Systemic Lupus Erythematosus

Lee Goldman MD , in Goldman-Cecil Medicine , 2020

Type I Interferon

Studies of gene expression in peripheral blood mononuclear cells of SLE patients using microarray and RNA sequencing technology take demonstrated a sustained and broad "signature" of type I interferon–induced gene transcripts that reverberate innate immune system activation. Interferon-α (IFN-α), along with other type I IFNs (e.g., IFN-β, IFN-ω) may be responsible for many of the immunologic alterations observed in SLE and is identified as a promising therapeutic target. Immune complexes containing Deoxyribonucleic acid or RNA are postulated to induce the production of type I interferon in SLE. Demethylated CpG-rich DNA or RNA associated with nucleic acid–binding proteins tin can activate plasmacytoid dendritic cells and other immune system cells through TLRs and thereby effect in the product of type I interferon (IFN-α or IFN-β) and other proinflammatory cytokines (E-Fig. 250-1). Sensing of intracellular RNA or DNA past cytosolic nucleic acid sensors represents another potential molecular pathway leading to blazon I interferon production. Diverse effects oftype I interferon on immune system part are consequent with the altered allowed responses observed in SLE patients, including maturation of dendritic cells, increased immunoglobulin class switching to mature immunoglobulin isotypes (immunoglobulin G [IgG] and IgA), consecration of soluble mediators that increase B-prison cell differentiation and inflammatory responses, such as B-lymphocyte stimulator (BLyS) and IFN-γ, and modulation of effector T-cell programs. Induction of an immunostimulatory microenvironment by IFN-α may support the development of a humoral immune response directed at self-antigens, particularly intracellular particles that incorporate nucleic acids and nucleic acid–bounden proteins. It is non known why some individuals initiate allowed system activation directed at self-antigens and others exercise not. In addition to its furnishings on immune system function, type I interferon has been associated with altered endothelial cell role and microglial part in the brain and may contribute to the evolution of atherosclerotic vascular pathology and CNS disease in patients with lupus. 15 , 16

NETosis in Autoimmunity

Geeta Rai , in Netosis, 2019

Neutrophil extracellular traps drive plasmacytoid dendritic cells to produce blazon I interferon in systemic lupus erythematosus

Type I interferons play a major role in SLE pathogenesis (Fig. 5.two). High level of blazon I interferons is noticed in the sera of SLE patients and positively correlates with disease prognosis (Hooks et al., 1979; Ytterberg and Schnitzer, 1982). A large number of IFN-inducible genes are found to exist upregulated in peripheral blood mononuclear cells of SLE patients (Baechler et al., 2003; Bennett et al., 2003). Type I interferons arm-twist differentiation of plasmacytoid dendritic cells (pDCs) from monocytes upon interacting with NET autoantigens. Thus it executes the breakup of peripheral tolerance in SLE. These IFN-induced DCs proficiently present autoantigens to helper T cells, resulting in aberrant expansion of autoreactive T and B cells (Barrat et al., 2005). Lande et al. (2011) reported that immune circuitous containing Dna and antimicrobial peptides, such as LL37 and human being neutrophil peptide (HNP), too activates pDCs with the production of IFNα.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128161470000058

Effector Mechanisms and Cellular Outputs

Tom P. Monie , in The Innate Immune System, 2017

3.1.3 The Interferon Family unit

Interferons can exist split into three subsets—type I, II, and 3 interferons. The blazon I interferons contain IFN-α, -β, -ε, -κ, and -ω; the type II interferons consist solely of IFNγ; and the type III interferons comprise IFNλ1, 2, three, and 4. From an immunological perspective the most important, and certainly the best studied, interferons are IFNα, IFNβ, and IFNγ. The type I interferon IFNβ is secreted from, and acts upon, almost all cell types, while IFNα and the type Ii interferon, IFNγ, although active on most, if not all cell types, are mainly produced from immune cells, with plasmacytoid dendritic cells representing a major source of both IFNα and IFNγ in response to viral infection.

The product and secretion of type I interferons is stimulated past the activation of a range of different PRRs following the activation of the transcription factors IRF3 and IRF7. These include TLR3, 4, 7, 8 and ix, RIG-I, LRRFIP1, RNAPolIII, and multiple intracellular Deoxyribonucleic acid sensors such equally IFI16, DAI, and DNA-PK, all of which seem to function via the protein STING (run into also Department 2.two.7.3). Following secretion, type I interferons collaborate with the heterodimeric receptor interferon alpha receptor (IFNAR) (Fig. 3.four), which results in activation of the JAK/STAT signaling pathway. The same pathway is also activated by IFNγ, albeit through the engagement of the IFNGR protein and recruitment of JAK1 and JAK2 every bit opposed to JAK1 and TYK2. Together these events consequence in the activation of interferon-stimulated genes (ISGs) such equally PKR, OAS1, MX1, ADAR, and APOBEC3G amid others. The function of these ISGs is to drive the antiviral immune response and create an environment within the stimulated cell that is nonpermissive for viral replication. This helps to limit the spread and damage associated with the infection. The deaminase APOBEC3G has been shown to play a particularly important role in the restriction of HIV-one infection.

Figure 3.four. The structure of Blazon I and Two interferons.

(A) Drawing and (B) surface representations of the type I interferon IFNα2 (cyan) in a ternary complex with its receptor interferon alpha receptor 1 (IFNAR1) (green) and IFNAR2 (magenta) (PDB 3SE3). IFNα2 has a helical structure and bridges between the two receptors. The membrane would be positioned at the bottom of the image. Sixteen type I interferons signal through the IFNARs only with different physiological responses that stalk, at least in function, from the mode in which the Type I IFN interacts with IFNAR. (C) and (D) Cylindrical and cartoon images of the bovine IFNγ dimer (PDB 1D9G). The ii monomers are colored cyan and green. Rather unusually this dimer is created through the swapping of helices betwixt the two monomers to create an intertwined structure rather than but possessing a dimer interface.

IFNγ (Fig. iii.four) is a highly proinflammatory cytokine. This is primarily due to its power to increment leukocyte recruitment, enhance phagocytosis, upregulate major histocompatibility complex (MHC) expression, and dramatically heighten the cytolytic activity of macrophages and NK cells. Activation of macrophages with IFNγ is a primal element in driving the destruction of phagocytosed microbes and in inhibiting and combating intracellular infection of the macrophages themselves. IFNγ forth with TNFα is a key driver of macrophage activation into a classical proinflammatory, or M1, phenotype. Activated NK cells are key producers of IFNγ early on in the allowed response, although γδ T cells also contribute. During the afterwards stages of the immune response, T cells become more important contributors to its synthesis. IFNγ has been associated with the progression of various autoinflammatory disorders including rheumatoid arthritis and type 1 diabetes.

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/commodity/pii/B978012804464300003X

Hematopoietic Organisation Toxicology

V. Bakthavatchalu , S. Muthupalani , in Comprehensive Toxicology (Third Edition), 2018

12.17.4.six Blastic Plasmacytoid Dendritic Cell Tumour

In humans, normal plasmacytoid dendritic cells are predominantly present in tonsils and lymph nodes and primarily secrete type I interferons. The plasmacytoid dendritic cells accrue as nodular aggregate adjacent to high endothelial venules in reactive lymph nodes. Proliferative disorders associated with plasmacytoid dendritic cells in humans are mature plasmacytoid dendritic prison cell proliferation associated with myeloid neoplasms and blastic plasmacytoid dendritic cell neoplasm (BPDCN). The BPDCN is a rare cancerous neoplasm of humans caused by clonal proliferation of immature plasmacytoid dendritic cells. The clinical manifestation of BPDCN is characterized by acute leukemia and nodular cutaneous form that slowly progresses to systemic involvement. The cutaneous lesion is the most common clinical presentation of BPDCN and the dermal tropism of the neoplastic cells is attributed to the expression of CLA and CD56 that are associated with skin migration. The acute leukemia is associated with leukocytosis and os marrow infiltration. The blast cells of BPDCN closely resemble myeloblasts or lymphoblasts. The medium-sized monomorphic neoplastic cells are characterized by scant cytoplasm without azurophilic granules and irregular nuclei with fine chromatin and distinct nucleoli. Immunophenotype of BPDCN neoplastic cells are characterized past expression of plasmacytoid dendritic cell specific marking CD303, and CD123, CD56, CD4, and TCL1. No cytogenetic abnormalities are associated with BPDCN. The most common genetic alteration associated with BPDCN pathogenesis is TET2 gene mutation (Facchetti et al., 2016).

Read full affiliate

URL:

https://www.sciencedirect.com/scientific discipline/article/pii/B9780128012383642538

Delivery strategies for STING agonists

Xin Sun , ... Jiahe Li , in Systemic Drug Delivery Strategies, 2022

2.3.three Microparticle-encapsulated cGAMP as an adjuvant formulation

Most of the adjuvants used for infection only stimulates humoral, simply not cellular immune responses [88]. Adjuvant candidates that can induce robust type I IFN have caught a broad interest due to the ability of blazon I IFN to promote balanced cellular and humoral immune responses in vaccination by promoting DC maturation and antigen presentation, and IgG class switching [109, 110]. To this end, the activation of the STING pathway by CDNs has been recognized as an highly-seasoned adjuvant candidate to induce cellular amnesty. All the same, as previously described, the bioavailability of STING agonists is very low due to the requirement for cytosolic targeting of STING. Junkins et al. reported that three′three′-cGAMP encapsulated within acrid-sensitive acetylated dextran (Ace-DEX) polymeric microparticles (MPs) by electrospray provided an efficient and potentially scalable strategy for the consecration of potent type I IFNs, too equally proinflammatory cytokine responses [88]. They demonstrated that these microparticles enhanced the production of type I IFNs nearly 1000-fold in vitro and fifty-fold in vivo, which resulted in up to a 104-fold boost in antibody titers, increased T helper type one (Th1)-associated responses, and expanded germinal eye B cells and memory T cells, compared to costless cGAMP. Furthermore, the encapsulated cGAMP had no detectable side effects in animals and protected mice against a lethal influenza infection seven months postimmunization with CDN adjuvant doses upwardly to 100-fold lower than that of previous reports. Together these results demonstrate that Ace-DEX MP-encapsulated cGAMP represents a promising strategy toward the balanced Th1/Th2-mediated humoral and cellular amnesty.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323857819000130

Biotechnology-Based Pharmaceutical Products

Pran Kishore Deb , ... Rakesh K. Tekade , in Biomaterials and Bionanotechnology, 2019

five.5.5.i Interferons

Interferons are a course of cytokines that have antiviral activity as well as potential anticancer effects. Interferons tin exist classified into two types, the type I consists of alpha-interferon and beta-interferons, while type II consists of gamma-interferon. Blazon I interferons are produced past different cells in response to diverse stimuli (Vilček and Feldmann, 2004). The cells include specialized dendritic cells and macrophages. The stimulus can be viruses or certain molecules such as double-stranded RNA. On the other paw, blazon 2 interferon is produced mainly by the natural killer cells as well equally the T cells and secreted in response to different stimuli. All the interferons act by binding to dissimilar heterodimeric receptors on the targeted cell'south surface and transduce the signal through the activation of the Janus-activated kinase likewise every bit bespeak transducer and activator of transcription. This leads to the expression of unlike genes to requite the required biological response (Darnell et al., 1994; Vilček and Feldmann, 2004).

All the iii mentioned interferons tin be used clinically for treating various atmospheric condition that are related to viral infections besides as cancer. Bachelor alpha-interferon preparations include recombinant interferon2a (Rofereon-A, Roche), which is produced as a nonglycosylated protein that consists of 165 amino acids. This product is indicated mainly for the treatment of hepatitis B and C as well equally Kaposi'south sarcoma (El-Baky and Redwan, 2015; Jones and Itri, 1986).

Interferon-beta1b (betaferon, Schering) is a man beta-interferon-based product produced for treating relapsing/remitting multiple sclerosis. The host cells used for expression are E. coli cells with identical amino acrid sequence except for one cysteine balance that is replaced by a serine residue for improving the stability during the synthesis process within the cells (Rojas et al., 2014; Zvonova et al., 2017).

Therapeutic preparations of gamma-interferon are as well bachelor; for instance, gamma-interferon1b is a polypeptide chain that is composed of 140 amino acids. Although the gamma-interferon produced naturally in the cells is a glycosylated polypeptide, the commercial form is nonglycosylated as the host used is Due east. coli cells. Indications of this product include severe malignant osteoporosis as well as chronic granulomatous (Watson, 2011).

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128144275000056

Allowed System Toxicology

R.A. Prell , J.M. Tarrant , in Comprehensive Toxicology (Third Edition), 2018

11.20.iii.xiii.1 Type I IFNs

The blazon I family of mammalian IFNs consists of 9 subtypes, including xiii known subtypes of IFNα equally well every bit IFNβ, IFNε, IFNκ and IFNω IFNδ, IFNτ, IFNν and IFNζ, of which IFNδ and IFNτ are establish only in pigs and ruminant animals, respectively (de Weerd and Nguyen, 2012). Although most cells are able to produce type I IFNs following recognition of pathogen-associated molecular patterns (PAMPs) past diverse toll-like receptors, the primary source of IFNα and IFNβ is leukocytes and fibroblasts, respectively (Jonasch and Haluska, 2001; Kalliolias and Ivashkiv, 2010). All type I IFNs signal through the ubiquitously expressed heterodimeric receptor that contains the depression-affinity IFNAR1 subunit and the loftier-affinity IFNAR2 subunit. Type I IFNs take the broadest range of biological activities that include potent antiviral properties, host defence force against other pathogens, tumor surveillance and immunoediting, tissue protective effects via induction of antiinflammatory cytokines and decreasing proinflammatory cytokines, and regulation of immune responses past promoting NK cell role as well as cellular and humoral amnesty (Kalliolias and Ivashkiv, 2010; de Weerd and Nguyen, 2012). Paradoxically, type I IFN can also lead to deleterious effects in the host in certain illness states by promoting backlog inflammation and autoimmunity. The biological outcome of type I IFN signaling is dependent on numerous influencing factors such as cellular composition within the target organ, relative timing and concentration of the cytokine, and context of the ongoing response (i.e., innate vs. adaptive immunity).

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B978012801238364237X

Lyme Illness

John Due north. Aucott , Benjamin J. Luft , in Infectious Diseases (4th Edition), 2017

Biology of B. burgdorferi

Borrelia burgdorferi sensu lato circuitous encompasses several species of Borrelia that crusade human infection. Borrelia burgdorferi sensu stricto (hereafter referred to as B. burgdorferi) is the etiologic agent of Lyme disease in North America, while B. burgdorferi, B. garinii and B. afzelii are all important in Eurasian disease. Clinical isolates differ in their outer surface protein expression 22 and genetic composition. 23 Although there is overlap in the clinical manifestation of infection between the unlike species of Borrelia, certain species have been associated with a greater propensity toward detail disease manifestations. For instance, B. burgdorferi is more than ordinarily associated with late Lyme arthritis, B. garinii with neurologic disease, and B. afzelii with a chronic skin infection called ECM. 6 Several other species belonging to the Borrelia burgdorferi sensu lato circuitous are occasionally isolated in symptomatic patients including B. spielmanii, B. bisettii, B. americana, B. andersonii and B. kurtenbachii. Borrelia miyamotoi, which is phylogenetically close to relapsing fever Borrelia, is now a recognized pathogen that causes a Lyme-like illness in the northern hemisphere. 24

B. burgdorferi strains may differ in their host specificity and the degree of human pathogenicity. These strains have been categorized co-ordinate to 2 different typing methods. The get-go is based on the outer-surface protein C (OspC) type and the second on polymorphisms of the 6S-23S rRNA intergenic spacer region (RST). RST1 (Osp C type A) is associated with hematogenous dissemination and greater inflammatory responses in patients with early on stage Lyme affliction and with higher likelihood of chronic symptoms afterward completion of antibiotic therapy for belatedly Lyme arthritis. 25,26

The complete DNA sequence of 22 strains of Borrelia is known. 27 The genetic makeup of B. burgdorferi is unusual with i big linear chromosome and several smaller linear and circular plasmids. The genome of B. burgdorferi is notably defective genes encoding for enzymes for the de novo synthesis of metabolites and as such is highly dependent on the host environment. 28 Also, no genes for known bacterial toxins take been identified. Surprisingly, Borrelia burgdorferi does not apply fe, but manganese instead. 29 Ii major glycolipids, BbGL-I and II, which business relationship for 36% of the total lipid mass of Bb, likely function as the principal components of the cell membrane, and are unique amid bacteria to B. burgdorferi. 30 Dissimilar Treponema pallidum, B. burgdorferi can exist grown in civilization although a specialized medium is required and cultures are non available for routine clinical use. B. burgdorferi tin penetrate endothelial monolayers and survive intracellularly in cultured fibroblasts, although the organism is thought to establish extracellular infection in vivo. 31

Evasion of the host immune system is a authentication of B. burgdorferi infection. The organism may hide its surface lipoproteins and other antigenic components by coating them with host plasmin and other proteins. 32 Antigenic variation of Vmp-similar sequence poly peptide (VlsE), a 35-kDa lipoprotein protein, may allow for immune evasion in a fashion like to that seen in relapsing fever. 33 Outer-surface proteins such as OspE and related protein families (Erps) can act as complement regulatory-acquiring surface proteins (CRASPs) binding the complement inhibitory factor H and causing resistance to complement-mediated killing. 34

An of import question is how B. burgdorferi avoids destruction in the presence of the vigorous specific T- and B-jail cell responses that are usually apparent within a few weeks of onset of disease. One hypothesis is that low levels of infection may be perpetuated through mechanisms such as survival in sequestered, immunologically protected sites. 35

Borrelia burgdorferi disseminates preferentially to certain target organs such equally the musculoskeletal and nervous organization. Tissue localization to areas rich in collagen may be mediated by the decorin binding proteins Dbp A/B. 36 Beast models of neurologic Lyme disease using the rhesus macaque monkey model bear witness localization to the dorsal root ganglia. 37

Host Immune Response and Genetic Factors

Lyme affliction is an inflammatory infection where the lipoproteins of Borrelia burgdorferi are capable of stimulating pro-inflammatory cytokines and chemokines through activation of the innate and adaptive immune system. 38 Binding of toll-similar receptor 2 (TLR2) on macrophages results in activation of the innate immune response past a signaling pour leading to activation of NF-κB resulting in production of pro-inflammatory cytokines. 39 In addition, B. burgdorferi RNA induces Type I and III interferons via toll-similar receptor 7 contributing to production of cytokines. xl

The early cytokine/chemokine response is characterized by interferon-gamma-dependent Th1 responses with elevated levels of the CD4 and CD8 T-cell chemokines CXCL9 and CXCL10. 28,41 The polymorphonuclear neutrophil (PMN) chemokine CCL8 (IL-8) is non elaborated consistent with the paucity of polymorphonuclear infiltrates in the skin lesions of EM. 41 The earliest evidence of humoral immunity occurs several weeks later an infecting tick bite, and approximately one calendar week after the identification of EM, with increasing levels of IgG antibodies produced in the months succeeding untreated infection. 42

Histologic studies of affected tissues accept provided evidence for immune-mediated inflammation in response to B. burgdorferi infection. EM lesions display a perivascular and interstitial lymphohistiocytic infiltrate with plasma cells in the dermis. 43 Endomyocardial biopsies have revealed similar changes in the middle, with a focal perivascular infiltrate of mononuclear cells and fibrin deposition in both the endocardium and myocardium. 44 Biopsies of afflicted nerves prove inflammatory infiltrates around endoneurial and perineurial vessels without vessel necrosis. 45 Synovial biopsies from involved joints take revealed synovial lining jail cell hyperplasia and hypertrophy, vascular proliferation and lymphocytic infiltration of the subsynovial areas. Aggregates of T and B cells, often with lymphoid follicle formation, are common and may exist full-bodied in perivascular areas with obliteration of vessels merely without vessel necrosis. 3 Spirochetes have been visualized in skin lesions, 46 heart tissue 44 and synovium, 47 just non in peripheral nerves.

Read total affiliate

URL:

https://www.sciencedirect.com/scientific discipline/commodity/pii/B9780702062858000460

Innate Immune Responses to Rotavirus Infection

A. Sen , H.B. Greenberg , in Viral Gastroenteritis, 2016

Abstract

Hosts have evolved highly sophisticated mechanisms to preclude and control viral infections. These include the innate immune response, hardwired into about eukaryotic cells and triggered soon after virus entry, as well equally the more specialized adaptive immune response, divers by aspects of antigen specificity and memory. Following host cell infection, most viruses trigger ane or more pattern recognition receptors, which have evolved to recognize virus-specific signatures, or pathogen associated molecular patterns (eg, five′-triphosphate RNA), and upon ligand binding, trigger conserved signaling pathways that culminate in the functional activation of critical host transcription factors involved in the initiation of various antiviral responses. Several virus stress-induced genes (vSIGs) are transcribed equally a result of this early activation, including those encoding the secretory blazon I and III interferons (IFNs). Expression and secretion of IFNs upshot in their binding to cognate surface receptors on cells in both autocrine and paracrine patterns, followed by ligand-stimulated activation of the JAK-STAT signaling cascade. Activated STATs, together with other accessory factors, then translocate to the nucleus and initiate a 2d wave of transcription—resulting in the expression of hundreds of genes that encode antiviral proteins targeting multiple aspects of viral replication, associates, maturation, and spread. This 2nd phase of the IFN response is also crucial for ensuring that initial IFN expression is amplified through positive feedback, thus ensuring robust institution of an antiviral state in unlike host cell types, both infected and uninfected. Coevolution of hosts and their viruses [also known equally the Reddish Queen Hypothesis (Muraille, 2013)] likely resulted non simply in the present complexity of the host innate response, but besides in the emergence of viral strategies to cake the innate response at multiple steps in order to ensure evolutionary advantage (Medzhitov and Janeway, 1997). Appropriately, most pathogenic viruses, including the rotaviruses, encode factors that target redundant steps of the IFN induction and amplification signaling pathways.

Read full affiliate

URL:

https://www.sciencedirect.com/science/article/pii/B9780128022412000122

Virus Infection of Airway Epithelial Cells

Jennifer Alexander-Brett , Michael J. Holtzman , in Mucosal Immunology (4th Edition), 2015

Astute Epithelial Responses to Respiratory Viral Infection: Inducing the "Antiviral State"

Considering epithelial cells are the initial portal of entry and site of replication for respiratory viruses, they are primed to answer to infection through distinct design recognition receptors (PRRs) and coordinated antiviral signaling programs. Similar to other surveillance cells in bulwark tissues, epithelial cells express PRRs that are categorized into three major groups: Price-like receptors (TLRs), retinoic acid-inducible factor 1 (RIG-I)-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs).

Toll-like receptors are a family of integral membrane proteins that recognize a wide multifariousness of pathogen-associated molecular patterns (PAMPs) and signal through common Cost/interleukin-1 (IL-i) receptor domain-containing adaptor molecules (Kawai and Akira, 2010). Of the 13 known receptors, TLRs 3, 7, 8, and 9 appear to answer to virus-associated molecular patterns, specifically viral nucleic acids, with recognition occurring primarily within intracellular endosomes (Barton and Kagan, 2009). Each of these viral recognition TLRs is expressed on airway epithelial cells and is capable of inducing type I and III interferons also as proinflammatory cytokines. TLR3 appears to exist especially relevant to the response of airway epithelial cells to respiratory viruses, including RSV (Groskreutz et al., 2006), RV (Hewson et al., 2005; Kato et al., 2007), and IAV (Guillot et al., 2005). Virus-associated ligands have been identified for TLRs seven, 8, and ix (double- and single-stranded RNA and CpG Deoxyribonucleic acid, respectively) (Diebold et al., 2004; Heil et al., 2004; Hemmi et al., 2000; Triantafilou et al., 2011), though their specific roles in the response to viral infection remain less certain. One particular question is the relative role of the epithelial TLR system in decision-making infection during acute illness versus inflammation during chronic illness, and farther studies are under way to accost this issue.

RIG-I and the related melanoma differentiation-associated protein five (MDA-five) are RNA helicases that likewise recognize viral nucleic acids, specifically double- and single-stranded RNA, respectively (Yoneyama et al., 2004; Gitlin et al., 2006; Kato et al., 2006). In dissimilarity to TLRs, the RLR group of sensors recognize intracellular viral RNA inside the cytoplasm and point through caspase recruitment domains as well as the adaptor mitochondrial antiviral signaling protein (MAVS/IPS-1/VISA/Cardif) to induce interferon regulatory cistron 3 (IRF-3) and subsequent interferon production (Kawai et al., 2005; Meylan et al., 2005; Seth et al., 2005; Xu et al., 2005). MDA-5 has been reported to sense small RNA viruses, such as RV, whereas RIG-I recognizes negative-sense unmarried-stranded viral RNAs, such equally IAV and RSV (Kato et al., 2006). However, MDA-5 tin can also specifically protect confronting SeV in mice (Gitlin et al., 2010), suggesting that RLR-dependent recognition may be more than generally used for defense against respiratory viral infection.

NLRs have been more than recently recognized equally an important component of the initial epithelial response to viral infection (Ichinohe et al., 2009; Thomas et al., 2009). For instance, the NOD-similar receptor protein three (NLRP3) inflammasome circuitous (Lamkanfi and Dixit, 2012) provides a signal for procaspase-1 activation and subsequent processing and release of select IL-1 family unit cytokines, including IL-1β and IL-eighteen, that mediate paracrine signals to neighboring cells (Muruve et al., 2008). It is still uncertain whether NLRP3 functions as a PRR directly or mediates a signal through other PRRs in any system, including the airway epithelial barrier (Allen et al., 2009).

PRR pathways lead to activation of several transcription factors, namely NF-κB, IRF-three, and IRF-vii, which induce interferon product and signaling and the consistent establishment of a cellular "antiviral state" (Levy and Garcia-Sastre, 2001; Samuel, 2001; Schoggins and Rice, 2011). Type I interferon is produced in a biphasic pattern via early on IRF-3 and belatedly IRF-3 and IRF-vii activation and autocrine/paracrine IFN-α/β signaling through the interferon receptor complex (IFNAR-1 and -ii) (Iversen and Paludan, 2010). Type III interferons can exist induced either past a combination of IRF-3 and -seven (IFN-λ1) or predominantly past IRF-seven (IFN-λ2, -three) (Osterlund et al., 2007) and appear to deed specifically on epithelial cells (Sommereyns et al., 2008). Blazon III interferons distinctly signal through a complex that includes the IL-ten receptor β chain and interferon-λ receptor-one chain (Kotenko et al., 2003; Sheppard et al., 2003). Withal, both type I and type III interferons activate Janus kinase/signaling transducer and activator of transcription signaling pathways and induce the expression of interferon-stimulated genes (ISGs). These ISGs orchestrate cellular processes aimed at inhibiting viral replication straight or stimulating immune prison cell recruitment and programmed death of infected cells to prevent viral broadcasting (Der et al., 1998). Viruses such as RSV and IAV have been shown to induce specific blazon I and Three interferon response patterns in airway epithelium (Jewell et al., 2007; Ioannidis et al., 2012; Okabayashi et al., 2011). Amid the genes induced in airway epithelial cells are several cytokines that function in proinflammatory, anti-inflammatory, and reparative processes during infection. The role of epithelial cytokines in the normal host response to respiratory viral infection and in the development of virus-associated chronic airway illness is adult in the next section.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780124158474000537