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.

A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents | Adolescent Medicine | JAMA Psychiatry | JAMA Network

Importance
Infections have been associated with increased risks for
mental disorders, such as schizophrenia and depression. However, the
association between all infections requiring treatment and the wide
range of mental disorders is unknown to date.

Objective
To investigate the association between all treated infections
since birth and the subsequent risk of development of any treated mental
disorder during childhood and adolescence.

Design, Setting, and Participants
Population-based cohort study using Danish nationwide
registers. Participants were all individuals born in Denmark between
January 1, 1995, and June 30, 2012 (N = 1 098 930). Dates of analysis
were November 2017 to February 2018.

Exposures
All treated infections were identified in a time-varying
manner from birth until June 30, 2013, including severe infections
requiring hospitalizations and less severe infection treated with
anti-infective agents in the primary care sector.

Main Outcomes and Measures
This study identified all mental disorders diagnosed in a
hospital setting and any redeemed prescription for psychotropic
medication. Cox proportional hazards regression was performed reporting
hazard rate ratios (HRRs), including 95% CIs, adjusted for age, sex,
somatic comorbidity, parental education, and parental mental disorders.

Results
A total of 1 098 930 individuals (51.3% male) were followed up
for 9 620 807.7 person-years until a mean (SD) age of 9.76 (4.91)
years. Infections requiring hospitalizations were associated with
subsequent increased risk of having a diagnosis of any mental disorder
(n = 42 462) by an HRR of 1.84 (95% CI, 1.69-1.99) and with increased
risk of redeeming a prescription for psychotropic medication
(n = 56 847) by an HRR of 1.42 (95% CI, 1.37-1.46). Infection treated
with anti-infective agents was associated with increased risk of having a
diagnosis of any mental disorder (HRR, 1.40; 95% CI, 1.29-1.51) and
with increased risk of redeeming a prescription for psychotropic
medication (HRR, 1.22; 95% CI, 1.18-1.26). Antibiotic use was associated
with particularly increased risk estimates. The risk of mental
disorders after infections increased in a dose-response association and
with the temporal proximity of the last infection. In particular,
schizophrenia spectrum disorders, obsessive-compulsive disorder,
personality and behavior disorders, mental retardation, autistic
spectrum disorder, attention-deficit/hyperactivity disorder,
oppositional defiant disorder and conduct disorder, and tic disorders
were associated with the highest risks after infections.

Conclusions and Relevance
Although the results cannot prove causality, these findings
provide evidence for the involvement of infections and the immune system
in the etiology of a wide range of mental disorders in children and
adolescents.

$1 Million Prize for Alzheimer’s Disease Germ Announced by Dr. Leslie Norins on ALZgerm.org

Leslie Norins, MD, PhD, CEO of Alzheimer’s Germ Quest, Inc., announces a
$1 million challenge award for the scientist who provides persuasive
evidence that an infectious agent is the root cause of Alzheimer’s
disease. The three-year contest begins January 16, 2018. Details are
provided at ALZgerm.org..

Building Bridges Between Infectious Disease Physicians and Psychiatrists

Complex problems require complex solutions with interdisciplinary cooperation.
When state mental hospitals were filled with mentally ill patients who
had syphilis, everyone recognized the close association between
infectious disease and psychiatric illness. In fact, in 1927, the first
Nobel prize in Psychiatry was awarded to Dr. Julius Wagner-Jauregg who
recognized the association between infections and mental illness and
introduced malaria inoculation, which proved to be very successful in
treating dementia paralytica. After the introduction of penicillin, the
gap between these two specialties widened with specialization and
fragmentation in medicine resulting in few physicians maintaining
updated capability in both infectious disease and psychiatry. Most
infectious disease physicians have very little current training in
neurochemistry, psychoimmunology, or the pathophysiology of mental
illness. Likewise, many psychiatrists have little current training in
infectious diseases and psychoimmunology.

More recently, this gap has been bridged by advances in evolutionary
medicine, a growing recognition of the significance of the microbiome,
improved brain imaging and testing capabilities and discoveries in
psychoimmunology which have greatly expanded our knowledge of the
pathophysiology of mental illness. Now, many, including the Center for
Disease and Prevention recognize chronic diseases and the mental
illnesses can stem from infectious agents.

Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease - IOS Press

Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy."



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Studies help explain link between autism, severe infection during pregnancy

 "Mothers who experience an infection severe enough to require hospitalization during pregnancy are at higher risk of having a child with autism. Two new studies from MIT and the University of Massachusetts Medical School shed more light on this phenomenon and identify possible approaches to preventing it.

In research on mice, the researchers found that the composition of bacterial populations in the mother's digestive tract can influence whether maternal infection leads to autistic-like behaviors in offspring. They also discovered the specific brain changes that produce these behaviors."



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‘Adrenaline’ of Immune System Discovered

Scientists at the Champalimaud Centre for the Unknown and the Instituto de Medicina Molecular, in Lisbon, Portugal, have discovered that neurons located at mucosal tissues can immediately detect an infection in the organism, promptly producing a substance that acts as an “adrenaline rush” for immune cells. Under the effect of this signal, immune cells rapidly become poised to fight the infection and repair the damage caused to surrounding tissues. These totally novel results have been published online in the journal Nature on September 6, 2017.


Published in Nature:- Neuronal regulation of type 2 innate lymphoid cells via neuromedin U” by Vânia Cardoso, Julie Chesné, Hélder Ribeiro, Bethania García-Cassani, Tânia Carvalho, Tiffany Bouchery, Kathleen Shah, Nuno L. Barbosa-Morais, Nicola Harris & Henrique Veiga-Fernandes in Nature. Published online September 6 2017 doi:10.1038/nature23469

Study finds link between upper GI infections and protein (synuclein) implicated in Parkinson’s disease

 "Acute and chronic infections in a person's upper gastrointestinal tract appear to be linked to Parkinson's disease, say scientists at Georgetown University Medical Center and their collaborators at the National Institutes of Health and other institutions.

Their study, published in the Journal of Innate Immunity, finds that alpha-Synuclein (αS), the protein implicated in Parkinson's disease and other forms of neurodegenerative diseases, is released when an infection occurs in the upper GI tract (the esophagus, stomach, and duodenum) inducing an immune response as part of the body's innate immune system. The researchers say that these findings suggest that frequent or chronic upper GI infections could overwhelm the body's capacity to clear αS, leading to disease."



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Related articles

• Could "Advanced Probiotics" Soon Treat Parkinson's Disease?

Prenatal fever and autism risk. - PubMed - NCBI

 Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09-1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks' gestation (aOR, 3.12; 1.28-7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks' gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD"



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Infections more common in people with schizophrenia

The researchers adjusted the data for other factors that might affect a person's risk of infection. They still found that people with schizophrenia had about twice the risk of skin, urological or genital infections, or tuberculosis than those in the general population.

The investigators also found that addiction and having other health problems were the most important factors associated with severe infection. Each one increased the risk of serious infection by 2.7 times in both people with schizophrenia and those in the general population.

Molecular Psychiatry - Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

 Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.



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Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment: Immunity

Highlights
•Viruses induce depressive behavior and ISG15 expression at the blood-brain barrier
•IFNAR1 expression on neural cells is not involved in IFN-β-induced sickness behavior
•IFNAR1 expression on brain endothelial and epithelial cells drives behavioral changes
•Brain endothelia- and epithelia-derived CXCL10 inhibits hippocampal synaptic plasticity

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy."



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Body’s defenses against common viruses may mess up neurons, spark depression | Ars Technica

Getting sick is definitely a bummer. But besides feeling icky and being stuck in bed, viral infections may cause us to actually be depressed. While scientists have been clued into this connection for a while, there was little data on how everyday viral infections, like the flu, might mess with our moods.

Now, data from a new mouse study shows that common viruses may spur sadness by causing the cells that line the blood-brain barrier to release signals that hush the chatter between neurons in the area of the brain responsible for mood. The findings, published this week in the journal Immunity, may finally explain the link between infections and mental health problems, and it could point researchers towards new strategies for treating depression and other mood disorders.

Researchers have been collecting hints of the connection between mental health and infections for years. Though it was first dismissed as people simply being blue about getting sick, doctors now accept that there is a condition called “sickness behavior.” This condition is marked by cognitive deficits, drowsiness, general malaise, and other depression-like symptoms in those with an infection. Moreover, in a 2013 Danish study, researchers found that people who had been treated for a severe infection were 62 percent more likely to suffer from mood disorders. Perhaps related, those that had an autoimmune disease were 45 percent more likely to have such a mental health issue."



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Mild Infection May Raise Risk for Severe Mental Illness

 "FLORENCE, Italy — Even mild infections significantly increase the risk of later developing schizophrenia and mood disorders, results of a large, population-based registry study indicate (from the Danish Register).

Regarding the prescribing of anti-infective medications as a proxy for mild infections, the team found that any prior prescription increased the risk for schizophrenia by 37% and the risk for mood disorders by 64%, fitting dose-response and temporal relationships."

Bacterial infection remodels the DNA methylation landscape of human dendritic cells

DNA methylation is an epigenetic mark thought to be robust
to environmental perturbations on a short time scale. Here, we challenge that
view by demonstrating that the infection of human dendritic cells (DCs) with a
live pathogenic bacteria is associated with rapid and active demethylation at
thousands of loci, independent of cell division. We performed an integrated
analysis of data on genome-wide DNA methylation, histone mark patterns,
chromatin accessibility, and gene expression, before and after infection. We
found that infection-induced demethylation rarely occurs at promoter regions
and instead localizes to distal enhancer elements, including those that
regulate the activation of key immune transcription factors. Active
demethylation is associated with extensive epigenetic remodeling, including the
gain of histone activation marks and increased chromatin accessibility, and is
strongly predictive of changes in the expression levels of nearby genes.
Collectively, our observations show that active, rapid changes in DNA
methylation in enhancers play a previously unappreciated role in regulating the
transcriptional response to infection, even in nonproliferating cells.

Can oral infection be a risk factor for Alzheimer’s disease?

Alzheimer’s disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (herpes simplex type I), and yeasts (Candida species). A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible etiology of late-onset AD (LOAD).

The association between infectious burden and Parkinson's disease: A case-control study. - PubMed - NCBI

The
etiology of Parkinson's disease (PD) remains unclear. The aim of this
study was to examine the association between common pathogenic
infections and PD.

METHODS:

Antibody titers to common infectious pathogens including cytomegalovirus (CMV),
Epstein Barr virus (EBV)，herpes simplex virus type-1 (HSV-1), Borrelia
burgdorferi (B. burgdorferi), Chlamydophila pneumoniae (C. pneumoniae)
and Helicobacter pylori (H. pylori) were measured by ELISA in serum of
131 PD patients and 141 normal controls. Infectious burden (IB) was
defined as a composite serologic measure of exposure to these common
pathogens.

RESULTS:

Seropositivities toward zero-two, three-four and five-six of these pathogens were found
in 11%, 74% and 15% of normal controls while in 4%, 61% and 35% of PD
patients, respectively. IB, bacterial burden and viral burden were
independently associated with PD. Schwab and England (S&E) scores
were negatively correlated with IB in patients with PD. Serum
α-synuclein protein levels and inflammatory cytokines (interleukin-1β
and interleukin-6) in individuals with higher IB were also significantly
higher.

CONCLUSIONS:

IB consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and
H. pylori is associated with PD. This study supports the role of
infection in the etiology of PD.

Infection and Inflammation in Schizophrenia and Bipolar Disorder: A Genome Wide Study for Interactions with Genetic Variation.

Inflammation and maternal or fetal infections have been suggested as
risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is
likely that such environmental effects are contingent on genetic
background. Here, in a genome-wide approach, we test the hypothesis that
such exposures increase the risk for SZ and BP and that the increase is
dependent on genetic variants. We use genome-wide genotype data, plasma
IgG antibody measurements against Toxoplasma gondii, Herpes simplex
virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen
gliadin as well as measurements of C-reactive protein (CRP), a
peripheral marker of inflammation. The subjects are SZ cases, BP cases,
parents of cases and screened controls. We look for higher levels of our
immunity/infection variables and interactions between them and common
genetic variation genome-wide. We find many of the antibody measurements
higher in both disorders. While individual tests do not withstand
correction for multiple comparisons, the number of nominally significant
tests and the comparisons showing the expected direction are in
significant excess (permutation p=0.019 and 0.004 respectively). We also
find CRP levels highly elevated in SZ, BP and the mothers of BP cases,
in agreement with existing literature, but possibly confounded by our
inability to correct for smoking or body mass index. In our genome-wide
interaction analysis no signal reached genome-wide significance, yet
many plausible candidate genes emerged. In a hypothesis driven test, we
found multiple interactions among SZ-associated SNPs in the HLA region
on chromosome 6 and replicated an interaction between CMV infection and
genotypes near the CTNNA3 gene reported by a recent GWAS. Our results
support that inflammatory processes and infection may modify the risk
for psychosis and suggest that the genotype at SZ-associated HLA loci
modifies the effect of these variables on the risk to develop SZ.

Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder.

Inflammation-related changes in the concentrations of kynurenine-pathway
metabolites occur in depression secondary to medical conditions but
have not been well characterized in primary bipolar disorder (BD), with
contradictory results potentially attributable to the presence or
absence of psychosis and/or medication effects. In contrast, reductions
in hippocampal and amygdalar volume that theoretically reflect dendritic
atrophy occurring in the context of a neurotoxic process are commonly
reported in unmedicated BD patients. Here we tested whether the
concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid,
QA) kynurenine-pathway metabolites were altered in primary BD and
whether these metabolites were associated with hippocampal and amygdalar
volume. Twenty-five moderately-to-severely depressed unmedicated
subjects and 38 moderately-to-severely depressed medicated subjects who
met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs)
completed a structural MRI scan and provided a blood sample for
kynurenine metabolite analysis, performed using high performance liquid
chromatography with tandem mass spectrometry. Gray matter volumes were
measured with the automated segmentation software, FreeSurfer. A
putative neuroprotective index, KynA/QA, was significantly lower in the
BD subjects relative to the HCs, a finding that was unrelated to current
treatment with medication or a prior history of psychosis. Further,
another putative neuroprotective index, KynA/3HK was positively
associated with hippocampal volume in the BD group after controlling for
age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK
was significantly associated with total amygdalar volume in the BD
group, but after controlling for age, sex, BMI, but not ICV, this
association was reduced to a trend. In addition, Kyn/3HK was positively
associated with amygdalar volume in the HCs although the association was
no longer significant after accounting for the effects of age, sex, and
BMI. The results raise the possibility that BD-associated abnormalities
in kynurenine metabolism may impact the structure of the hippocampus
and amygdala, highlighting a pathway through which inflammation may
exert neuropathological effects in the context of depression.

Reconceptualizing major depressive disorder as an infectious disease

In this article, I argue for a reconceptualization of major depressive disorder (major
depression) as an infectious disease. I suggest that major depression may result from
a parasitic, bacterial, or viral infection and present examples that illustrate possible
pathways by which these microorganisms could contribute to the etiology of major depression.
I also argue that the reconceptualization of the human body as an ecosystem for these
microorganisms and the human genome as a host for non-human exogenous sequences may
greatly amplify the opportunity to discover genetic links to the illness. Deliberately
speculative, this article is intended to stimulate novel research approaches and expand
the circle of researchers taking aim at this vexing illne