Types of interferons
Interferons are signaling molecules that regulate the immune system and protect the body from pathogens. Interferons are divided into three groups: IFN-I, IFN-II, and IFN-III.
Interferon type I: IFN-alpha, beta, delta, epsilon, zeta, kappa, nu, tau, omega-have a direct antiviral effect. All of them bind to the same type I interferon receptor (IFNAR1), but they can act differently depending on the context and subtype. IFN-I activates innate and acquired immunity. However, they can also weaken the activation of the immune system.
Interferon type II: IFN-gamma-acts mainly on specialized immune cells-macrophages.
Interferon type III: IFN-lambda, IL-28/29 – is a vital component of the innate immune response. It protects the mucous membrane from viruses, fungi, and protozoa. IFN-lambda has been proven to play an important role in protecting against the hepatitis C virus.
Triggering the interferon response
In viral infections, the type I interferon response is usually triggered. Pattern recognition receptors (PRRS) located on the cell surface, cytoplasm, and endosomes recognize foreign nucleic acids and pathogen-associated molecular patterns (PAMP). The most important factors that trigger the IFN-I response are Toll-like receptors 3, 4, 7, 8, and 9, cytosolic PRR, MDA-5, Cardif, and cGAS. Interferons bind to the cytosolic IFNAR receptor and activate IFN-stimulated genes (ISG), limiting the virus’s life cycle in infected cells and cause an antiviral state in witness cells.
Antiviral effect of interferon
Almost all nucleated cells can respond to IFN-I. When transmitting IFN-I signals, several antiviral genes are activated. One of the first ISG – myxovirus resistance protein (Mx). Mx1 fights the protein shells of the virus before replication. Mx2 prevents HIV-1 from entering the cell nucleus. Both of them cause the destruction of the protein envelope of the virus and the viral genome.
At the stage of viral protein synthesis, the OAS enzyme is activated, which cleaves viral RNA. The PKR enzyme restricts the synthesis of cellular and viral proteins.
The last step in the life cycle of the virus is the exit from the cell. ISG Tetherin captures the viral particles of many enveloped viruses, attaching them to the host cell.
Interferons and systemic autoimmunity
In addition to fighting pathogens, IFN-I plays various roles in autoimmune diseases:
- Elevated levels of IFN-I contribute to the pathogenesis of systemic lupus erythematosus.
- Interferon type I can accelerate the development of type I diabetes.
- By blocking interferon-gamma, the onset of diabetes can be suppressed.
Interferons in the central nervous system (CNS)
In a healthy brain, type I interferon is produced. It is proved by research:
- Microglia with a deficiency of the enzyme Usp18, which stops the transmission of the IFN-I signal, could not suppress the ISG response. That led to a hyperactive state of IFN-I.
- The production of low levels of IFN-beta increases the activation of microglia and phagocytosis of myelin residues and dead cells in the central nervous system, thereby reducing inflammation. Microglia produces IFN-beta in autoimmune encephalomyelitis: microglia was found in inflamed foci with myelin fragments.
- On the other hand, the complete absence of IFN-beta was accompanied by neurodegeneration.
These data indicate that fine-tuning of IFN signaling is important not only during infection but also for optimal brain functioning.
Viruses trigger an interferon response in the brain
Microglia are resident macrophages in the central nervous system, which play a critical role in physiological and immunological processes in the brain. They are the primary producers of IFN-I in the central nervous system after infection with the herpes simplex virus type 1.
Astrocytes also produce type I interferon-IFN-beta, reacting to neurotropic viruses: rabies virus, vesicular stomatitis virus, and Tayler mouse encephalomyelitis virus.
- When infected with a monkey and human immunodeficiency viruses (SIV and HIV), IFN-alpha is produced in the brain.
- When mice are infected with the La Crosse virus (LACV), microglia and astrocytes produce IFN-beta.
- Studies of human cerebral organoids containing many developing neurons have shown that LACV can infect neurons and cause death. The reactions in the cells varied depending on the stage of development. Neurons expressing lower levels of ISG died faster. The maturation of neurons increased the rate of their death from LACV due to lower sensitivity to IFN.
Brain in HIV infection
When the brain is infected with lentiviruses, human and feline immunodeficiency viruses (HIV-1 and FIV), neuronal damage, inflammation, and neurobehavioral disorders may occur. In the study, it was shown that ISG acts on the endothelial cells of the microvessels of the human brain. It may partially explain the dysfunction of the blood-brain barrier in HIV infection. The expression of ISG: Mx1 and CD317 are increased in the brain of HIV-infected patients. In vivo studies on animals infected with feline immunodeficiency virus strains FIV (ch) or FIV (ncsu) showed that animals infected with FIV (ch) had memory and movement speed disorders compared to groups infected with FIV (ncsu) and falsely infected.
IFN-I protects the brain from viral infection
A reovirus infection can also trigger an IFN-I response in the brain. In mice, after intracranial administration of serotype 3 (T3) or serotype 1 (T1) reovirus, increased expression of IFN-alpha, IFN-beta, and ISG Mx1 was observed in brain tissue. The absence of this IFN-I response increased the mortality of mice. That indicates the protective role of IFN-I in the brain.
The mouse hepatitis virus (MHV) triggers an IFN-beta response in the brain that suppresses infection. The MDA5 receptor recognizes MHV and triggers the IFN-I response in microglia.
Interferon in the fetus brain
Depending on the stage of pregnancy, certain infections are known as TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus), and other viral infections such as parvovirus B19, chickenpox, and Zika virus seriously affect the fetus. In addition to some other symptoms, there are often such disorders of the central nervous system as a decrease in the size of the brain (microcephaly), accumulation of excess cerebrospinal fluid in the ventricles of the brain (hydrocephalus), and calcium deposition in various areas of the brain (cerebral calcification).
The Zika virus causes severe fetal pathology and disorders in infants, including fetal death, brain damage, intrauterine development delay and microcephaly. Pigs without congenital disabilities had a high level of IFN-alpha in their blood plasma a month after birth, while the offspring affected by the Zika virus had an abrupt shutdown of IFN-alpha during social stress. Consequently, infection of the fetus with the Zika virus changes the response to IFN-I and causes a molecular pathology of the brain, which persists after birth in the offspring in the absence of congenital Zika syndrome.
The migration of neural crest cells (NCC) is mandatory for the normal development of the cerebral cortex. Mutations in the DCX gene lead to abnormal neuronal migration, which causes microcephaly and developmental delay. Prolonged exposure to IFN-beta at low concentrations suppresses the migration of NCC. Thus, innate exposure to IFN-beta at a vulnerable stage of development contributes to various CNS anomalies, as in TORCH infections. A genetic disease described as Pseudo-TORCH 2 (PTORCH2) confirms this assumption. PTORCH2 is characterized by mutations in the USP18 gene, which lead to a complete absence of the USP18 protein and a violation of the regulation of IFN-I expression. Patients with PTORCH2 had various neurological symptoms, including microcephaly, cerebral calcification, thrombocytopenia, and others. Similarly, mice with USP18 deficiency have neuropathological symptoms and hydrocephalus.
Aicardi-Gutierrez syndrome (AGS 1-7) is a group of inflammatory diseases with various severe neurological symptoms, increased activity of IFN-alpha in the cerebrospinal fluid and blood, and increased levels of ISG in the peripheral blood in the absence of infection.
Interferons regulate inflammation in the brain
IFN-I and IFN-gamma play different roles in the recruitment of immune cells in the central nervous system. These interferons are essential for maintaining, protecting, and repairing the brain.
Interferon therapy is one of the treatment options for multiple sclerosis. The benefits of IFN-beta therapy have been demonstrated in several studies:
- In patients receiving IFN-beta-1a, interferon significantly slowed down the atrophy of the grey matter and the brain as a whole compared to the control group that refused interferon treatment.
- Although the exact molecular mechanism of IFN-I therapy in patients with multiple sclerosis has yet to be shown, several studies suggest that this may be due to modification of the blood-brain barrier. IFN-beta stabilizes the blood-brain wall.
- Treatment of IFN-beta patients with multiple sclerosis activates the JAK-STAT signaling pathway.
- Patients who did not respond to IFN-beta therapy showed greater activation of the JAK-STAT signaling pathway with increased levels of IFNAR1 and pSTAT1 in monocytes.
In another autoimmune disease-systemic lupus erythematosus (SLE), an increased level of IFN-I is considered a sign of the disease. Patients with SLE have chronically high levels of IFN and ISG. In some patients with SLE, the level of ISG often increases due to IFN-gamma. However, the most common cause is IFN-alpha. Also, another IFN-I is elevated in the blood of patients with SLE: IFN-beta and IFN-omega. Scientists suggest that IFN-alpha activates neurotoxic lymphocytes, which can cause damage to the central nervous system.
Interferon in the blood-brain barrier and blood circulation
The blood-brain barrier protects the central nervous system from pathogens. It regulates the passage of molecules and cells into the central nervous system and consists of tightly connected endothelial cells of the brain microvessels, pericytes embedded in the basement membrane of microvessels, and astrocyte processes covering the microvessels. Changes in the blood-brain barrier are a sign of several diseases, including multiple sclerosis.
Violation of the blood-brain barrier facilitates the penetration of circulating pathogens into the central nervous system. However, it may also be required for cellular immunity and the complete elimination of pathogens from the central nervous system.
In addition to the fact that IFN-beta has an immunomodulatory function, it stabilizes the blood-brain barrier.
IFN-III can also protect the brain from infection. A recent study using the West Nile virus showed that, although IFN-III does not have a direct antiviral effect, it reduces the permeability of the blood-brain barrier. In this study, IFN-III protected the brain from the spread of the virus and improved the survival of mice.
IFN-II (IFN-gamma) is secreted by natural killer cells (NK) and activated T cells. In response to IFN-gamma, some cells secrete the protein CXCL10. This protein attracts white blood cells to the focus of infection. Nevertheless, because of this, CXCL10 and IFN-gamma indirectly destroy the blood-brain barrier, as it happens when infected with the rabies virus. However, another study reports that IFN-gamma directly disrupts the regulation of the barrier functions of the vascular endothelium.
Interestingly, IFN-I reduces cognitive function during aging. The study showed that the expression of genes stimulated by IFN-I was increased in the vascular plexus of the ventricles of the brain of old mice. The same was found in the brains of older people. Blocking the transmission of IFN-I signals in the aged brain partially restores cognitive functions and neurogenesis of the hippocampus and restores IFN type II-dependent activity of the vascular plexus, lost with age.
Another study showed that poly (I:C) preliminary administration protects against cerebral ischemic damage. Poly (I) processing:C) triggers the IFN-beta response in astrocytes and microglia and supports paracellular and transcellular transport through the endothelium, and weakens the drop in transendothelial electrical resistance. It means that the activation of the TLR pattern recognition receptor triggers an interferon response in the brain, which protects the brain from stroke.
Type I interferon in cognitive, psychological functions and degeneration
People infected with the virus often have painful behavior and cognitive dysfunction. Changes in behavior depending on the endothelial and epithelial chains of the IFN-I receptor of the brain. In response to IFN-beta stimulation, the endothelium and epithelium of the brain produce the protein CXCL10, which disrupts synaptic plasticity and causes behavioral changes. Therefore, IFN-I treatment can cause depression as a side effect. It is observed in patients who are treated with IFN-I for hepatitis C virus. A recent study showed that standard treatment of the hepatitis C virus with IFN-alpha and ribavirin activated 15 genes associated with severe depression. The onset of depression in the treatment of IFN-alpha correlated with a decrease in serum levels of brain neurotrophic factors. These data suggest that IFN-alpha can cause depression, reducing neuroprotective ability.
The degeneration of axons containing serotonin and norepinephrine is involved in the pathophysiology of depression. The study showed that IFN-alpha reduces the density of serotonergic axons in the ventral medial prefrontal cortex and amygdala and the density of noradrenergic axons in the dorsal medial prefrontal cortex, ventral medial prefrontal cortex, and dentate gyrus.
IFN-I can regulate the cognitive functions of the brain. A study in which HIV was injected into the brains of mice showed that HIV triggers an IFN-alpha response in the brain, which correlates with working memory errors in mice with HIV-infected macrophages.
IFN-alpha can cause insomnia. Pro-inflammatory cytokines, such as interleukin-1 β (IL1) and tumor necrosis factor α (TNF-α), have proven vital sleep regulators. Chronic insomnia is associated with an increase in the level of IL-6, as well as with the transition from night to day secretion of IL-6 and TNF-α. In addition, in patients with hepatitis C virus treated with IFN-alpha, the duration and depth of sleep decreased, and the sleep mode corresponded to insomnia. Therefore, sleep disorders may be associated with altered levels of inflammatory mediators.
Conclusions
Under physiological conditions, CNS astrocytes produce IFN-beta, which plays a vital role in maintaining brain functions. Interferon-beta regulates the removal of myelin residues by microglia and maintains the integrity of the blood-brain barrier.
When neurotropic viruses infect the brain, the body fights them with the help of innate immune responses of microglia and astrocytes, the production of IFN-alpha and/or beta, and the subsequent adaptive immune response.
Violation of the blood-brain barrier promotes the penetration of peripheral lymphocytes and is therefore often required for the complete elimination of pathogens from the central nervous system. This is an inflammatory process. However, inflammation in the brain can also cause neurological disorders. Neurological disorders depend on the infecting virus and viral load and the constitution and genetic background of the body.
Viral infections at vulnerable stages of embryonic development cause severe fetal pathology and disorders in infants. Due to the excessive production of interferon at the stage of brain development, such neurological symptoms as microcephaly, hydrocephalus, cerebral calcification may occur in infants. The same symptoms are observed in PTORCH2 disease.
Due to which IFN-alpha is constantly produced in the cerebrospinal fluid, genetic mutations cause severe neurological symptoms, as in Aicardi-Gutierrez syndrome. With such genetic mutations, an increased level of ISG is observed in the peripheral blood, although there is no infection.
In autoimmune diseases, such as systemic lupus erythematosus, IFN levels are also changed. Autoimmune diseases can cause psychological and cognitive disorders.
Fine-tuning of the interferon system is necessary for effective infection control and optimal brain function.
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