Immune response and pathogen invasion at the choroid plexus in the onset of cerebral toxoplasmosis

Abstract Background Toxoplasma gondii (T. gondii) is a highly successful parasite being able to cross all biological barriers of the body, finally reaching the central nervous system (CNS). Previous studies have highlighted the critical involvement of the blood–brain barrier (BBB) during T. gondii invasion and development of subsequent neuroinflammation. Still, the potential contribution of the choroid plexus (CP), the main structure forming the blood–cerebrospinal fluid (CSF) barrier (BCSFB) have not been addressed. Methods To investigate T. gondii invasion at the onset of neuroinflammation, the CP and brain microvessels (BMV) were isolated and analyzed for parasite burden. Additionally, immuno-stained brain sections and three-dimensional whole mount preparations were evaluated for parasite localization and morphological alterations. Activation of choroidal and brain endothelial cells were characterized by flow cytometry. To evaluate the impact of early immune responses on CP and BMV, expression levels of inflammatory mediators, tight junctions (TJ) and matrix metalloproteinases (MMPs) were quantified. Additionally, FITC-dextran was applied to determine infection-related changes in BCSFB permeability. Finally, the response of primary CP epithelial cells to T. gondii parasites was tested in vitro. Results Here we revealed that endothelial cells in the CP are initially infected by T. gondii, and become activated prior to BBB endothelial cells indicated by MHCII upregulation. Additionally, CP elicited early local immune response with upregulation of IFN-γ, TNF, IL-6, host-defence factors as well as swift expression of CXCL9 chemokine, when compared to the BMV. Consequently, we uncovered distinct TJ disturbances of claudins, associated with upregulation of MMP-8 and MMP-13 expression in infected CP in vivo, which was confirmed by in vitro infection of primary CP epithelial cells. Notably, we detected early barrier damage and functional loss by increased BCSFB permeability to FITC-dextran in vivo, which was extended over the infection course. Conclusions Altogether, our data reveal a close interaction between T. gondii infection at the CP and the impairment of the BCSFB function indicating that infection-related neuroinflammation is initiated in the CP.

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Immune Response and Pathogen Invasion at the Choroid Plexus in the Onset of Cerebral Toxoplasmosis

10.21203/rs.3.rs-910513/v1 ◽

2021 ◽

Author(s):

Caio Andreeta Figueiredo ◽

JOhannes Steffen ◽

Lorena Morton ◽

Sushmita Arumugam ◽

OLiver Liesenfeld ◽

...

Keyword(s):

Immune Response ◽

Endothelial Cells ◽

Epithelial Cells ◽

Choroid Plexus ◽

The Body ◽

Potential Contribution ◽

Pathogen Invasion ◽

The Impact

Abstract Background: Toxoplasma gondii ( T. gondii ) is a highly successful parasite being able to cross all biological barriers of the body, finally reaching the central nervous system (CNS). Previous studies have highlighted the critical involvement of the blood-brain barrier (BBB) during T. gondii invasion and development of subsequent neuroinflammation. Still, the potential contribution of the choroid plexus (CP), a main structure forming the blood-cerebrospinal fluid (CSF)-barrier (BCSFB) have not been addressed. Methods: To investigate T. gondii invasion and the onset of neuroinflammation, the CP and brain microvessels (BMV) were isolated and analysed for parasite burden. Additionally, immuno-stained brain sections and three dimensional whole mount preparations were evaluated for parasite localization and morphological alterations. Activation of choroidal and brain endothelial cells were characterized by flow cytometry. To evaluate the impact of early immune responses on CP and BMV, expression levels of inflammatory mediators, tight junctions (TJ) and matrix metalloproteinases (MMPs) were quantified. Additionally, FITC-dextran was applied to determine infection-related changes in BCSFB permeability. Finally, the response of primary CP epithelial cells to T. gondii parasites was tested in vitro . Results: Here we revealed that endothelial cells in the CP are initially infected by T. gondii, and become activated prior to BBB endothelial cells indicated by MHCII upregulation. Additionally, CP elicited early local immune response with upregulation of IFN-γ, TNF, IL-6, host-defence factors as well as swift expression of CXCL9 chemokine, when compared to the BMV. Consequently, we uncovered distinct TJ disturbances of claudins, associated with upregulation of MMP-8 and MMP-13 expression in infected CP in vivo , which was confirmed by in vitro infection of primary CP epithelial cells. Notably, we detected early barrier damage and functional loss by increased BCSFB permeability to FITC-dextran in vivo , which was extended over the infection course. Conclusions: Altogether, our data reveal a close interaction between T. gondii infection at the CP and the impairment of the BCSFB function indicating that infection-related neuroinflammation is initiated in the CP.

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Ellagitannins, Gallotannins and their Metabolites- The Contribution to the Anti-Inflammatory Effect of Food Products and Medicinal Plants

Current Medicinal Chemistry ◽

10.2174/0929867323666160919111559 ◽

2019 ◽

Vol 25 (37) ◽

pp. 4946-4967 ◽

Cited By ~ 18

Author(s):

Anna K. Kiss ◽

Jakub P. Piwowarski

Keyword(s):

Immune Response ◽

Gastrointestinal Tract ◽

Gut Microbiota ◽

Health Effects ◽

Biological Effects ◽

Food Products ◽

Anti Inflammatory ◽

The Impact

The popularity of food products and medicinal plant materials containing hydrolysable tannins (HT) is nowadays rapidly increasing. Among various health effects attributable to the products of plant origin rich in gallotannins and/or ellagitannins the most often underlined is the beneficial influence on diseases possessing inflammatory background. Results of clinical, interventional and animal in vivo studies clearly indicate the antiinflammatory potential of HT-containing products, as well as pure ellagitannins and gallotannins. In recent years a great emphasis has been put on the consideration of metabolism and bioavailability of natural products during examination of their biological effects. Conducted in vivo and in vitro studies of polyphenols metabolism put a new light on this issue and indicate the gut microbiota to play a crucial role in the health effects following their oral administration. The aim of the review is to summarize the knowledge about HT-containing products’ phytochemistry and their anti-inflammatory effects together with discussion of the data about observed biological activities with regards to the current concepts on the HTs’ bioavailability and metabolism. Orally administered HT-containing products due to the limited bioavailability of ellagitannins and gallotannins can influence immune response at the level of gastrointestinal tract as well as express modulating effects on the gut microbiota composition. However, due to the chemical changes being a result of their transit through gastrointestinal tract, comprising of hydrolysis and gut microbiota metabolism, the activity of produced metabolites has to be taken into consideration. Studies regarding biological effects of the HTs’ metabolites, in particular urolithins, indicate their strong and structure-dependent anti-inflammatory activities, being observed at the concentrations, which fit the range of their established bioavailability. The impact of HTs on inflammatory processes has been well established on various in vivo and in vitro models, while influence of microbiota metabolites on silencing the immune response gives a new perspective on understanding anti-inflammatory effects attributed to HT containing products, especially their postulated effectiveness in inflammatory bowel diseases (IBD) and cardiovascular diseases.

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A Comparative Transcriptome Analysis of Human and Porcine Choroid Plexus Cells in Response to Streptococcus suis Serotype 2 Infection Points to a Role of Hypoxia

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.639620 ◽

2021 ◽

Vol 11 ◽

Author(s):

Alexa N. Lauer ◽

Rene Scholtysik ◽

Andreas Beineke ◽

Christoph Georg Baums ◽

Kristin Klose ◽

...

Keyword(s):

Epithelial Cells ◽

Inflammatory Response ◽

Choroid Plexus ◽

Cellular Proliferation ◽

Inflammatory Responses ◽

Streptococcus Suis ◽

Gene Set Enrichment Analysis ◽

Rna Seq

Streptococcus suis (S. suis) is an important opportunistic pathogen, which can cause septicemia and meningitis in pigs and humans. Previous in vivo observations in S. suis-infected pigs revealed lesions at the choroid plexus (CP). In vitro experiments with primary porcine CP epithelial cells (PCPEC) and human CP epithelial papilloma (HIBCPP) cells demonstrated that S. suis can invade and traverse the CP epithelium, and that the CP contributes to the inflammatory response via cytokine expression. Here, next generation sequencing (RNA-seq) was used to compare global transcriptome profiles of PCPEC and HIBCPP cells challenged with S. suis serotype (ST) 2 infected in vitro, and of pigs infected in vivo. Identified differentially expressed genes (DEGs) were, amongst others, involved in inflammatory responses and hypoxia. The RNA-seq data were validated via quantitative PCR of selected DEGs. Employing Gene Set Enrichment Analysis (GSEA), 18, 28, and 21 enriched hallmark gene sets (GSs) were identified for infected HIBCPP cells, PCPEC, and in the CP of pigs suffering from S. suis ST2 meningitis, respectively, of which eight GSs overlapped between the three different sample sets. The majority of these GSs are involved in cellular signaling and pathways, immune response, and development, including inflammatory response and hypoxia. In contrast, suppressed GSs observed during in vitro and in vivo S. suis ST2 infections included those, which were involved in cellular proliferation and metabolic processes. This study suggests that similar cellular processes occur in infected human and porcine CP epithelial cells, especially in terms of inflammatory response.

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Human Cytomegalovirus Cell Tropism and Host Cell Receptors

Vaccines ◽

10.3390/vaccines7030070 ◽

2019 ◽

Vol 7 (3) ◽

pp. 70 ◽

Cited By ~ 11

Author(s):

Gerna ◽

Kabanova ◽

Lilleri

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Epithelial Cells ◽

Human Cytomegalovirus ◽

Current Data ◽

Immunosuppressed Patient ◽

Cell Tropism ◽

Virus Envelope

In the 1970s–1980s, a striking increase in the number of disseminated human cytomegalovirus (HCMV) infections occurred in immunosuppressed patient populations. Autopsy findings documented the in vivo disseminated infection (besides fibroblasts) of epithelial cells, endothelial cells, and polymorphonuclear leukocytes. As a result, multiple diagnostic assays, such as quantification of HCMV antigenemia (pp65), viremia (infectious virus), and DNAemia (HCMV DNA) in patient blood, were developed. In vitro experiments showed that only low passage or endothelial cell-passaged clinical isolates, and not laboratory-adapted strains, could reproduce both HCMV leuko- and endothelial cell-tropism, which were found through genetic analysis to require the three viral genes UL128, UL130, and UL131 of the HCMV UL128 locus (UL128L). Products of this locus, together with gH/gL, were shown to form the gH/gL/pUL128L pentamer complex (PC) required for infection of epithelial cells/endothelial cells, whereas gH/gL and gO form the gH/gL/gO trimer complex (TC) required for infection of all cell types. In 2016, following previous work, a receptor for the TC that mediates entry into fibroblasts was identified as PDGFRα, while in 2018, a receptor for the PC that mediates entry into endothelial/epithelial cells was identified as neuropilin2 (Nrp2). Furthermore, the olfactory receptor family member OR14I1 was recently identified as a possible additional receptor for the PC in epithelial cells. Thus, current data support two models of viral entry: (i) in fibroblasts, following interaction of PDGFRα with TC, the latter activates gB to fuse the virus envelope with the cell membrane, whereas (ii) in epithelial cells/endothelial cells, interaction of Nrp2 (and OR14I1) with PC promotes endocytosis of virus particles, followed by gB activation by gH/gL/gO (or gH/gL) and final low-pH entry into the cell.

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Monocyte recruitment to the inflamed central nervous system: migration pathways and distinct functional polarization

10.1101/2020.04.04.025395 ◽

2020 ◽

Author(s):

Daniela C. Ivan ◽

Sabrina Walthert ◽

Giuseppe Locatelli

Keyword(s):

Central Nervous System ◽

Endothelial Cells ◽

Nervous System ◽

Choroid Plexus ◽

Arginase 1 ◽

Choroid Plexuses ◽

Inflammatory Macrophages ◽

Functional Polarization

ABSTRACTThe central nervous system (CNS) parenchyma is enclosed by anatomical interfaces including multilayered meninges, the blood-brain barrier (BBB), the choroid plexuses within ventricles and the glia limitans. These border areas hold distinct functional specializations which control the trafficking of monocyte-derived cells toward the CNS parenchyma, altogether maintaining CNS homeostasis. By crossing activated endothelial, epithelial and glial borders, circulating leukocytes gain however access to the CNS parenchyma in several inflammatory diseases including multiple sclerosis.Studies in animal models of neuroinflammation have helped describing the phenotypic specifications of these invading monocyte-derived cells, able to exert detrimental or beneficial functions depending on the local environment. In this context, in vivo visualization of iNOS+ pro-inflammatory and arginase-1+ anti-inflammatory macrophages has recently revealed that these distinct cell phenotypes are highly compartmentalized by CNS borders. While arginase-1+ macrophages densely populate the leptomeninges, iNOS+ macrophages rather accumulate in perivascular spaces and at the pia mater-CNS parenchymal interface.How and where these macrophages acquire their functional commitment, and whether differentially-activated monocyte-derived cells infiltrate the CNS through distinct gateways, remains however unclear.In this study, we have investigated the interaction of monocyte-derived macrophages with endothelial (BBB) and epithelial (choroid plexus) barriers of the CNS, both in vitro and in vivo. By using primary mouse brain microvascular endothelial cells as in vitro model of the BBB, we observed that, compared to unpolarized primary macrophages, adhesion of functionally-committed macrophages to endothelial cells was drastically reduced, literally abrogating their diapedesis across the BBB. Conversely, when interacting with an activated choroid plexus epithelium, both pro- and anti-inflammatory macrophages displayed substantial adhesive and migratory properties. Accordingly, in vivo analysis of choroid plexuses revealed increased macrophage trafficking and a scattered presence of polarized cells upon induction of anti-CNS inflammation.Altogether, we show that acquisition of distinct macrophage polarizations significantly alters the adhesive and migratory properties of these cells in a barrier-specific fashion. While monocytes trafficking at the level of the BBB seem to acquire their signature phenotype only following diapedesis, other anatomical interfaces can be the entry site for functionally activated monocyte-derived cells. Our study highlights the choroid plexus as a key access gateway for macrophages during neuroinflammation, and its stroma as a potential priming site for their functional polarization.

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The impact of size on particle drainage dynamics and antibody response

10.1101/2020.09.28.316612 ◽

2020 ◽

Author(s):

Simon Zinkhan ◽

Anete Ogrina ◽

Ina Balke ◽

Gunta Reseviča ◽

Andris Zeltins ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

Lymphoid Organs ◽

Cowpea Chlorotic Mottle Virus ◽

Chlorotic Mottle Virus ◽

Chlorotic Mottle ◽

Secondary Lymphoid Organs ◽

The Impact

AbstractVaccine-induced immune response can be greatly enhanced by mimicking pathogen properties. The size and the repetitive geometric shape of virus-like particles (VLPs) influence their immunogenicity by facilitating drainage to secondary lymphoid organs and enhancing interaction with and activation of B-cells and other innate humoral immune components. VLPs derived from the plant Bromovirus genus, specifically cowpea chlorotic mottle virus (CCMV), are T=3 icosahedron particles. They can be easily expressed in an E. coli host system and package ssRNA during the expression process. Recently, we have engineered CCMV-VLPs by incorporating the universal tetanus toxoid (TT) epitope at the N-terminus. The modified CCMVTT-VLPs successfully form icosahedral particles T=3, with a diameter of ∼30nm analogous to the parental VLPs. Interestingly, incorporating TT epitope at the C-terminus of CCMVTT-VLPs results in the formation of Rod-shaped VLPs, ∼1µm in length and ∼30nm in width. In this study, we have investigated the draining kinetics and immunogenicity of both engineered forms (termed as Round-shaped CCMVTT-VLPs and Rod-shaped CCMVTT-VLPs) as potential B cell immunogens using different in vitro and in vivo assays. Our results reveal that Round-shaped CCMVTT-VLPs are more efficient in draining to secondary lymphoid organs to charge antigen-presenting cells as well as B-cells. Furthermore, compared to Rod-shaped CCMVTT-VLPs, Round-shaped CCMVTT-VLPs led to more than 100-fold increased systemic IgG and IgA responses accompanied by prominent formation of splenic germinal centers. Round-shaped CCMVTT-VLPs could also polarize the induced immune response towards TH1. Up to our knowledge, this is the first study investigating and comparing the draining kinetics and immunogenicity of one and the same VLP monomer forming nano-sized icosahedrons or rods in the micrometer size.

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Development and Application of Endothelial Cells Derived From Pluripotent Stem Cells in Microphysiological Systems Models

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.625016 ◽

2021 ◽

Vol 8 ◽

Author(s):

Crystal C. Kennedy ◽

Erin E. Brown ◽

Nadia O. Abutaleb ◽

George A. Truskey

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Blood Vessels ◽

Pluripotent Stem Cells ◽

The Body ◽

Organ Systems ◽

Temporal Waveform ◽

Induced Pluripotent

The vascular endothelium is present in all organs and blood vessels, facilitates the exchange of nutrients and waste throughout different organ systems in the body, and sets the tone for healthy vessel function. Mechanosensitive in nature, the endothelium responds to the magnitude and temporal waveform of shear stress in the vessels. Endothelial dysfunction can lead to atherosclerosis and other diseases. Modeling endothelial function and dysfunction in organ systems in vitro, such as the blood–brain barrier and tissue-engineered blood vessels, requires sourcing endothelial cells (ECs) for these biomedical engineering applications. It can be difficult to source primary, easily renewable ECs that possess the function or dysfunction in question. In contrast, human pluripotent stem cells (hPSCs) can be sourced from donors of interest and renewed almost indefinitely. In this review, we highlight how knowledge of vascular EC development in vivo is used to differentiate induced pluripotent stem cells (iPSC) into ECs. We then describe how iPSC-derived ECs are being used currently in in vitro models of organ function and disease and in vivo applications.

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Hemoglobin stimulates vigorous growth of Streptococcus pneumoniae and shapes the pathogen's global transcriptome

Scientific Reports ◽

10.1038/s41598-020-71910-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Fahmina Akhter ◽

Edroyal Womack ◽

Jorge E. Vidal ◽

Yoann Le Breton ◽

Kevin S. McIver ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Positive Influence ◽

The Body ◽

Host Proteins ◽

Vigorous Growth ◽

Cultivation In Vitro ◽

The Impact ◽

Heme Binding Protein

Abstract Streptococcus pneumoniae (Spn) must acquire iron from the host to establish infection. We examined the impact of hemoglobin, the largest iron reservoir in the body, on pneumococcal physiology. Supplementation with hemoglobin allowed Spn to resume growth in an iron-deplete medium. Pneumococcal growth with hemoglobin was unusually robust, exhibiting a prolonged logarithmic growth, higher biomass, and extended viability in both iron-deplete and standard medium. We observed the hemoglobin-dependent response in multiple serotypes, but not with other host proteins, free iron, or heme. Remarkably, hemoglobin induced a sizable transcriptome remodeling, effecting virulence and metabolism in particular genes facilitating host glycoconjugates use. Accordingly, Spn was more adapted to grow on the human α − 1 acid glycoprotein as a sugar source with hemoglobin. A mutant in the hemoglobin/heme-binding protein Spbhp-37 was impaired for growth on heme and hemoglobin iron. The mutant exhibited reduced growth and iron content when grown in THYB and hemoglobin. In summary, the data show that hemoglobin is highly beneficial for Spn cultivation in vitro and suggest that hemoglobin might drive the pathogen adaptation in vivo. The hemoglobin receptor, Spbhp-37, plays a role in mediating the positive influence of hemoglobin. These novel findings provide intriguing insights into pneumococcal interactions with its obligate human host.

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Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21031143 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1143 ◽

Cited By ~ 1

Author(s):

Madeleine Goeritzer ◽

Eva Bernhart ◽

Ioanna Plastira ◽

Helga Reicher ◽

Christina Leopold ◽

...

Keyword(s):

Endothelial Cells ◽

Sickness Behavior ◽

Brain Endothelial Cells ◽

Brain Capillaries ◽

Barrier Dysfunction ◽

Pharmacological Inhibition ◽

Regulated Gene Expression ◽

The Impact

During inflammation, activated leukocytes release cytotoxic mediators that compromise blood–brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO−/− compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction.

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Programming the anti-tumor immune response in vitro and its application to stop the growth of tumor cells and prolonging the lifespan of mice with carcinoma in vivo

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/igpp.2017.4.8525 ◽

2017 ◽

pp. 67-73

Author(s):

С.В. Калиш ◽

С.В. Лямина ◽

А.А. Раецкая ◽

О.П. Буданова ◽

И.Ю. Малышев

Keyword(s):

Immune Response ◽

Tumor Growth ◽

Tumor Cells ◽

The Body ◽

Ehrlich Carcinoma ◽

Ec Cells ◽

Growth Of Tumor ◽

Immune Response In Vitro

Цель - представить доказательства правомерности гипотезы, что комбинированный пул репрограммированных in vitro макрофагов и лимфоцитов будет эффективно ограничивать пролиферацию опухолевых клеток in vitro , а при введении в организм будет существенно ограничивать развитие опухоли in vivo . Методика. Размножение опухолевых клеток инициировали in vitro путем добавления клеток карциномы Эрлиха (КЭ) в среду культивирования RPMI-1640. Развитие асцитной опухоли in vivo воспроизводили путем внутрибрюшной инъекции клеток КЭ мышам. Результаты. Установлено, что M3 макрофаги вместе с антиген-репрограммированными лимфоцитами оказывают выраженный противоопухолевый эффект и in vitro, и in vivo , который был существеннее противоопухолевого эффекта цисплатина. Заключение. Факты, свидетельствующие, что М3 макрофаги в сочетании с in vitro антиген-репрограммированными лимфоцитами значительно подавляют рост опухоли in vivo , делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли путем предварительного программирования противоопухолевого иммунного ответа «в пробирке». Aim. To test a hypothesis that a combined pool of in vitro reprogrammed macrophages and lymphocytes will effectively limit growth of tumor cells in vitro , and injections of these cells into the body will considerably limit development of a tumor in vivo . Methods. Tumor growth was initiated in vitro by addition of Ehrlich carcinoma (EC) cells to the RPMI-1640 cell culture medium and in vivo by intraperitoneal injection of EC cells into mice. Results. M3 macrophages in combination with antigen-reprogrammed lymphocytes exerted a pronounced antitumor effect both in vitro and in vivo, which was superior to the effect of cisplatin. Conclusion. M3 macrophages in combination with in vitro antigen-reprogrammed lymphocytes significantly inhibited the tumor growth in vivo . This fact justifies development of a clinical version of the tumor growth restricting biotechnology using pre-programming of the antitumor immune response in vitro .

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