The major way by which the innate immune system blocks viral infections is to induce the expression of type I IFNs, whose most important action is to inhibit viral replication. Earlier in the chapter, we discussed how several pattern recognition receptors, including some TLRs, NLRs, RLRs, and CDSs, generate signals that stimulate IFN-α and IFN-β gene expression in many different cell types. These type I IFNs are secreted from the cells that are exposed to viruses and act mainly on other uninfected cells to prevent the spread of viral infection. In this section, we will describe the proper ties of type I IFNs and the antiviral actions of these cytokines. Type III interferons, made up of four members of the IFN-λ family, are the main antiviral interferons made by many epithelia and by conventional dendritic cells and have the same functions as type I IFNs.

Type I IFNs are a large family of structurally related cytokines that mediate the early innate immune response to viral infections. The term interferon derives from the ability of these cytokines to interfere with viral replication. There are many type I IFNs, which are structurally homologous and are encoded by genes in a single cluster on chromosome 9. The most important type I IFNs in viral defense are IFN-α, which includes 13 closely related proteins, and IFN-β, which is a single protein. Plasmacytoid DCs are the major sources of IFN-α, but it may also be produced by mononuclear phagocytes. IFN-β is produced by many cell types in response to viral infection.

Several biochemical pathways trigger type 1 IFN production, as has been discussed earlier in this chapter when we described RNA and DNA sensors (Fig. 1). The most potent stimuli for type I IFN synthesis are viral nucleic acids. Recall that RIG-like receptors recognize viral RNA in the cytosol, DNA sensors recognize dsDNA also in the cytosol, and TLRs 3, 7, 8, and 9 recognize microbial nucleic acids in endosomal vesicles. All these nucleic acid sensors initiate signaling pathways that activate the IRF family of transcription factors and NF-κB, which stimulate the transcription of type I IFN genes.

Fig1. Production of type I interferons. Viral nucleic acids in infected cells activate numerous pathways that lead to the production of antiviral type I interferons (IFNs). If viruses enter the cell by endocytosis, viral RNA and DNA can bind to TLRs in the endosomal membrane, which induces signals that activate IFN regulatory factors (IRFs) and NF-κB, which induce type I IFN gene expression. During viral replication, viral RNA in the cytosol can activate RIG-like receptors MDA-5 and RIG-I, and viral dsDNA can activate the cGAS-STING pathway, both leading to IRF and NF-κB activation and type I IFN gene expression. cGAS, Cyclic guanosine monophosphate–adenosine monophosphate; ds, double stranded; MDA-5, melanoma differentiation associated gene 5; NF-κB, nuclear factor kappa B; PAMP, pathogen-associated molecular pattern; RIG, retinoid acid inducible gene; STING, stimulator of IFN genes; TLR, Toll-like receptor.

The receptor for type I IFNs, which binds both IFN-α and IFN-β, is a heterodimer of two structurally related polypeptides, IFNAR1 and IFNAR2, which are expressed on most nucleated cells. This receptor signals to activate STAT1, STAT2, and IRF9 transcription factors, which induce expression of several different genes whose protein products contribute to antiviral defense in various ways:

• Type I IFNs activate the expression of several genes encoding proteins that confer on cells a resistance to viral infection called an antiviral state (Fig. 2). Several of these type I IFN–induced genes encode proteins that block viral gene transcription and translation. For example, double-stranded RNA–activated serine/threonine protein kinase (PKR) blocks viral transcriptional and translational events; 2,5-oligoadenylate synthetase and RNase L promote viral RNA degradation. Interferon-induced proteins with tetratricopeptide repeats (IFITs) inhibit viral protein translation by binding to the eukaryotic initiation factor 3 (eIF3) translation initiation complex. IFITs also bind to the uncapped 5′-triphosphate motifs of RNA viruses, thereby blocking viral replication. Another family of proteins induced by type I IFNs, called interferon-induced transmembrane proteins (IFITMs), insert into viral membranes and block the entry of enveloped viruses, including influenza A virus and coronaviruses, into host cells. The antiviral action of type I IFN is primarily a paracrine action in that a virally infected cell or a plasmacytoid DC activated by viral PAMPs secretes IFN to act on and protect neighboring cells that are not yet infected. IFNs secreted by an infected cell may also act in an autocrine fashion to inhibit viral replication in that cell.

• Type I IFNs cause sequestration of lymphocytes in lymph nodes, thus maximizing the opportunity for encounter with microbial antigens. The mechanism for this effect of type I IFNs is the induction of a molecule on the lymphocytes called CD69, which forms a complex with, and reduces sur face expression of, the sphingosine 1-phosphate (S1P) receptor S1PR1. Recall from Chapter 3 that lymphocyte egress from lymphoid tissues depends on S1P binding to S1PR1. Therefore reduced S1PR1 inhibits this egress and keeps lymphocytes in lymphoid organs.

• Type I IFNs increase the cytotoxic activity of NK cells and CD8+ CTLs and promote the differentiation of naive T cells to the Th1 subset of helper T cells. These effects of type I IFNs enhance both innate and adaptive immunity against intracellular infections, including viruses and some bacteria.

• Type I IFNs upregulate the expression of MHC-I molecules and thereby increase the probability that virally infected cells will be recognized and killed by CD8+ CTLs. Virus specific CD8+ CTLs recognize peptides derived from viral proteins bound to MHC-I molecules on the surface of infected cells. (We will discuss the details of T-cell recognition of peptide-MHC and CTL killing of cells in Chapters 6 and 11.) Therefore, by increasing the amount of MHC-I synthesized by a virally infected cell, type I IFNs increase the number of viral peptide–MHC-I complexes on the cell surface that the CTLs can see and respond to. The end result is increased killing of virus-infected cells and eradication of viral infections.

Fig2. Biologic actions of type I interferons. Type I interferons (IFN-α, IFN-β) are produced by virus infected cells in response to intracellular Toll-like receptor signaling and other sensors of viral RNA. Type I IFNs bind to receptors on neighboring uninfected cells (and on the infected cells, not shown) and activate JAK STAT signaling pathways, which induce expression of genes whose products interfere with different steps of viral replication, including viral gene transcription and translation. Type I IFNs also induce in infected cells the expression of MHC class I molecules, which enhances the cell’s susceptibility to cytotoxic T lymphocyte (CTL)–mediated killing (not shown). dsRNA, Double-stranded RNA; eIF, eukaryotic translation initiation fac tor; IFITs, IFN-induced protein with tetratricopeptide repeats; PKR, double-stranded RNA–activated protein kinase.

The important role of type I IFN in combatting viral infections has been established by clinical and experimental evidence. For example, patients who develop severe COVID-19 disease caused by the SARS-CoV-2 virus often show defects in type I IFN. About 10% of severely ill COVID-19 patients produce autoantibodies against their own type I IFN (which may predate the infection), and another ~4% have inherited mutations that diminish type I IFN production or signaling. Knockout mice lacking the receptor for type I IFNs are susceptible to viral infections. IFN-α is in clinical use as an antiviral agent in certain forms of viral hepatitis. IFN-α is also used for the treatment of some tumors, perhaps because it boosts CTL activity or inhibits the proliferation of some tumor cells. IFN-β is used as a therapy for multiple sclerosis, but the mechanism of its beneficial effect in this disease is not known.

Protection against viruses is due in part to the activation of intrinsic apoptotic death pathways in infected cells and enhanced sensitivity to extrinsic inducers of apoptosis. Viral proteins synthesized in infected cells may be misfolded and their accumulation triggers an unfolded protein response that may culminate in apoptosis of the infected cells if the misfolded protein accumulation cannot be corrected. Abundant TNF is made by plasmacytoid DCs and macrophages in response to viral infections, in addition to type I IFNs, and virally infected cells are hypersensitive to TNF-induced apoptosis.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تقيم مجلس عزاء لإحياء ذكرى شهادة الإمام جعفر الصادق (عليه السلام)

بعد مرور أربع سنوات على تأسيسه قسم شؤون المعارف يعلن منجزات مركز التراث الإسلامي في إيران

قسم الشؤون الفكرية يختتم مسابقة (معز المؤمنين الثقافية) ويكرِّم الفائزين في كربلاء وبابل

قسم الصيانة ينفذ أعمالًا تطويرية في مجمع الإمام الهادي (عليه السلام)

المزيد

الآخبار الصحية

الشاشات ليست مجرد ترفيه.. تأثيرات طويلة المدى على دماغ طفلك

الأسباب الرئيسية لنقص الطاقة في الجسم

الكاكاو وتأثيره على العين.. نتائج واعدة من تجارب مخبرية

طبيب يحذر: أطعمة شائعة الاستهلاك أخطر على صحتنا من التدخين

المزيد

الآخبار التكنلوجية

باحثون في "نيويورك أبوظبي" يطورون تقنيات لرصد وعلاج الأورام

جيتكس إفريقيا.. المغرب يجمع "رواد التكنولوجيا" من 103 دول

طاقم أرتميس 2 يحطم رقما قياسيا ويستعرض الجانب البعيد للقمر

"أرتيميس 2" تنطلق حول القمر وتحطم الرقم القياسي

المزيد

مواضيع ذات صلة

Rh Blood Types

O-A-B Blood Types

Allergy and Hypersensitivity

Migration of B Lymphocytes

Migration of Effector T Lymphocytes to Sites of Infection

Exit of Naive and Effector T Cells from Lymph Nodes

Lymphocytes are Responsible for Acquired Immunity

The Major Proinflammatory Cytokines of Innate Immunity

Migration of Naive T Cells Into Lymph Nodes

Migration of Neutrophils and Monocytes to Sites of Infection or Tissue Injury

Leukocyte-Endothelial Interactions and Leukocyte Recruitment into Tissues

Formation of Pus