Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. A role for excess neurotrophic sAPPα and reduced antimicrobial Aβ - ScienceDirect

Prenatal and early childhood infections have been implicated in autism.
Many autism susceptibility genes (206 Autworks genes) are localised in
the immune system and are related to immune/infection pathways. They are
enriched in the host/pathogen interactomes of 18 separate microbes
(bacteria/viruses and fungi) and to the genes regulated by bacterial
toxins, mycotoxins and Toll-like receptor ligands. This enrichment was
also observed for misregulated genes from a microarray study of
leukocytes from autistic toddlers. The upregulated genes from this
leukocyte study also matched the expression profiles in response to
numerous infectious agents from the Broad Institute molecular signatures
database. They also matched genes related to sudden infant death
syndrome and autism comorbid conditions (autoimmune disease, systemic
lupus erythematosus, diabetes, epilepsy and cardiomyopathy) as well as
to estrogen and thyrotropin responses and to those upregulated by
different types of stressors including oxidative stress, hypoxia,
endoplasmic reticulum stress, ultraviolet radiation or
2,4-dinitrofluorobenzene, a hapten used to develop allergic skin
reactions in animal models. The oxidative/integrated stress response is
also upregulated in the autism brain and may contribute to myelination
problems. There was also a marked similarity between the expression
signatures of autism and Alzheimer's disease, and 44 shared
autism/Alzheimer's disease genes are almost exclusively expressed in the
blood-brain barrier. However, in contrast to Alzheimer's disease,
levels of the antimicrobial peptide beta-amyloid are decreased and the
levels of the neurotrophic/myelinotrophic soluble APP alpha are
increased in autism, together with an increased activity of α-secretase.
sAPPα induces an increase in glutamatergic and a decrease in GABA-ergic
synapses creating and excitatory/inhibitory imbalance that has also
been observed in autism. A literature survey showed that multiple autism
genes converge on APP processing and that many are able to increase
sAPPalpha at the expense of beta-amyloid production. A genetically
programmed tilt of this axis towards an overproduction of
neurotrophic/gliotrophic sAPPalpha and underproduction of antimicrobial
beta-amyloid may explain the brain overgrowth and myelination
dysfunction, as well as the involvement of pathogens in autism.

Food additive found in candy, gum could alter digestive cell structure and function: Small intestinal cells hindered by chronic exposure to common food additive -- ScienceDaily

"The ability of small intestine cells to absorb nutrients and act as a barrier to pathogens is 'significantly decreased' after chronic exposure to nanoparticles of titanium dioxide, a common food additive found in everything from chewing gum to bread, according to new research."



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What Sensory Receptors Do Outside of Sense Organs | The Scientist Magazine®

Odor, taste, and light receptors are present in many different parts of the body, and they have surprisingly diverse functions.

Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour : Nature

Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.

Alzheimer’s disease could be caused by herpes virus, warn experts - Telegraph

"Alzheimer’s disease could be caused by viruses like herpes, a group of renowned dementia experts have warned, as they call for urgent investigation into the link.
The worldwide team of 31 senior scientists and clinicians, which include specialists from Oxford, Cambridge, Edinburgh and Manchester Universities and Imperial College, have written an editorial which suggests that microbes are the major cause of dementia.
The herpes virus - the type which causes cold sores - and chlamydia bacteria are named as the major culprits, as well as a type of corkscrew-shaped bacteria called spirochaetes."

Cat scratches, not bites, are associated with unipolar depression - cross-sectional study. - PubMed - NCBI

 A recent study performed on 1.3 million patients showed a strong association between being bitten by a cat and probability of being diagnosed with depression. Authors suggested that infection with cat parasite Toxoplasma could be the reason for this association.

METHOD:

A cross sectional internet study on a non-clinical population of 5,535 subjects was undertaken.

RESULTS:

The subjects that reported having been bitten by a dog and a cat or scratched by a cat have higher Beck depression score. They were more likely to have visited psychiatrists, psychotherapists and neurologists in past two years, to have been previously diagnosed with depression (but not with bipolar disorder). Multivariate analysis of models with cat biting, cat scratching, toxoplasmosis, the number of cats at home, and the age of subjects as independent variables showed that only cat scratching had positive effect on depression (p = 0.004). Cat biting and toxoplasmosis had no effect on the depression, and the number of cats at home had a negative effect on depression (p = 0.021).

CONCLUSIONS:

Absence of association between toxoplasmosis and depression and five times stronger association of depression with cat scratching than with cat biting suggests that the pathogen responsible for mood disorders in animals-injured subjects is probably not the protozoon Toxoplasma gondii but another organism; possibly the agent of cat-scratched disease - the bacteria Bartonella henselae.

Infectious and inflammatory markers in schizophrenia

A number of infectious and inflammatory markers have been associated
with schizophrenia but previous investigations have not yielded
definitive conclusions. We examined multiple antibodies to infectious
agents and food antigens as well as protein markers of inflammation in
well-characterized individuals with a recent onset of psychosis (N = 106), persistent schizophrenia (N = 261), and controls (N = 233).
Linear regression methods were used to calculate the association
between the markers in both patient groups in comparison with controls
adjusting for demographic factors. For the recent onset group,
significant associations were found for IgG antibodies to measles (t = 8.31, p < .001), gliadin (t = 5.90, p < .001), bovine casein (t = 4.74, p < .001), human coronavirus (t = 2.89, p = .004), Toxoplasma gondii (t = 2.20, p = .029), and the group D retroviruses, Mason-Pfizer monkey virus (t = 3.97, p < .001) and murine leukemia virus (t = 3.27, p = .001). For the persistent schizophrenia group, significant associations were found for C-reactive protein (t = 7.47, p ⩽ .001); IgG antibodies to wheat gliadin (t = 2.58, p = .010), Saccharomyces cerevisiae (t = −2.78, p < .006), measles (t = 2.37, p = .018), Herpes simplex virus (HSV) type 2 (t = 2.56, p = .011), and human coronavirus (t = 2.67, p = .008).
No significant case-control differences were found for antibodies to
cytomegalovirus, HSV-1, Epstein-Barr Virus, varicella-zoster virus, or
influenza viruses. These results indicate overlap between the markers
found in recent onset psychosis and in persistent schizophrenia. Future
studies that assess patients throughout the course of the illness may
further identify the infectious and inflammatory factors that contribute
to disease pathogenesis.

An observational study of inflammation in the central nervous system in patients with bipolar disorder.

OBJECTIVES:

The potential influence of infections andimmunological changes on the aetiology and pathogenesis of bipolar disorder (BD) has been discussed. Our aim was to detect intrathecal specific antibody synthesis against the neurotropic infectious agents that have previously been linked to BD.

METHODS:

Paired cerebrospinal fluid (CSF) and serum samples from 40 patients with BD
were analysed using the enzyme-linked immunosorbent assay to detect the
concentration of antibodies against the following neurotropic infectious
pathogens: Toxoplasma gondii (T. gondii), herpes simplex virus (HSV)
types 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The
specific antibody index (AI) was calculated, and an AI > 1.4 was
considered to be evidence of intrathecal specific antibody synthesis.
Twenty-six patients with pseudotumour cerebri served as controls.

RESULTS:

Eight out of 40 patients with BD displayed specific intrathecal antibody synthesis against at least one of the tested neurotropic agents compared to only one patient in the control group (p = 0.061, not significant) . Of these eight patients with BD, no significant prevalence of any particular neurotropic pathogen was evident. Five out of 40 patients with BD showed oligoclonal bands in the CSF, suggestive of a chronic immune reaction in the central nervous system (CNS).

CONCLUSIONS:

We found evidence for increased production of antibody in the CSF of individuals with BD. However, the trend for polyspecific intrathecal antibody synthesis, as well as the presence of oligoclonal bands, might indicate activation of the intrathecal humoral immune system in a subgroup of patients with BD, as it is known to be associated with autoimmune disorders of the CNS.

Characterization of salivary proteins of schizophrenic and bipolar disorder patients by top-down proteomics.

The analysis of whole saliva of 32 subjects with diagnosis of
schizophrenia (SZ), 17 with diagnosis of bipolar disorder (BD), and 31
healthy subjects divided in non smokers (HN; n=19) and smokers (HS;
n=12) using an HPLC-ESI-MS top-down platform is reported in this study.
Both SZ and BD revealed more than 10 fold mean increase of α-defensins
1-4, S100A12, cystatin A and S-derivatives of cystatin B levels with
respect to the HN and HS control groups. No differences of protein
levels were observed between SZ and BD groups and between HN and HS
groups. Moreover, the correlations coefficients among the different
proteins were significantly better in BD group than in SZ group.

SIGNIFICANCE:

This
study on whole saliva confirms a shizophrenia-associated dysregulation
of immune pathway of peripheral white blood cells and suggests that the
dysregulation of BD group could involve the activation of more specific
cell type than those of SZ group.

Specific inhibition of diverse pathogens in human cells by synthetic microRNA-like oligonucleotides inferred from RNAi screens

Systematic genetic perturbation screening in human cells remains technically challenging. Typically, large libraries of chemically synthesized siRNA oligonucleotides are used, each designed to degrade a specific cellular mRNA via the RNA interference (RNAi) mechanism. Here, we report on data from three genome-wide siRNA screens, conducted to uncover host factors required for infection of human cells by two bacterial and one viral pathogen. We find that the majority of phenotypic effects of siRNAs are unrelated to the intended “on-target” mechanism, defined by full complementarity of the 21-nt siRNA sequence to a target mRNA. Instead, phenotypes are largely dictated by “off-target” effects resulting from partial complementarity of siRNAs to multiple mRNAs via the “seed” region (i.e., nucleotides 2–8), reminiscent of the way specificity is determined for endogenous microRNAs. Quantitative analysis enabled the prediction of seeds that strongly and specifically block infection, independent of the intended on-target effect. This prediction was confirmed experimentally by designing oligos that do not have any on-target sequence match at all, yet can strongly reproduce the predicted phenotypes. Our results suggest that published RNAi screens have primarily, and unintentionally, screened the sequence space of microRNA seeds instead of the intended on-target space of protein-coding genes. This helps to explain why previously published RNAi screens have exhibited relatively little overlap. Our analysis suggests a possible way of identifying “seed reagents” for controlling phenotypes of interest and establishes a general strategy for extracting valuable untapped information from past and future RNAi screens.

Relationships Between Metals Exposure and Epidemiological Parameters of Two Pathogens in Urban Pigeons.

 Human activities often generate or increase concentration of chemical compounds including pesticides, hydrocarbons and metals that can potentially affect ecological interactions. We found that elevated levels of zinc in pigeon feathers were associated with both low prevalence of Chlamydiaceae (ornithosis disease) and low intensity of blood pathogens (Haemosporidian parasites). In contrast, high levels of lead in pigeon feathers were associated with high blood pathogens intensities. Our results suggest that metals linked to human activities in cities such as zinc and lead may play a significant role in the ecology of host-parasite interactions and could potentially affect the epidemiology of diseases in the urban environment.

.............................................Perhaps more important than it looks given the involvement of pollutants and pathogens in many human diseases.

Antimicrobial peptide beta-defensin-1 expression is upregulated in Alzheimer's brain.

The human beta-defensins (hBDs) are a highly conserved family of cationic antimicrobial and immunomodulatory peptides expressed primarily by epithelial cells in response to invasion by bacteria, fungi and some viruses. To date, the most studied members of this family of peptides are hBD-1, -2, and -3. Expression of hBD-1 and -2 has been demonstrated previously in cultured microglia and astrocytes of both mouse and human brain. Unlike inducible hBD-2 and -3, hBD-1 is constitutively expressed and is not generally upregulated by proinflammatory factors. In this study, we investigated whether hBDs, as active components of the innate immune response, are affected by pathological events in the Alzheimer's disease (AD) brain. We assessed the expression of hBD-1, -2, and -3 in tissue obtained at autopsy from AD and age-matched control brains.
METHODS:
Fixed and frozen choroid plexus and the CA1 region of the hippocampus were obtained at autopsy from individuals diagnosed with AD, or from age-matched control brains without diagnosed neurodegenerative disease. Histopathologically diagnosed AD brain tissue was obtained for our study. Immunocytochemical analysis was performed using affinity purified polyclonal antibodies directed against hBD-1, -2, or -3. TaqMan gene expression assays were used to quantify the mRNA of hBD-1, -2, and -3 in the choroid plexus and hippocampus. Immunocytochemical detection of iron deposits was achieved using a modified Perl's stain for redox-active iron. In vitro experiments were performed on human primary oral epithelial cells to model the human choroid plexus epithelial response to ferric chloride. Cells were then exposed to ferric chloride added to selected wells at 0, 1, or 10 mM concentrations for 24 h at 37[degree sign]C. Total mRNA was isolated to quantify hBD-1 mRNA expression by RTqPCR.
RESULTS:
hBD-1 peptide is apparent in astrocytes of the AD hippocampus and hippocampal neurons, notably within granulovacuolar degeneration structures (GVD). A higher level of hBD-1 was also seen in the choroid plexus of AD brain in comparison to age-matched control tissue. Increased expression of hBD-1 mRNA was observed only in the choroid plexus of the AD brain when compared to expression level in age-matched control brain. Redox-active iron was also elevated in the AD choroid plexus and in vitro addition of Fe+3Cl3 to cultured epithelial cells induced hBD-1 mRNA expression.
CONCLUSIONS:
Our findings suggest interplay between hBD-1 and neuroimmunological responses in AD, marked by microglial and astrocytic activation, and increased expression of the peptide within the choroid plexus and accumulation within GVD. As a constitutively expressed component of the innate immune system, we propose that hBD-1 may be of considerable importance early in the disease process. We also demonstrate that increased iron deposition in AD may contribute to the elevated expression of hBD-1 within the choroid plexus. These findings represent a potentially important etiological aspect of Alzheimer's disease neuropathology not previously reported.

Expelled DNA that traps toxins may backfire in obese

The body's most powerful immune cells may have a radical way of catching their prey that could backfire on people who are overweight and others at risk for cancer, diabetes and chronic inflammation, suggests a new Cornell study.The study is the first to show that the DNA of macrophages, the biggest immune cells, can unravel and move outside the cell to snag invading pathogens. Called extracellular traps, these sticky DNA remnants can occur anywhere, but the study found a troubling number inside rafts of macrophages surrounding dead fat cells in obese mice.
In that extracellular environment, the traps feed a vicious cycle of inflammation, increasing risk of several major diseases, the scientists predict. Uncovering what causes macrophage DNA to unravel, the study included a description indicating new preventative therapies for these diseases may be near at hand.

How Do Immune Cells Detect Infections?

Previous research, published in Nature Immunology by investigators in the US suggested that the T cells of the immune system behave in a similar way to bees when coordinating responses to disease pathogens and vaccines - sharing essential information in the same way.

This study, which was published in the journal Physical Review Letters, involved using computational models to find out what solutions the immune system uses to identify foreign antigens (which can cause infections).

Cell - Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease

The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer’s disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.

Global rise in type 1 diabetes may be linked to reduced exposure to pathogens in early life

 "Countries with lower mortality from infectious disease exhibit higher rates of type 1 diabetes, according to a new study by Dr. A. Abela and Professor S. Fava of the University of Malta. The findings, collating data from three major international studies and presented at the Society for Endocrinology annual conference in Harrogate UK, suggest that the as yet unexplained global rise in type 1 diabetes may be linked to reduced exposure to pathogens in early life."

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Pathogen free conditions slow the onset of neurodegeneration in a mouse model of nerve growth factor deprivation.

Several studies suggest that systemic infection occurring during aging and chronic neurodegenerative diseases can evoke an exaggerated immune response that contributes to the progression of neurodegeneration and cognitive decline. However, studies directly addressing the relationship between microbial environment and the onset of neurodegeneration in Alzheimer's disease animal models are lacking. Here we show that the onset of neurodegeneration that transgenic mice develop when raised in conventional husbandry slows down when raising anti-nerve growth factor transgenic mice in a murine pathogen free condition.

Scientists discover dendritic cells key to activating human immune responses

Scientists at A*STAR’s Singapore Immunology Network (SIgN), in collaboration with Newcastle University, UK, the Singapore Institute of Clinical Sciences and clinicians from multiple hospitals in Singapore, have identified a new subset of dendritic cells (DCs) in human peripheral tissue which have a critical role in activating our immune response against harmful pathogens. This research will have significant impact on the design of vaccines and other targeted immunotherapies. The scientists also showed for the first time that DC subsets are conserved between species, facilitating the translation of mouse functional DC studies to the human setting. These research findings were published in the July issue of the prestigious journal Immunity.

How infectious disease may have shaped human origins

Mutations in immune-related genes resulting in increased resistance to pathogens may have shaped human evolution, promulgating the explosion and expansion of the human population 100, 000 years ago. 

Scientists discover 'switch' to boost anti-viral response to fight infectious diseases

Singapore scientists from Bioprocessing Technology Institute (BTI) under the Agency of Science, Technology and Research have for the first time, identified the molecular ‘switch’ that directly triggers the body’s first line of defence against pathogens, more accurately known as the body’s “innate immunity”. The scientists found that this ‘switch’ called Bruton’s tyrosine kinase (BTK) when turned on, activates the production of interferons - a potent class of virus killers that enables the body to fight harmful pathogens such as dengue and influenza viruses.