Cellular Signaling and Innate Immune Responses to RNA Virus Infections

Toll-like receptor
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Rehermann B. Pestka S. Thomas D. Huang Y. Khakoo S. Shin E. Interferon Cytokine Res. Morrow M. Kabelitz D. Bigger C. Chen L. Sarasin-Filipowicz M. Hiscott J. Panne D. Sato M. Grandvaux N. Wang C. Onoguchi K. Loo Y. Sumpter R. Wang N. Chang S. Leukocyte Biol. Yoneyama M. Schlee M. Myong S. Seth R. Kawai T. Meylan E. Saito T. Fitzgerald K. Gack M. Saha S. Oganesyan G. Yoshida R. Michallet M. Poeck H. Moore C. Kato H. Foy E. Baril M. Liang Y.

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Cheng G. Otsuka M. Tasaka M. Chen Z. Yang Y. Alexopoulou L. Funami K. Liu L. Sato S. Oshiumi H. Matsumoto M. Sarkar S. Seki E. Nakamura M. Jouan L. Dansako H. Ferreon J. Takeuchi O. Barbalat R. Abe T. Gilliet M. Lau D. Takahashi K.

Virology Lectures 2018 #13: Intrinsic and Innate Defenses

Decalf J. Kanto T. Lee J. Zhang Y. Lin W. Bode J. Blindenbacher A. Duong F. Christen V. Kim K. Malakhova O. Randall G. Gale M. Taylor D. Pflugheber J. Shimoike T. Jiang D. NKT cells develop in the thymus and have the same common lymphoid precursor of conventional T cells, but they have phenotypic and functional characteristics different of T cells [ ]. In addition, NKT cells recognize glycolipid antigens that are presented through CD1d molecules, MHC-like molecules that are constitutively expressed by antigen presenting cells such as DCs, B cells, and macrophages.

NKT cells also have the ability to respond to cells participating in innate immunity with minimal involvement of the T cell receptor TCR , and memory cells through a portion of the TCR, which makes them capable to be a bridge between the innate and adaptive immune response [ ]. Pathogens that invade a human host are controlled by the immune system, both innate and adaptive. The adaptive immune system, which is mediated by T and B cells, recognizes pathogens with high affinity through the rearrangement of certain receptors.

However, the establishment of this adaptive immune response is often not fast enough to eradicate pathogens, and it also involves cell proliferation, genetic activation, and protein synthesis [ ]. Thus, the fastest defense of a host mechanism is provided by the innate immune system, which has developed the ability to recognize invading pathogens and thus effectively eliminate them so that they do not cause damage to host cells.

The recognition of pathogens occurs through cells involved in the innate immunity response by nonspecific molecules that are commonly shared by most pathogens called PAMPs. PAMPs are highly conserved products and are produced by numerous microorganisms. These PAMPs do not show specific structures with antigenic variability, and host cells do not share the same molecular patterns with pathogens, resulting in recognition of the immune system, capable to discriminate between self and nonself [ ].

However, pathogens are not the only cause of cell and tissue damage. DAMPs include any endogenous molecule that experiences a change of state in association with a tissue injury, which allows the immune system to be informed that any damage has occurred [ ]. When these DAMPs are released from damaged or necrotic cells, together with PAMPs, are recognized by certain PRRs for their subsequent activation and induction of a potent acute inflammatory response [ ]. They were originally identified in the Drosophila fly as an important gene for its ontogenesis and its immunological resistance against fungal infections.

In addition, it was found that during microbial infections of flies, Toll receptors induce the production of antimicrobial peptides [ ]. In humans, the first protein structurally related to the Drosophila Toll receptor was identified and called the Toll-1 receptor TLR TLR-3 recognizes double-stranded RNA ligands, which are produced by most viruses in replication stages. TLR-5 responds to bacterial flagellin ligands. TLR-9 binds to ligands containing CpG motifs [ ]. TLRs are a family of transmembrane receptors that are key in the response and regulation of both innate and adaptive immunity [ ], since they recognize diverse pathogens and help to eliminate them.

There are other receptors such as NLRs, which are a family of 23 members that have been identified in humans. Among the most important members of these receptors are NOD1 and NOD2, which recognize specific ligands from various pathogens. This family is involved in increasing the proinflammatory events caused by cell death, pyroptosis and pyronecrosis, and several more proinflammatory processes [ ].

Another family of receptors is the RIGs. They are intracellular recognition receptors for patterns involved in the recognition of viruses by the action of the innate immune system. They act as sensors for viral replication within human host cells necessary to mediate antiviral responses [ ]. In innate immunity, a large number of soluble mediators such as cytokines, chemokines, and the complement system participate. All these mediators provide protection in the initial phase of contact with pathogens and are responsible for preventing potentially harmful infections.

The complement system has been considered as an effector response of the innate immune system capable of eliminating a great diversity of pathogens including bacteria, viruses, and parasites [ ].

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The complement system is composed of plasma proteins, which are present as inactive proteins [ ]. After activation, the products that are generated from the complement system facilitate the recruitment of cells from the immune system to the site of damage to eliminate the pathogen through opsonization or direct destruction [ ]. Activation of the complement system occurs through three pathways: 1 the classical pathway for the antigen—antibody complex; 2 the alternating pathway through the spontaneous hydrolysis of C3; and 3 the lectin pathway where certain sugars are recognized on the surface of the pathogens through mannose-binding lectin MLB.

Once activated, the pathway of the complement system generates a multimolecular enzyme complex that cuts to C3 and forms C3a and C3b. The C3b fragment that is generated binds to C3 convertase to form the C5 convertase, and once formed, this complex cuts to C5 to form C5a and C5b [ ].

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Then, C5b begins to recruit complement components C6, C7, C8, and C9 to form the membrane attack complex which is a lytic pore inserted into the membrane of the pathogen [ ]. Since the complement system uses multiple activation pathways, it has the ability to maximize the number of pathogens that it can recognize and thus eliminating a great diversity of these. In addition, it is responsible for eliminating apoptotic cells, this occurs through depositing a low amount of C3b molecules which facilitates the removal of these cells by macrophages [ ].

Cytokines form a molecular network that is synthesized and released by different cell types. These molecules act in a paracrine and endocrine way through their receptors that express the target cell. These molecules are synthesized and released in response to some damage or recognition of specific structures of the pathogens through their receptors e.

Initially, the cytokines were defined based on the activity they performed, among these activities are regulating the immune system but also exerting an effector function on the cells, these effects not only occur at local level but also occur through the tissues or systems. Cytokines are involved in regulating the homeostasis of the organism but when its production or its signaling pathway in the cell is not regulated, this homeostasis is altered, which can trigger in a pathology [ , ].

Cytokines may increase systemic level during some pathological condition, either acute or chronic, these molecules exert their effect by binding to their receptors, where the signal translation is given, which leads to the gene expression and finally can regulate the function of the target cell. The cytokine pattern that is released from the cell depends primarily on the nature of the antigenic stimulus and the type of cell being stimulated.

Cytokines compromise leukocytes to respond to a microbial stimulus, through regulating positively the expression of adhesion molecules on endothelial cells and amplifying the release of molecules such as reactive oxygen species and nitrogen, histamine, serotonin, as well as arachidonic acid derivatives, which regulate the release of the cytokines. On the other hand, cytokines can promote apoptosis by binding to receptors that contain death domains, for example TNF receptor 1 R1 [ ]. Chemokines or chemotactic cytokines are small molecules which constitute a large family of peptides 60— amino acids structurally related to cytokines.

Their main function is to stimulate leukocyte migration. They are secreted in response to some signals such as proinflammatory cytokines, where they play an important role in selectively recruiting monocytes, neutrophils, and lymphocytes [ , ]. The CC chemokine family is the largest and can be subdivided into several subfamilies. The second family consists of CXC chemokines; the prototype of these chemokines is IL-8 CXCL8 ; mainly this chemokine attracts polymorphonuclear cells to the site of acute inflammation. Also, CXCL8 activates monocytes and can recruit these cells to vascular injury.

The third family, consisting of a single member is Fraktalkine CX3CL1 which is one of the two transmembrane chemokines and has two isoforms, one binds to the membrane and the other is a soluble form. According to its isoform, it may have different functions, the form that is anchored to the membrane serves as adhesion molecule for cells expressing CX3CR1, while the soluble form possesses a potent chemotactic activity [ ].

The fourth family has only one member lymphotoxin XCL1 ; this chemokine is similar to members of the CC and CXC families, but the lack of two of the four cysteine residues are characteristic of this chemokine.

RIG-I-like Receptors

Its chemotactic function is for lymphocytes and not for monocytes and neutrophils as do other chemotactic chemokines [ ]. Inflammation is a protective response to extreme challenges to homeostasis, such as infection, tissue stress, and injury [ ], which is characterized by its cardinal signs: redness, swelling, heat, pain, and disrupted function [ ]. A typical inflammatory response consists of four components: 1 inflammatory inducers: depending on the type of infection bacterial, viral, fungi or parasitic [ ]; 2 sensors that detect the inflammatory inducers: these sensors are receptors of the innate immune system such as TLRs, NLRs and RLRs [ , ]; 3 inflammatory mediators induced by the sensors, such as cytokines, chemokines and the complement system [ ]; 4 target tissues that are affected by the inflammatory mediator.

Each component comes in multiple forms and their combinations function in distinct inflammatory pathways. The inflammatory reaction is characterized by successive phases: 1 silent phase, where cells reside in the damaged tissue releases in the first inflammatory mediators, 2 a vascular phase, where vasodilation and increased vascular permeability occur, 3 cellular phase, which is characterized by the infiltration of leukocytes to the site of injury [ ], and 4 resolution of inflammation, which is the process to return tissues to homeostasis [ , ].

In an infection by extracellular bacteria, the host triggers a series of responses to combat the pathogen and prevent its spread. Both the alternative and the lectin pathways of the complement system participate in the bacteria opsonization and potentiate their phagocytosis.

A TRAF3-NIK module differentially regulates DNA vs RNA pathways in innate immune signaling

To perform the correct phagocytosis, activation of several surface receptors in phagocytes, including scavenger receptors, mannose, Fc, and mainly TLRs is required. Activation of these receptors results in inflammation, by recruiting leukocytes to the site of infection [ ]. On the other hand, the humoral adaptive immune response is the main protective against extracellular bacteria. Its primary function is to block infection, through the release of antibodies that are directed against the antigens of the bacterial cell wall, as well as of the toxins secreted by certain extracellular bacteria.

The effector mechanisms used by the antibodies include neutralization, opsonization, and classical complement pathway activation, which allow bacteria phagocytosis. The Th17 cells are also involved in recruiting monocytes and neutrophils, promoting local inflammation.

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Immune response against bacteria. Mechanisms of the innate immune response to eradicate bacteria are A phagocytosis, B inflammatory response, and C participation of the complement system. Description in the text. In the case of infection by intracellular bacteria, they have the ability to survive and replicate within phagocytic cells, which causes the circulating antibodies to be inaccessible to intracellular bacteria.


The innate immune response against these bacteria is mediated primarily by phagocytes and NK cells [ ]. Among the phagocytes involved are neutrophils and then macrophages. However, these pathogens are resistant to degradation, but their products are recognized by TLRs and NLR receptors that are responsible for activating more phagocytes. NK cells are also activated in this type of infections and participate by stimulating the production of cytokine IL by DCs and macrophages. But usually this immune response is ineffective against infection.


Recently, two different virus infection models have of acquired immune responses. and TLR-independent RNA virus signaling, activation of CD8+ T cell. Keywords: innate immunity, double-stranded RNA, type I interferon, antiviral, the IFN signaling pathway such as IRF3/7 and antiviral effectors that limit viral . In a viral infection, the dsRNA would be intracellular during its.

All this to eradicate the infection of the host [ ]. Most fungi are present in the environment, so animals including humans are exposed and then can inhale spores or yeasts [ ]. The mechanisms for defense against the fungi comprise of both innate and adaptive immune responses. TLR2 activation induces oxidative pathways in polymorphonuclear PMN cells with the release of gelatinases and inflammatory cytokines.

TLRs can be combined to recognize a large number of fungal structures and thus generate a broader response against the various fungal structures [ , ]. Type C lectin receptors CTLRs make up a receptors family that can recognize several molecules like proteins, carbohydrates, and lipids. Among these receptors, the best studied are dectin-1, dectin-2, dendritic cell-specific intercellular adhesion moleculegrabbing nonintegrin DC-SIGN , macrophage inducible C-type lectin, and mannose receptor MR involved in the recognition of some structures of the fungi [ ].

Dectin-1 activation can also induce mast cells to produce proinflammatory and TH2-polarizing cytokines, such as IL-4 and IL In addition, dectin-2 promotes Th17 polarization by inducing ILA, which is crucial in neutralizing some fungi. The MR recognizes mannose, fucose, or N-acetylglucosamine residues present in fungi.

MR generates a Th17 response and promotes fungi phagocytosis [ ]. The response that occurs through the activation of these receptors includes the binding to fungi and their phagocytosis, the induction of antifungal effector mechanisms and the production of soluble mediators such as cytokines, chemokines, and inflammatory lipids [ ]. The immunity against fungi requires the recruitment and activation of phagocytosis, which is mediated through factors that induce inflammatory molecules such as proinflammatory cytokines and chemokines. The PRRs interaction with fungal structures plays an important role in the control of infections against these pathogens, since this interaction is determinant for the generation of the profile of cytokines or chemokines that influence the immune response.

Immune response against fungi. The activation of these receptors includes the binding to fungi and their phagocytosis. In an infectious process, the most common host response is to generate inflammation. Viruses in the absence of cytopathologic damage at early stages of infection inhibit the induction of acute phase protein response because early monocytes are not activated. Type I interferons are the major cytokines responsible for defending the human host against viral infections.

It has been shown that interferons do not exert their antiviral effects by direct action on viruses, but they help in the gene activation that results in the production of antiviral proteins, which participate as mediators in the inhibition of viral replication, as well as mediating the effects of suppressor T cells [ ].

The adaptive immune response against this type of infection is primarily composed of the humoral immune response with the antibody production directed against viral antigens. However, the cellular immune response is the most important for virus eradication. However, certain viruses have developed mechanisms of immune evasion to survive longer and thus be able to replicate without any problem until causing serious damage to the host [ ]. Immune response against viruses. B Antibody production directed against viral antigens. Due to there being a large variety of parasites and that each of their life cycles are very complex, in this section, we will focus on the immune response against helminth parasites.

This is because more than 1 billion people are currently infected with helminth parasites worldwide [ ], making them one of the most prevalent infectious agents responsible for many diseases in both animals and humans [ ]. The investigation of these parasitic infections is not only of direct relevance to human and animal health but also because they present a constant and important challenge to the host immune system, since both in humans and animals, helminth parasites establish chronic infections [ ] associated with a significant downregulation of the immune response.

Thus, helminth parasites will interact with the mucus layer and in many cases will have to cross it to reach the epithelial layer and thus thrive and reproduce within it [ ]. The immune response against helminth parasites involves both the innate and adaptive immune response [ , ].


In human carcinoma cells, we visualize the voltage response to growth factor stimulation, stably recording a mV hyperpolarization over minutes. Briefly, when the ligand-receptor interaction occurs, subsequent events are activated based on the nature of these ligands and receptors. J Virol 80 10 — Nat Commun 6: Activating cytokines.

Immune response against parasites. Thanks to the authors who collaborated in the writing of this chapter: Dr. Pamela Castro, Dr. Alejandra Moreno and Dr. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. Edited by Nima Rezaei. We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists.

Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. Downloaded: Abstract Pathogen infections are recognized by the immune system, which consists of two types of responses: an innate immune response and an antigen-specific adaptive immune response.

Keywords innate immune response eosinophils mast cells cytokines inflammatory response bacteria fungi viruses parasites. Introduction The immune system consists of a series of effector mechanisms capable of destroying pathogenic organisms such as bacteria, fungi, viruses, and parasites [ 1 ].

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Innate immune system cells The cells of the innate immune system have several functions that are essential for defense against pathogens. Nonmyeloid cells Nonmyeloid cells include epithelial cells, fibroblasts, etc. Myeloid cells Myeloid cells include monocytes, macrophages, dendritic cells DCs , neutrophils, eosinophils, basophils, mast cells, and platelets. Macrophages Monocytes are precursor cells that are produced in the bone marrow, which are mobilized into the bloodstream and then differentiate into macrophages at the site of inflammation [ 15 ]. Dendritic cells Monocytes circulate in the blood, bone marrow, and spleen [ 29 , 30 ] and represent immune effector cells equipped with chemokine and adhesion receptors that mediate cell migration from blood to tissues during infection.

Neutrophils In humans, about billion neutrophils enter the bloodstream each day [ 37 ].