Immune Cells Mistake Heart Attacks for Viral Infections

 What is it about dying cells in the heart that stimulates the immune
system? To answer this, researchers looked deep inside thousands of
individual cardiac immune cells and mapped their individual
transcriptomes using a method called single cell RNA-Seq. This led to
the discovery that after a heart attack, DNA from dying cells
masquerades as a virus and activates an ancient antiviral program called
the type I interferon response in specialized immune cells. ¬¬ The
researchers named these "interferon inducible cells (IFNICs)."


When investigators blocked the interferon response, either
genetically or with a neutralizing antibody given after the heart
attack, there was less inflammation, less heart dysfunction, and
improved survival. Specifically, blocking antiviral responses in mice
improved survival from 60 percent to over 95 percent. These findings
reveal a new potential therapeutic opportunity to prevent heart attacks
from progressing to heart failure in patients.

Here's the paper:-

IRF3 and type I interferons fuel a fatal response to myocardial infarction

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

Summary 

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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A pilot study on the use of interferon beta-1a in early Alzheimer's disease subjects.

Despite the fact that multiple sclerosis (MS) and Alzheimer's disease
(AD) share common neuroimmunological features, interferon beta 1a
(IFNβ1a), the well-established treatment for the prevention of disease
progression and cognitive decline in MS patients, has never been used in
AD. We evaluated the safety and efficacy of IFNβ1a in subjects affected
by mild-to-moderate AD in a double-blind, randomized,
placebo-controlled, multicenter pilot study. Forty-two early Alzheimer's
patients were randomized to receive either a 22 mcg subcutaneous
injection of IFNβ1a or placebo three times per week. A treatment period
of 28 weeks was followed by 24 weeks of observation. IFNβ1a was well
tolerated and adverse events were infrequent and mild to moderate.
Although not statistically significant, a reduction in disease
progression during follow-up was measured in IFNβ1a-treated patients by
the Alzheimer's Disease Assessment Scale cognitive subscale.
Interestingly, the treatment group showed significant improvements in
the Instrumental Activities of Daily Living and Physical
Self-maintenance Scale. This study suggests that IFNβ1a is safe and well
tolerated in early AD patients, and its possible beneficial role should
be further investigated in larger studies.

Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.

Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified cholesterol-25-hydroxylase (CH25H) as a broadly antiviral ISG. CH25H converts cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). 25HC treatment in cultured cells broadly inhibited growth of enveloped viruses including VSV, HSV, HIV, and MHV68 and acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. It suppressed viral growth by blocking membrane fusion between virus and cell. In animal models, Ch25h-deficient mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and reversed T cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.

Paradoxical downregulation of HLA-A expression by IFNγ associated with schizophrenia and noncoding genes.

Neuronal MHC/HLA regulates the synapses of the central nervous system (CNS). The expression of MHC/HLA is, in turn, regulated by immune cytokines. We were therefore interested in the regulation of schizophrenia-associated HLA antigens, specifically their regulation of expression by interferons. We had previously observed a moderately increased frequency of HLA-A10 expression in schizophrenic patients. While searching for the "true" disease gene near the HLA-A gene, we discovered that homozygosity of the HLA-J M80469 pseudogene allele, in combination with HLA-A10 or HLA-A9, was associated with a high risk of schizophrenia (HLA-A10 relative risk=29.33, p=0.00019, patients N=77, controls N=214). The allele HLA-J M80468, which codes for interferon-inducible mRNA, conferred protection on carriers of HLA-A9 and HLA-A10 (HLA-A10 relative risk=0.022, p=0.00017). Functional analysis revealed that interferon γ (IFNγ) downregulated the expression of HLA-A9 and HLA-A10 in monocytes from HLA-J M80469 homozygous patients but not from carriers of the HLA-J M80468 allele. This is the first demonstration of an inverse effect of IFNγ on HLA expression that is associated with non-coding gene variants and schizophrenia. Our findings suggest that the interferons secreted during acute and chronic infections may interfere in synaptic regulation via neuronal HLA and that this disturbance in synaptic regulation may induce the symptoms of mental illness.

Scientists discover likely new trigger for epidemic of metabolic syndrome

UC Davis scientists have uncovered a key suspect in the destructive inflammation that underlies heart disease and diabetes. The new research shows elevated levels of a receptor present on leucocytes of the innate immune response in people at risk for these chronic diseases. The receptors are the body's first line of defense against infectious invaders, and they trigger a rush of cytokines, the body's aggressive immune soldiers, into the bloodstream.