Passively Administered Pooled Human Immunoglobulins Exert IL-10 Dependent Anti-Inflammatory Effects that Protect against Fatal HSV Encephalitis

HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1–3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b+ Ly6Chigh monocytes and inhibited their spontaneous degranulation in vitro. FcγRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45+ Ly6Clow monocytes but not for inhibiting development of Ly6Chigh monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3+ CD4+ T regulatory cells (Tregs) and FoxP3− ICOS+ CD4+ T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS+ CD4+ T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti-inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases

Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4+ and CD8+ T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag−/−, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections

The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice is a Major Cause of CNS Pathology Resulting in Fatal Encephalitis

This study was undertaken to investigate possible immune mechanisms in fatal HSV-1 encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brainstem lesions of primarily F4/80+ macrophages and Gr-1+ neutrophils detectable by MRI as early as day 6 post infection (PI). Depletion of macrophages and neutrophils significantly enhanced survival of infected 129 mice. Immunodeficient B6 (IL-7R-/-Kitw41/w41) mice lacking adaptive cells (B6-E mice) transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control non-transplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 bone marrow or B6 bone marrow. Acyclovir treatment of 129 mice beginning day 4 PI (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brainstem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brainstem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells

Effects of Acyclovir and IVIG on Behavioral Outcomes after HSV1 CNS Infection

Herpes simplex virus 1 (HSV) encephalitis (HSE) has serious neurological complications, involving behavioral and cognitive impairments that cause significant morbidity and a reduced quality of life. We showed that HSE results from dysregulated central nervous system (CNS) inflammatory responses. We hypothesized that CNS inflammation is casually involved in behavioral abnormalities after HSE and that treatment with ACV and pooled human immunoglobulin (IVIG), an immunomodulatory drug, would improve outcomes compared to mice treated with phosphate buffered saline (PBS) or ACV alone. Anxiety levels were high in HSV-infected PBS and ACV-treated mice compared to mice treated with ACV + IVIG, consistent with reports implicating inflammation in anxiety induced by lipopolysaccharide (LPS) or stress. Female, but not male, PBS-treated mice were cognitively impaired, and unexpectedly, ACV was protective, while the inclusion of IVIG surprisingly antagonized ACV’s beneficial effects. Distinct serum proteomic profiles were observed for male and female mice, and the antagonistic effects of ACV and IVIG on behavior were paralleled by similar changes in the serum proteome of ACV- and ACV + IVIG-treated mice. We conclude that inflammation and other factors mediate HSV-induced behavioral impairments and that the effects of ACV and IVIG on behavior involve novel mechanisms

Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4+ and CD8+ T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag−/−, B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections

Colorimetric nanofibers as optical sensors

Sensors play a major role in many applications today, ranging from biomedicine to safety equipment, where they detect and warn us about changes in the environment. Nanofibers, characterized by high porosity, flexibility, and a large specific surface area, are the ideal material for ultrasensitive, fastresponding, and user-friendly sensor design. Indeed, a large specific surface area increases the sensitivity and response time of the sensor as the contact area with the analyte is enlarged. Thanks to the flexibility of membranes, nanofibrous sensors cannot only be applied in high-end analyte detection, but also in personal, daily use. Many different nanofibrous sensors have already been designed; albeit, the most straightforward and easiest-to-interpret sensor response is a visual change in color, which is of particular interest in the case of warning signals. Recently, many researchers have focused on the design of so-called colorimetric nanofibers, which typically involve the incorporation of a colorimetric functionality into the nanofibrous matrix. Many different strategies have been used and explored for colorimetric nanofibrous sensor design, which are outlined in this feature article. The many examples and applications demonstrate the value of colorimetric nanofibers for advanced optical sensor design, and could provide directions for future research in this area

Identification of Common Differentially Expressed Genes in Urinary Bladder Cancer

BACKGROUND: Current diagnosis and treatment of urinary bladder cancer (BC) has shown great progress with the utilization of microarrays. PURPOSE: Our goal was to identify common differentially expressed (DE) genes among clinically relevant subclasses of BC using microarrays. METHODOLOGY/PRINCIPAL FINDINGS: BC samples and controls, both experimental and publicly available datasets, were analyzed by whole genome microarrays. We grouped the samples according to their histology and defined the DE genes in each sample individually, as well as in each tumor group. A dual analysis strategy was followed. First, experimental samples were analyzed and conclusions were formulated; and second, experimental sets were combined with publicly available microarray datasets and were further analyzed in search of common DE genes. The experimental dataset identified 831 genes that were DE in all tumor samples, simultaneously. Moreover, 33 genes were up-regulated and 85 genes were down-regulated in all 10 BC samples compared to the 5 normal tissues, simultaneously. Hierarchical clustering partitioned tumor groups in accordance to their histology. K-means clustering of all genes and all samples, as well as clustering of tumor groups, presented 49 clusters. K-means clustering of common DE genes in all samples revealed 24 clusters. Genes manifested various differential patterns of expression, based on PCA. YY1 and NFκB were among the most common transcription factors that regulated the expression of the identified DE genes. Chromosome 1 contained 32 DE genes, followed by chromosomes 2 and 11, which contained 25 and 23 DE genes, respectively. Chromosome 21 had the least number of DE genes. GO analysis revealed the prevalence of transport and binding genes in the common down-regulated DE genes; the prevalence of RNA metabolism and processing genes in the up-regulated DE genes; as well as the prevalence of genes responsible for cell communication and signal transduction in the DE genes that were down-regulated in T1-Grade III tumors and up-regulated in T2/T3-Grade III tumors. Combination of samples from all microarray platforms revealed 17 common DE genes, (BMP4, CRYGD, DBH, GJB1, KRT83, MPZ, NHLH1, TACR3, ACTC1, MFAP4, SPARCL1, TAGLN, TPM2, CDC20, LHCGR, TM9SF1 and HCCS) 4 of which participate in numerous pathways. CONCLUSIONS/SIGNIFICANCE: The identification of the common DE genes among BC samples of different histology can provide further insight into the discovery of new putative markers

An extended impedance‐based fault location algorithm in power distribution system with distributed generation using synchrophasors

Abstract Accurately locating power distribution faults reduces the total outage duration and provides better system reliability. Fault location using the traditional impedance‐based method may be very challenging in an active distribution system. However, taking into consideration the ease of implementation and cost effectiveness, a novel impedance‐based method is proposed to locate the fault by using the highly accurate time‐synchronized voltage and current phasors obtained from distribution phasor measurement units. The synchrophasor measurements obtained from the substation and various feeder segments are used in a two‐step algorithm based on the apparent impedance calculation to locate the exact source of the event. The algorithm uses phasor estimates to first identify the faulted feeder sub‐region and later uses measurements from a remote end device to eliminate pseudo‐faulted points to obtain the actual fault location. The effectiveness of the proposed method is realized using IEEE 34 bus system. Based on different fault types simulated at various parts of the system, the algorithm accurately estimates fault location in the range of ±1% of the line length. The proposed method is effective in locating faults for any type of network and topologies, with as many or as few (minimum 2) phasor measurement units in the system