worldwide. Although Escherichia coli (E. coli) is the most common etiology of neonatal meningitis, the underlying mechanisms governing bacterial blood-brain barrier (BBB) disruption during infection remain elusive. We observed that infection of human brain microvascular endothelial cells with meningitic E. coli triggers the activation of early growth response 1 (Egr-1), a host transcriptional activator. Through integrated chromatin immunoprecipitation sequencing and transcriptome analysis, we identified Egr-1 as a crucial regulator for maintaining BBB integrity. Mechanistically, Egr-1 induced cytoskeletal changes and downregulated tight junction protein expression by directly targeting VEGFA, PDGFB, and ANGPTL4, resulting in increased BBB permeability. Meanwhile, Egr-1 also served as a master regulator in the initiation of neuroinflammatory response during meningitic E. coli infection. Our findings support an Egr-1-dependent mechanism of BBB disruption by meningitic E. coli, highlighting a promising therapeutic target for bacterial meningitis.

The phosphoproteome of choroid plexus epithelial cells following infection with Neisseria meningitidis.

The Gram-negative bacterium Neisseria meningitidis, which causes meningitis in humans, has been demonstrated to manipulate or alter host signalling pathways during infection of the central nervous system (CNS). However, these complex signalling networks are not completely understood. We investigate the phosphoproteome of an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB) based on human epithelial choroid plexus (CP) papilloma (HIBCPP) cells during infection with the N. meningitidis serogroup B strain MC58 in presence and absence of the bacterial capsule. Interestingly, our data demonstrates a stronger impact on the phosphoproteome of the cells by the capsule-deficient mutant of MC58. Using enrichment analyses, potential pathways, molecular processes, biological processes, cellular components and kinases were determined to be regulated as a consequence of N. meningitidis infection of the BCSFB. Our data highlight a variety of protein regulations that are altered during infection of CP epithelial cells with N. meningitidis, with the regulation of several pathways and molecular events only being detected after infection with the capsule-deficient mutant. Mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD038560.

Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway.

Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer's disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.

Streptococcus pneumoniae meningitis and the CNS barriers.

Streptococcus pneumoniae (SPN) is a globally significant cause of meningitis, the pathophysiology of which involves damage to the brain by both bacterial virulence factors and the host inflammatory response. In most cases of SPN meningitis bacteria translocate from the blood into the central nervous system (CNS). The principal site of SPN translocation into the CNS is not known, with possible portals of entry proposed to be the cerebral or meningeal blood vessels or the choroid plexus. All require SPN to bind to and translocate across the vascular endothelial barrier, and subsequently the basement membrane and perivascular structures, including an additional epithelial barrier in the case of the blood-CSF barrier. The presence of SPN in the CNS is highly inflammatory resulting in marked neutrophilic infiltration. The secretion of toxic inflammatory mediators by activated neutrophils within the CNS damages pathogen and host alike, including the non-replicative neurons which drives morbidity and mortality. As with the translocation of SPN, the recruitment of neutrophils into the CNS in SPN meningitis necessitates the translocation of neutrophils from the circulation across the vascular barrier, a process that is tightly regulated under basal conditions - a feature of the 'immune specialization' of the CNS. The brain barriers are therefore central to SPN meningitis, both through a failure to exclude bacteria and maintain CNS sterility, and subsequently through the active recruitment and/or failure to exclude circulating leukocytes. The interactions of SPN with these barriers, barrier inflammatory responses, along with their therapeutic implications, are explored in this review.

Cerebrospinal Fluid from Healthy Pregnant Women Does Not Harbor a Detectable Microbial Community.

Cerebrospinal fluid (CSF) circulating in the human central nervous system has long been considered aseptic in healthy individuals, because normally, the blood-brain barrier can protect against microbial invasions. However, this dogma has been called into question by several reports that microbes were identified in human brains, raising the question of whether there is a microbial community in the CSF of healthy individuals without neurological diseases. Here, we collected CSF samples and other samples, including one-to-one matched oral and skin swab samples (positive controls), from 23 pregnant women aged between 23 and 40 years. Normal saline samples (negative controls), sterile swabs, and extraction buffer samples (contamination controls) were also collected. Twelve of the CSF specimens were also used to evaluate the physiological activities of detected microbes. Metagenomic and metatranscriptomic sequencing was performed in these 116 specimens. A total of 620 nonredundant microbes were detected, which were dominated by bacteria (74.6%) and viruses (24.2%), while in CSF samples, metagenomic sequencing found only 26 nonredundant microbes, including one eukaryote, four bacteria, and 21 viruses (mostly bacteriophages). The beta diversity of microbes compared between CSF metagenomic samples and other types of samples (except negative controls) was significantly different from that of the CSF self-comparison. In addition, there was no active or viable microbe in the matched metagenomic and metatranscriptomic sequencing of CSF specimens after subtracting those also found in normal saline, DNA extraction buffer, and skin swab specimens. In conclusion, our results showed no strong evidence of a colonized microbial community present in the CSF of healthy individuals. IMPORTANCE The microbiome is prevalent throughout human bodies, with profound health implications. However, it remains unclear whether it is present and active in human CSF, which has been long considered aseptic due to the blood-brain barrier. Here, we applied unbiased metagenomic and metatranscriptomic sequencing to detect the presence of a microbiome in CSF collected from 23 pregnant women with matched controls. Analysis of 116 specimens found no strong evidence to support the presence of a colonized microbiome in CSF. Our findings will strengthen our understanding of the internal environment of the CSF in healthy people, which has strong implications for human health, especially for neurological infections and disorders, and will help further disease diagnostics, prevention, and therapeutics in clinical settings.

Capsule-dependent impact of MAPK signalling on host cell invasion and immune response during infection of the choroid plexus epithelium by Neisseria meningitidis.

BACKGROUND: The Gram-negative bacterium Neisseria meningitidis (Nm) can cause meningitis in humans, but the host signalling pathways manipulated by Nm during central nervous system (CNS) entry are not completely understood. METHODS: We investigate the role of the mitogen-activated protein kinases (MAPK) Erk1/2 and p38 in an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB) based on human epithelial choroid plexus (CP) papilloma (HIBCPP) cells during infection with Nm serogroup B (NmB) and serogroup C (NmC) strains. A transcriptome analysis of HIBCPP cells following infection with Nm by massive analysis of cDNA ends (MACE) was done to further characterize the cellular response to infection of the barrier. RESULTS: Interestingly, whereas NmB and NmC wild type strains required active Erk1/2 and p38 pathways for infection, invasion by capsule-deficient mutants was independent of Erk1/2 and, in case of the NmB strain, of p38 activity. The transcriptome analysis of HIBCPP cells following infection with Nm demonstrated specific regulation of genes involved in the immune response dependent on Erk1/2 signalling. Gene ontology (GO) analysis confirmed loss of MAPK signalling after Erk1/2 inhibition and revealed an additional reduction of cellular responses including NFκB and JAK-STAT signalling. Interestingly, GO terms related to TNF signalling and production of IL6 were lost specifically following Erk1/2 inhibition during infection with wild type Nm, which correlated with the reduced infection rates by the wild type in absence of Erk1/2 signalling. CONCLUSION: Our data point towards a role of MAPK signalling during infection of the CP epithelium by Nm, which is strongly influenced by capsule expression, and affects infection rates as well as the host cell response.

Invasion of the choroid plexus epithelium by Neisseria meningitidis is differently mediated by Arp2/3 signaling and possibly by dynamin dependent on the presence of the capsule.

Neisseria meningitis (Nm) is a human-specific bacterial pathogen that can cause sepsis and meningitis. To cause meningitis Nm must enter the central nervous system (CNS) across one of the barriers between the blood and the brain. We have previously shown that a capsule-depleted Serogroup B strain of Nm displays enhanced invasion into human choroid plexus (CP) epithelial papilloma (HIBCPP) cells, which represent an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB). Still, the processes involved during CNS invasion by Nm, especially the role of host cell actin cytoskeleton remodeling, are not investigated in detail. Here, we demonstrate that invasion into CP epithelial cells by encapsulated and capsule-depleted Nm is mediated by distinct host cell pathways. Whereas a Serogroup B wild-type strain enters HIBCPP cells by a possibly dynamin-independent, but actin related protein 2/3 (Arp2/3)-dependent mechanism, invasion by a capsule-depleted mutant is reduced by the dynamin inhibitor dynasore and Arp2/3-independent. Both wild-type and mutant bacteria require Src kinase activity for entry into HIBCPP cells. Our data show that Nm can employ different mechanisms for invasion into the CP epithelium dependent on the presence of a capsule.

Central Nervous System-Infecting Pathogens Escherichia coli and Cryptococcus neoformans Exploit the Host Pdlim2 for Intracellular Traversal and Exocytosis in the Blood-Brain Barrier.

Microbial penetration of the blood-brain barrier, a prerequisite for the development of central nervous system (CNS) infection, involves microbial invasion, intracellular traversal, and exocytosis. Microbial invasion of the blood-brain barrier has been investigated, but the molecular basis for microbial traversal and exit from the blood-brain barrier remains unknown. We performed transcriptome analysis of human brain microvascular endothelial cells (HBMEC) infected with Escherichia coli and Cryptococcus neoformans, representative bacterial and fungal pathogens common in CNS infections. Among the targets upregulated in response to E. coli and C. neoformans infection, PDLIM2 was knocked down by small hairpin RNA (shRNA) in HBMEC for further investigation. We demonstrated that Pdlim2 specifically regulated microbial traversal and exit from HBMEC by assessing microbial invasion, transcytosis, intracellular multiplication, and egression. Additionally, the defective exocytosis of internalized E. coli cells from the PDLIM2 shRNA knockdown cells was restored by treatment with a calcium ionophore (ionomycin). Moreover, we performed proximity-dependent biotin labeling with the biotin ligase BioID2 and identified 210 potential Pdlim2 interactors. Among the nine Pdlim2 interactors enriched in response to both E. coli and C. neoformans infection, we selected MPRIP and showed that HBMEC with knockdown of MPRIP mimicked the phenotype of PDLIM2 knockdown cells. These results suggest that the CNS-infecting microbes hijack Pdlim2 and Mprip for intracellular traversal and exocytosis in the blood-brain barrier.

Meningitic Escherichia coli α-hemolysin aggravates blood-brain barrier disruption via targeting TGFß1-triggered hedgehog signaling.

Bacterial meningitis is a life-threatening infectious disease with severe neurological sequelae and a high mortality rate, in which Escherichia coli is one of the primary Gram-negative etiological bacteria. Meningitic E. coli infection is often accompanied by an elevated blood-brain barrier (BBB) permeability. BBB is the structural and functional barrier composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGFß1 physiologically maintained the BBB permeability by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic E. coli infection could subvert this intercellular communication within BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we identified E. coli α-hemolysin as the critical determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction and triggering Ca2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG exhibited promising protection against the infection-caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism during meningitic E. coli-caused BBB disruption and suggested that activating hedgehog signaling within BBB could be a potential protective strategy for future therapy of bacterial meningitis.

Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier.

The neurovascular unit, which consists of vascular cells surrounded by astrocytic end-feet and neurons, controls cerebral blood flow and the permeability of the blood-brain barrier (BBB) to maintain homeostasis in the neuronal milieu. Studying how some pathogens and drugs can penetrate the human BBB and disrupt neuronal homeostasis requires in vitro microphysiological models of the neurovascular unit. Here we show that the neurotropism of Cryptococcus neoformans-the most common pathogen causing fungal meningitis-and its ability to penetrate the BBB can be modelled by the co-culture of human neural stem cells, brain microvascular endothelial cells and brain vascular pericytes in a human-neurovascular-unit-on-a-chip maintained by a stepwise gravity-driven unidirectional flow and recapitulating the structural and functional features of the BBB. We found that the pathogen forms clusters of cells that penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism. The neurovascular-unit-on-a-chip may facilitate the study of the mechanisms of brain infection by pathogens, and the development of drugs for a range of brain diseases.

Impaired blood-brain barrier in the microbiota-gut-brain axis: Potential role of bipolar susceptibility gene TRANK1.

Bipolar disorder (BD) is a common psychiatric illness with high prevalence and disease burden. Accumulating susceptibility genes for BD have been identified in recent years. However, the exact functions of these genes remain largely unknown. Despite its high heritability, gene and environment interaction is commonly accepted as the major contributing factor to BD pathogenesis. Intestine microbiota is increasingly recognized as a critical environmental factor for human health and diseases via the microbiota-gut-brain axis. BD individuals showed altered diversity and compositions in the commensal microbiota. In addition to pro-inflammatory factors, such as interleukin-6 and tumour necrosis factor-α, type 1 interferon signalling pathway is also modulated by specific intestinal bacterial strains. Disruption of the microbiota-gut-brain axis contributes to peripheral and central nervous system inflammation, which accounts for the BD aetiology. Administration of type 1 interferon can induce the expression of TRANK1, which is associated with elevated circulating biomarkers of the impaired blood-brain barrier in BD patients. In this review, we focus on the influence of intestine microbiota on the expression of bipolar gene TRANK1 and propose that intestine microbiota-dependent type 1 interferon signalling is sufficient to induce the over-expression of TRANK1, consequently causing the compromise of BBB integrity and facilitating the entrance of inflammatory mediators into the brain. Activated neuroinflammation eventually contributes to the occurrence and development of BD. This review provides a new perspective on how gut microbiota participate in the pathogenesis of BD. Future studies are needed to validate these assumptions and develop new treatment targets for BD.

M. fortuitum-induced CNS-pathology: Deciphering the role of canonical Wnt signaling, blood brain barrier components and cytokines.

Molecular underpinning of mycobacteria-induced CNS-pathology is not well understood. In the present study, zebrafish were infected with Mycobacterium fortuitum and the prognosis of CNS-pathogenesis studied. We observed M. fortuitum triggers extensive brain-pathology. Evans blue extravasation demonstrated compromised blood-brain barrier (BBB) integrity. Further, decreased expression in tight-junction (TJ) and adherens junction complex (AJC) genes were noted in infected brain. Wnt-signaling has emerged as a major player in host-mycobacterial immunity but its involvement/role in brain-infection is not well studied. Sustained expression of wnt2, wnt3a, fzd5, lrp5/6 and ß-catenin, with concordant decline in degradation complex components axin, gsk3ß and ß-catenin regulator capn2a were observed. The surge in ifng1 and tnfa expression preceding il10 and il4 suggested cytokine-interplay critical in M. fortuitum-induced brain-pathology. Therefore, we suggest adult zebrafish as a viable model for studying CNS-pathology and using the same, conclude that M. fortuitum infection is associated with repressed TJ-AJC gene expression and compromised BBB permeability. Our results implicate Wnt/ß-catenin pathway in M. fortuitum-induced CNS-pathology wherein Th1-type signals facilitate bacterial clearance and Th2-type signals prevent the disease sequel.

Quantitative analysis reveals internalisation of Cryptococcus neoformans by brain endothelial cells in vivo.

Migration of Cryptococcus neoformans from the blood to the brain parenchyma is crucial to cause fatal meningoencephalitis. Although mechanisms involved in brain migration of C. neoformans have been widely studied in vitro, less is known about how the fungus crosses the blood-brain barrier (BBB) in vivo. This is in part because of the lack of an approach to quantitatively analyse the dynamics of fungal transmigration into the brain across the BBB in vivo. In this study, we report a novel approach to quantitatively analyse the interactions between C. neoformans and brain endothelial cells in a mouse model using flow cytometry. Using this system, we show that C. neoformans was internalised by brain endothelial cells in vivo and that mice infected with acapsular or heat-killed C. neoformans yeast cells displayed a lower frequency of brain endothelial cells containing the yeast cell compared to mice infected with wild-type or viable yeast cells, respectively. We further demonstrate that brain endothelial cells were invaded by serotype A strain (H99 strain) at a higher rate compared to serotype D strain (52D strain). Our experiments established that internalisation of C. neoformans by brain endothelial cells occurred in vivo and offered a powerful approach to quantitatively analyse fungal migration into the brain.

Crosstalk between Gut and Brain in Alzheimer's Disease: The Role of Gut Microbiota Modulation Strategies.

The gut microbiota (GM) represents a diverse and dynamic population of microorganisms and about 100 trillion symbiotic microbial cells that dwell in the gastrointestinal tract. Studies suggest that the GM can influence the health of the host, and several factors can modify the GM composition, such as diet, drug intake, lifestyle, and geographical locations. Gut dysbiosis can affect brain immune homeostasis through the microbiota-gut-brain axis and can play a key role in the pathogenesis of neurodegenerative diseases, including dementia and Alzheimer's disease (AD). The relationship between gut dysbiosis and AD is still elusive, but emerging evidence suggests that it can enhance the secretion of lipopolysaccharides and amyloids that may disturb intestinal permeability and the blood-brain barrier. In addition, it can promote the hallmarks of AD, such as oxidative stress, neuroinflammation, amyloid-beta formation, insulin resistance, and ultimately the causation of neural death. Poor dietary habits and aging, along with inflammatory responses due to dysbiosis, may contribute to the pathogenesis of AD. Thus, GM modulation through diet, probiotics, or fecal microbiota transplantation could represent potential therapeutics in AD. In this review, we discuss the role of GM dysbiosis in AD and potential therapeutic strategies to modulate GM in AD.

CC17 group B Streptococcus exploits integrins for neonatal meningitis development.

Group B Streptococcus (GBS) is the major cause of human neonatal infections. A single clone, designated CC17-GBS, accounts for more than 80% of meningitis cases, the most severe form of the infection. However, the events allowing blood-borne GBS to penetrate the brain remain largely elusive. In this study, we identified the host transmembrane receptors α5ß1 and αvß3 integrins as the ligands of Srr2, a major CC17-GBS-specific adhesin. Two motifs located in the binding region of Srr2 were responsible for the interaction between CC17-GBS and these integrins. We demonstrated in a blood-brain-barrier cellular model that both integrins contributed to the adhesion and internalization of CC17-GBS. Strikingly, both integrins were overexpressed during the postnatal period in the brain vessels of the blood-brain barrier and blood-cerebrospinal fluid barrier and contributed to juvenile susceptibility to CC17 meningitis. Finally, blocking these integrins decreased the ability of CC17-GBS to cross into the CNS of juvenile mice in an in vivo model of meningitis. Our study demonstrated that CC17-GBS exploits integrins in order to cross the brain vessels, leading to meningitis. Importantly, it provides host molecular insights into neonate's susceptibility to CC17-GBS meningitis, thereby opening new perspectives for therapeutic and prevention strategies of GBS-elicited meningitis.

Cryptococcus neoformans-astrocyte interactions: effect on fungal blood brain barrier disruption, brain invasion, and meningitis progression.

Cryptococcus neoformans is an opportunistic, neurotropic, and encapsulated fungus that causes life-threatening cryptococcal meningitis (CM), especially in regions of the world where AIDS is endemic. The polysaccharide capsule of C. neoformans is the fungus major virulent factor, being copiously released during infection and causing immunosuppressive defects in the host. Although the capsular material is commonly associated with reactive astrocytes in fatal CM, little is known about the molecular and cellular interactions among astroglia and C. neoformans. As astrocytes also make up the neurovascular unit at the blood-brain barrier (BBB), which C. neoformans must transverse to colonize the central nervous system and cause CM; these cells may play a significant regulatory role in the prevention and progression of infection. For example, astrocytes are implicated in neurological disease including the regulation of cerebral intracranial pressure, immune function, and water homeostasis. Hence, in this review, we provide a general overview of astroglia biology and discuss the current knowledge on C. neoformans-astrocyte interactions including their involvement in the development of CM. This "gliocentric view" of cerebral cryptococcosis suggests that therapeutic interventions particularly targeting at preserving the neuroprotective function of astrocytes may be used in preventing and managing C. neoformans BBB transmigration, brain invasion, colonization, and meningitis.

Alzheimer's disease and gastrointestinal microbiota; impact of Helicobacter pylori infection involvement.

Background: Alzheimer disease (AD) is a leading cause of global burden with great impact on societies. Although research is working intensively on promising therapy, the problem remains up-to-date. Among the various proposed hypotheses regarding causality and therapy, emerging evidence supports the hypothesis that gastrointestinal microbiota through the so-called 'gut-brain axis' interacts with immune system and brain and shape the balance between homeostasis and disease; the involvement of gastrointestinal microbiota in the pathophysiology of AD is less defined, even though the role of 'gut-brain axis' has been well verified for other neurodegenerative conditions.Methods: We performed a systematic review of PubMed/MEDLINE database from 1st January 1990 to 17th October 2018, to investigate the accessible literature regarding possible association between AD and gastrointestinal microbiota. Inclusion criteria were available full text in English language, original clinical papers implicating AD patients and any sort of gastrointestinal microbiota.Results: Through our query, an initial number of 241 papers has been identified. After removing duplicates and through an additional manual search, twenty-four papers met our inclusion criteria. The great majority of eligible publications supported a possible connection between AD and gastrointestinal microbiota. The most common investigated microorganism was Helicobacter pylori.Conclusion: Our own systematic review, showed a possible association between AD and gastrointestinal microbiota mainly including Helicobacter pylori, and thus further research is required for substantiation of causality as well as for the establishment of promising novel therapies.