Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer’s Disease | Frontiers in Aging Neuroscience

Alzheimer’s disease (AD) is the leading cause of dementia in elderly
people. The etiology of this disease remains a matter of intensive
research in many laboratories. We have advanced the idea that
disseminated fungal infection contributes to the etiology of AD. Thus,
we have demonstrated that fungal proteins and DNA are present in nervous
tissue from AD patients. More recently, we have reported that bacterial
infections can accompany these mycoses, suggesting that polymicrobial
infections exist in AD brains. In the present study, we have examined
fungal and bacterial infection in brain tissue from AD patients and
control subjects by immunohistochemistry. In addition, we have
documented the fungal and bacterial species in brain regions from AD
patients and control subjects by next-generation sequencing (NGS). Our
results from the analysis of ten AD patients reveal a variety of fungal
and bacterial species, although some were more prominent than others.
The fungal genera more prevalent in AD patients were Alternaria, Botrytis, Candida, and Malassezia.
We also compared these genera with those found in elderly and younger
subjects. One of the most prominent genera in control subjects was Fusarium.
Principal component analysis clearly indicated that fungi from frontal
cortex samples of AD brains clustered together and differed from those
of equivalent control subjects. Regarding bacterial infection, the
phylum Proteobacteria was the most prominent in both AD patients and controls, followed by Firmicutes, Actinobacteria, and Bacteroides. At the family level, Burkholderiaceae and Staphylococcaceae
exhibited higher percentages in AD brains than in control brains. These
findings could be of interest to guide targeted antimicrobial therapy
for AD patients. Moreover, the variety of microbial species in each
patient may constitute a basis for a better understanding of the
evolution and severity of clinical symptoms in each patient.

Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer’s Disease - IOS Press

As early as the 1980s, molecular virologist Ruth Itzhaki began to
investigate if there was a causal connection between infections and
neurodegenerative disorder. Although the theory has yet to be
universally embraced, in 2016 Itzhaki and 33 other scientists from all
over the world published a review
article in this very journal presenting evidence for the causal role of
pathogens in Alzheimer’s disease (AD). Exactly how and in what way
pathogens affect the induction of AD has yet to be determined, but one
possible answer may involve the cross-reactivity of different pathogens
with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum
and cerebrospinal fluid of AD patients and in some healthy individuals.
In the present study our major goal was to investigate whether
antibodies made against Aβ would react both with other brain proteins as
well as pathogens associated with AD as a result of molecular mimicry
or the binding of bacterial toxins to Aβ42. Our study used a specific
monoclonal antibody made against Aβ42, which not only reacted strongly
with Aβ42, tau protein, and α-synuclein, but also had from weak to
strong reactions with 25 different pathogens or their molecules, some of
which have been associated with AD. The homology between peptide
stretches of microbial origin and proteins involved in AD could be a
mechanism by which antibodies to homologous peptides mount attacks
against autoantigens in AD. We concluded that bacterial molecules bind
to Aβ protein, forming small oligomers, then encasing pathogens and
their molecules to form amyloid plaques, the tell-tale markers of AD.
Conversely, these same Aβ peptides induce the production of antibodies
to both Aβ42 and bacterial molecules, which may inhibit bacterial
pathogenesis, but in the process may promote amyloid plaque formation.

Commensal Microbes May Initiate and Drive Immune Responses in Lupus | Taconic Biosciences

At the end of March, researchers at Yale University published a paper entitled "Commensal orthologs of the human autoantigen Ro60 as triggers of autoimmunity in lupus"
in the journal Science Translational Medicine in which the authors
demonstrated that Ro60 orthologs exist in commensal bacteria commonly
found in or on the human body.


Greiling et al. demonstrated in human and mouse studies that
these bacterial orthologs of Ro may generate autoimmune responses that
drive lupus. The authors revealed that a high level of homology exists
between the major T and B cell epitopes within human Ro60 (hRo60) and
commensal Ro60 orthologs. Antibodies from anti-Ro60 positive lupus
patients, but not negative control patients preferentially
coimmunoprecipitated Ro60 ribonucleoproteins (RNPs) from a Ro60
ortholog-containing commensal organism. Further demonstrating the
cross-reactivity of orthologous Ro60, hRo60-reactive T cell clones, and
freshly isolated anti-Ro60-positive memory T cells responded to epitopes
derived from commensal Ro60 in vitro.

Study finds bacteria in milk linked to rheumatoid arthritis

A team of UCF College of Medicine researchers has discovered a link between rheumatoid arthritis and Mycobacterium avium subspecies paratuberculosis,
known as MAP, a bacteria found in about half the cows in the United
States. The bacteria can be spread to humans through the consumption of
infected milk, beef and produce fertilized by cow manure.

Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammat... - PubMed - NCBI

 OBJECTIVES:
Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored.
SUBJECTS:
Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice.
INTERVENTIONS:
The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used.

MEASUREMENTS AND MAIN RESULTS:
Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation.

CONCLUSIONS:
These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis."



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Confronted with bacteria, infected cells die so others can live, study finds -- ScienceDaily

 The immune system is contantly performing surveillance to detect foreign organisms that might do harm. But pathogens, for their part, have evolved a number of strategies to evade this detection, such as secreting proteins that hinder a host's ability to mount an immune response.

In a new study, a team of researchers led by Igor E. Brodsky of the University of Pennsylvania, identified a "back-up alarm" system in host cells that responds to a pathogen's attempt to subvert the immune system.

"In the context of an infection, the cells that are dying are talking to the other cells that aren't infected," said Brodsky, an assistant professor in the Department of Pathobiology in Penn's School of Veterinary Medicine and senior author on the study. "I don't think of it as altruistic, exactly, but it's a way for the cells that can't respond any longer to still alert their neighbors that a pathogen is present.""



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Polymicrobial Infections In Brain Tissue From Alzheimer's Disease Patients.

Several studies have advanced the idea that the etiology of Alzheimer's disease (AD) could be microbial in origin. In the present study, we tested the possibility that polymicrobial infections exist in tissue from the entorhinal cortex/hippocampus region of patients with AD using immunohistochemistry (confocal laser scanning microscopy) and highly sensitive (nested) PCR. We found no evidence for expression of early (ICP0) or late (ICP5) proteins of herpes simplex virus type 1 (HSV-1) in brain sections. A polyclonal antibody against Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested PCR in the ten patients analyzed. By contrast, two independent Chlamydophila antibodies revealed several structures that resembled fungal cells and hyphae, and prokaryotic cells, but most probably were unrelated to Chlamydophila spp. Finally, several structures that could belong to fungi or prokaryotes were detected using peptidoglycan and Clostridium antibodies, and PCR analysis revealed the presence of several bacteria in frozen brain tissue from AD patients. Thus, our results show that polymicrobial infections consisting of fungi and bacteria can be revealed in brain tissue from AD patients."



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Frontiers | 16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain | Frontiers in Aging Neuroscience

The neurological deterioration associated with Alzheimer’s disease (AD), involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene-specific Next generation sequencing (NGS) of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal."

Researchers add to evidence that common bacterial cause of gum disease may drive rheumatoid arthritis -- ScienceDaily

In a report on the work, published in the Dec. 14 edition of the journal Science Translational Medicine, the investigators say the common denominator they identified in periodontal disease (gum disease) and in many people with rheumatoid arthritis is Aggregatibacter actinomycetemcomitans. An infection with A. actinomycetemcomitans appears to induce the production of citrullinated proteins, which are suspected of activating the immune system and driving the cascade of events leading to rheumatoid arthritis."

Translational Medicine paper:-

Aggregatibacter actinomycetemcomitans–induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

A Bacterial Component to Alzheimer’s-Type Dementia Seen via a Systems Biology Approach that Links Iron Dysregulation and Inflammagen Shedding to Disease

The progression of Alzheimer’s disease (AD) is accompanied by a great many observable changes, both molecular and physiological. These include oxidative stress, neuroinflammation, and (more proximal to cognitive decline) the death of neuronal and other cells. A systems biology approach seeks to organize these observed variables into pathways that discriminate those that are highly involved (i.e., causative) from those that are more usefully recognized as bystander effects. We review the evidence that iron dysregulation is one of the central causative pathway elements here, as this can cause each of the above effects. In addition, we review the evidence that dormant, non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted."



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Antiobesity effect of Pediococcus pentosaceus LP28 on overweight subjects: a randomized, double-blind, placebo-controlled clinical trial : European Journal of Clinical Nutrition

Background/Objectives:
The population of the obese is increasing worldwide. Prevention and improvement of obesity are indispensable for decreasing the risk of metabolic disorders. We have recently shown that obesity and fatty liver are reduced by a plant-derived lactic acid bacterium, Pediococcus pentosaceus LP28 (LP28), in high-fat diet-induced obese mice. The aim of the present clinical study is to prove that LP28 is effective for reducing body fat and body weight, as shown in the experiment using mice.

Subjects/Methods:

The clinical trial was carried out as a double-blind, randomized, placebo-controlled study comprising 62 subjects (20–70 years of age, BMI 25–30 kg/m2). These subjects were randomly assigned to three groups that received living LP28, heat-killed LP28 or a placebo powder, administered orally once a day for 12 weeks.

Results:

Heat-killed LP28 reduced BMI (0.45 kg/m2, 95% CI (0.04, 0.86), P=0.035), body fat percentage (1.11%, (0.39, 1.82), P=0.002), body fat mass (1.17 kg (0.43, 1.92), P=0.004) and waist circumference (2.84 cm (0.74, 4.93), P=0.009) when compared with a placebo group. Fasting plasma glucose, HbA1c, fasting insulin, HOMA-IR and serum lipids levels did not change by either living LP28 or heat-killed LP28 intake.

Conclusions:

Heat-killed LP28 displays an antiobesity effect that reduces BMI, body fat and waist circumference, suggesting that the plant-derived lactic acid bacterium LP28 would be a promising preventive of metabolic syndrome."



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Microbial DNA records historical delivery of anthropogenic mercury

 "Mercury (Hg) is an anthropogenic pollutant that is toxic to wildlife and humans, but the response of remote ecosystems to globally distributed Hg is elusive. Here, we use DNA extracted from a dated sediment core to infer the response of microbes to historical Hg delivery. We observe a significant association between the mercuric reductase gene (merA) phylogeny and the timing of Hg deposition. Using relaxed molecular clock models, we show a significant increase in the scaled effective population size of the merA gene beginning ~200 years ago, coinciding with the Industrial Revolution and a coincident strong signal for positive selection acting on residues in the terminal region of the mercuric reductase. This rapid evolutionary response of microbes to changes in the delivery of anthropogenic Hg indicates that microbial genomes record ecosystem response to pollutant deposition in remote regions."



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Bacterial remodelling of the host epigenome: functional role and evolution of effectors methylating host histones. - PubMed - NCBI

The modulation of the chromatin organization of eukaryotic cells plays
an important role in regulating key cellular processes including host
defence mechanisms against pathogens. Thus, to successfully survive in a
host cell, a sophisticated bacterial strategy is the subversion of
nuclear processes of the eukaryotic cell. Indeed, the number of
bacterial proteins that target host chromatin to remodel the host
epigenetic machinery is expanding. Some of the identified bacterial
effectors that target the chromatin machinery are "eukaryotic-like"
proteins as they mimic eukaryotic histone writers in carrying the same
enzymatic activities. The best-studied examples are the SET-domain
proteins that methylate histones to change the chromatin landscape. In
this review we will discuss SET-domain proteins identified in the
Legionella, Chlamydia and Bacillus genomes that encode enzymatic
activities targeting host histones. Moreover, we discuss their possible
origin as having evolved from prokaryotic ancestors or having been
acquired from their eukaryotic hosts during their co-evolution. The
characterization of such bacterial effectors as modifiers of the host
chromatin landscape is an exciting field of research as it elucidates
new bacterial strategies to manipulate host functions through histone
modifications but it also may identify new modifications of the
mammalian host cells not known before.

Bacteria (Staph aureus )may cause type 2 diabetes -- ScienceDaily

The research team led by Patrick Schlievert, PhD, professor and DEO of
microbiology at the UI Carver College of Medicine, found that prolonged
exposure to a toxin produced by Staphylococcus aureus (staph)
bacteria causes rabbits to develop the hallmark symptoms of Type 2
diabetes, including insulin resistance, glucose intolerance, and
systemic inflammation.

Bacterial protein implicated in eating disorders - Medical News Today

Eating disorders (ED) such as anorexia nervosa, bulimia, and binge eating disorder affect approximately 5-10% of the general population, but the biological mechanisms involved are unknown.

Researchers at Inserm Unit 1073, "Nutrition, inflammation and dysfunction of the gut-brain axis" (Inserm/University of Rouen) have demonstrated the involvement of a protein produced by some intestinal bacteria that may be the source of these disorders. Antibodies produced by the body against this protein also react with the main satiety hormone, α-melanocyte-stimulating hormone, which is similar in structure. According to the researchers, it may ultimately be possible to correct this mechanism that causes variations in food intake.

These results are published in the journal Translational Psychiatry, in the online issue of 7 October 2014.
Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide α-MSH, at the origin of eating disorders

Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes.

BACKGROUND:

A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs
accumulate inactivating mutations or deletions and thus lose the ability
to replicate. Additionally, REs can be transcriptionally repressed by
dedicated mechanisms of the host. Nevertheless, many of them still
possess and express intact open reading frames, and their
transcriptional activity has been associated with many physiological and
pathological processes of the host. However, this association remains
tenuous due to incomplete understanding of the mechanism by which RE
transcription is regulated. Here, we use a bioinformatics tool to
examine RE transcriptional activity, measured by microarrays, in murine
and human immune cells responding to microbial stimulation.

RESULTS:

Immune cell activation by microbial signals in vitro caused extensive changes
in the transcription not only of the host genes involved in the immune
response, but also of numerous REs. Modulated REs were frequently found
near or embedded within similarly-modulated host genes. Focusing on
probes reporting single-integration, intergenic REs, revealed extensive
transcriptional responsiveness of these elements to microbial signals.
Microbial stimulation modulated RE expression in a cell-intrinsic
manner. In line with these results, the transcriptional activity of
numerous REs followed characteristics in different tissues according to
exposure to environmental microbes and was further heavily altered
during viral infection or imbalances with intestinal microbiota, both in
mice and humans.

CONCLUSIONS:

Together, these results highlight the utility of improved methodologies in assessing RE
transcription profiles in both archived and new microarray data sets.
More importantly, application of this methodology suggests that immune
activation, as a result of infection with pathogens or dysbiosis with
commensal microbes, causes global modulation of RE transcription. RE
responsiveness to external stimuli should, therefore, be considered in
any association between RE transcription and disease.

Bacteria help explain why stress, fear trigger heart attacks

Scientists believe they have an explanation for the axiom that stress,
emotional shock, or overexertion may trigger heart attacks in vulnerable
people. Hormones released during these events appear to cause bacterial
biofilms on arterial walls to disperse, allowing plaque deposits to
rupture into the bloodstream, according to research published in
published today in mBio, the online open-access journal of the American Society for Microbiology. At least one species of bacteria - Pseudomonas aeruginosa - commonly
associated with carotid arteries in our studies, was able to undergo a
biofilm dispersion response when exposed to norepinephrine, a hormone
responsible for the fight-or-flight response in humans," said Davies.
Because the biofilms are closely bound to arterial plaques, the
dispersal of a biofilm could cause the sudden release of the surrounding
arterial plaque, triggering a heart attack.

Microbes and Cancer

Gum disease bacteria may cause heart disease

A University of Florida study shows that the same bacteria that cause gum disease also promotes heart disease – a discovery that could change the way heart disease is diagnosed and treated. Researchers report their findings today at the annual meeting of the American Society for Microbiology.

"We report evidence that introduction of oral bacteria into the bloodstream in mice increased risk factors for atherosclerotic heart disease. Our hope is that the American Heart Association will acknowledge causal links between oral disease and increased heart disease. That will change how physicians diagnose and treat heart disease patients," says Irina M. Velsko, a graduate student in the University of Florida's College of Medicine, who presented the data.

Galectins direct immunity against bacteria that employ camouflage

Our bodies produce a family of proteins that recognize and kill
bacteria whose carbohydrate coatings resemble those of our own cells too
closely, scientists have discovered.


Called galectins, these proteins recognize carbohydrates (glycans) from a
broad range of disease-causing bacteria, and could potentially be
deployed as antibiotics to treat certain infections. The results are
scheduled for publication in Nature Chemical Biology.

In contrast to antibodies, the galectins kill the bacteria directly,
without needing other parts of the immune system to pile on. The
researchers identified several varieties of bacteria (Pseudomonas
aeruginosa, Providencia alcalifaciens, Klebsiella pneumoniae, and
Serratia marcescens, for example) targeted for killing by galectins. In
some cases, only certain strains of a given bacteria were vulnerable,
because only those strains carried the target glycan.