Thus, a better understanding of mechanisms responsible for NK cell activation and function in the control of viral infections will help develop NK cell-based therapies. In this review, we will first discuss how NK cells are activated in response to viral infections.
We will then focus on the recruitment of activated NK cells to the site of infection as well as on NK cell effector mechanisms against virally infected cells. Natural killer NK cells are unique lymphocytes without a clonally specific receptor [ 1 ].
As lymphocytes of the innate immune system, NK cells lack antigen-specific receptors and do not resemble T and B cells. This identity contributed to speculation that NK cells, originally discovered through their ability to destroy tumor cells without prior sensitization, mediate cytolysis in a nonspecific fashion [ 2 , 3 ].
It is now better understood that the activation of NK cells and their functions are regulated by both activating and inhibitory signals. While initial work demonstrated their antitumor activities, NK cells are also critical for the control of certain infections, particularly viral infections. In humans, NK cells are important to the innate immune response against members of the herpesvirus, poxvirus and papillomavirus families [ 5 , 6 ].
Patients with identified NK cell deficiencies are predisposed to particularly severe, recurrent viral infections. Mouse models provide additional evidence that NK cells give critical help to control several viral infections, most notably murine cytomegalovirus MCMV , poxviruses and influenza [ 7 , 8 ]. In this review, we will detail how NK cells are activated in response to viral infections.
We will then proceed to describe the recruitment of activated NK cells to the site of infection and NK cell effector mechanisms against virally infected cells. However, in many circumstances, NK cells can efficiently eliminate virus-infected cells that maintain expression of the inhibitory MHC class I [ 9 , 10 ].
Recent advances have indicated that NK cell activation and function are regulated by the interplay between the inhibitory and activating receptors [ 11 , 12 ]. Indeed, accumulating evidence has revealed the importance of NK cell-activating receptors in antiviral defense. The first NK cell-activating receptor identified to be critical for viral control in vivo was Ly49H, which is necessary to clear MCMV infection [ 13 ].
This ligand was identified by two independent groups using heterologous reporter cells exposed to MCMV-infected cells [ 14 , 15 ]. Deletion of the genetic locus of Ly49H, Cmv1 r , or use of Ly49H-blocking antibodies confers susceptibility to the virus [ 16 ]. Deletion of m also facilitates viral escape and persistence later in the infection.
The Ly49 lectin-like receptors do not exist in humans. However, structurally different killer immunoglobulin-like receptors KIRs function similarly and recognize peptide-loaded MHC class I molecules. The natural cytotoxicity receptors represent another class of activating receptors that recognize viral-derived products [ 17 ]. Of these, NKp46 is the most prominent and is found on all NK cells.
NKp46 recognizes hemagglutinin of influenza virus and hemagglutinin-neuraminidase of parainfluenza virus, suggesting that it may be involved in resistance to these viruses [ 17 ]. Indeed, mice deficient in NCR1, a murine homolog of NKp46, fail to protect against lethal influenza infection [ 18 ].
NKp46 and another activating receptor, DNAM-1, are critical for activation in response to human CMV-infected myeloid dendritic cells; however, a cellular ligand for NKp46 remains to be identified [ 19 ].
NKG2D, a C-type lectin-like homodimer, promotes NK cell activation by recognizing host stress proteins induced upon viral infections. NKG2D is also critical in NK cell-mediated control of infection with vaccinia virus [ 23 ] and adenovirus [ 24 ]. One recent study described a pathway in which lipopolysaccharide treatment of macrophages upregulated MICA expression by increasing its transcription, promoting its translational or posttranslational processing, and downregulating micro-RNAs that target MICA [ 26 ].
Downstream of these activating receptors, ligand recognition triggers an intracellular kinase cascade to transmit the activation signal [ 11 ].
Recent studies have shown that NKG2D signaling alone is not sufficient to activate NK cells and that efficient NK cell activation requires cooperation of other activating receptors acting synergistically [ 28 ].
Intranasally administered CpG can in fact activate and recruit NK cells to the lung [ 34 ]. Recent studies have demonstrated that direct TLR2 stimulation on murine NK cells is critical for their activation and function in the control of vaccinia viral infection in vivo [ 23 ].
Similarly, direct activation of TLR4 by a bacterial component fimbrial protein, FimH, appears to be important for the activation of both mouse and human NK cells [ 35 ]. To control inappropriate activating signals, there is a repertoire of inhibitory receptors that repress NK cell activation [ 36 ]. These inhibitory receptors survey MHC class I molecules and seem to protect healthy cells from inappropriate NK cell-mediated killing.
Some inhibitory receptors also recognize other ligands such as cadherins and collagen. Despite the structural differences between the lectin and immunoglobulin receptors, these classes of receptors signal downstream similarly. The balance between activating and inhibitory receptors is achieved within the cell, downstream of receptor-ligand binding [ 36 ]. Contradictory signaling between the activating and inhibitory receptors depends on the ITAMs and immunoreceptor tyrosine-based inhibition motifs ITIMs , respectively.
Upon stimulation of inhibitory receptors, ITIMs on the cytosolic domains of inhibitory receptors become phosphorylated by Src kinases.
Phosphorylated ITIMs activate phosphatases to counter the kinase cascade of the activating receptors. Viral Activation of Immunity The term immunity as used in this chapter covers the mechanisms by which a host may specifically recognize and react to viruses. Figure The immune system response to a virus. Viral Antigens The degree to which viral antigens are exposed to the host immune defenses is governed by the intracellular replication of viruses and by the several possible types of virus-host cell interaction Fig.
Figure Virus-host cell interactions. Acute Cytolytic Infection Acute cytolytic infection, the most common form of virus-host cell interaction Fig.
Persistent Infections Some viruses produce a chronic steady-state infection rather than an acute infection of the host cell: progeny virions are released continuously, with little adverse effect on cellular metabolism. Latent Infections Latent infections result when an infecting virus e. Integrated Virus Infection There is another type of persistent virus-host cell interaction, integrated virus infection, in which all or part of the viral nucleic acid becomes integrated into the genome of the host cell.
Virus Spread Another important consideration in how viral infections trigger an immune response is the way in which a particular virus spreads in the host. Virus Location The location of the virus in the host is important not only for understanding the immune response, but also for developing and administering a vaccine. Multiplicity of Immune Defenses Recent studies have revealed a great complexity of host immune defenses against viral infections.
Humoral Immunity: B Lymphocytes As described in Chapter 1 , specific B lymphocytes respond to viral antigen introduced by immunization or infection. Figure Mechanisms of virus neutralization by antibody at the cellular level. Figure Extracellular neutralization of virus by antibody. Antibody effects on virus-infected cells Antibody also can act on virus-infected cells by recognizing virus-specific antigens on the surface of infected cells Fig.
Physical barriers to antibody Before antibody can combine with and neutralize the virus, it must reach the site of virus replication. IgG Antibodies IgG is the most thoroughly studied antibody class and is responsible for most antiviral activity in serum. Production and the roles of antibody classes After immunization or infection with viruses, various classes of antibody appear sequentially. IgE antibodies and immediate hypersensitivity Recent information suggests that viruses that bind to IgE antibodies may trigger immediate hypersensitivity responses through the release of vasoactive mediators see Ch.
Complement Complement enhances the phagocytosis of many viruses. Hypogammaglobulinemia A small minority of patients with impaired B-lymphocyte function hypogammaglobulinemia limited to impairment of humoral immunity have a significantly increased frequency of severe poliovirus and enterovirus infections of the nervous system in addition to more frequent and severe infections with pyogenic bacteria.
Cell-Mediated Immunity Cell-mediated immunity CMI was once thought to be mediated solely by T lymphocytes; however, it is now clear that it is mediated by a variety of cell types, cell factors, or both.
Figure Lysis of virus-infected cells by cytotoxic effector cells. Figure Cell-mediated events in viral infections. T Lymphocytes Much evidence indicates that T lymphocytes are important in recovery from viral infections. Cytotoxic T lymphocytes The generation of virus-specific cytotoxic T lymphocytes CTLs is believed to be important in preventing viral multiplication Fig.
Macrophages Macrophages are important in both specific and nonspecific responses to viral infections e. Natural Killer Cells Natural killer NK cells exhibit cytotoxic activity against a number of tumor cell lines, particularly against virus-infected or virus-transformed cells Fig. Lymphokines and Monokines Soluble factors from T lymphocytes lymphokines and macrophages monokines regulate the degree and duration of the immune responses generated by T lymphocytes, B lymphocytes, and macrophages see Ch.
Virus-Induced Immunopathology A host clearly has numerous mechanisms to recognize and eliminate the viruses that it encounters. Roles of Immune functions During Viral Infections On the basis of the mechanisms described here and in Chapter 49 , a hypothetical model can be constructed that shows how the immune components defend against viruses Fig. Nonspecific Defenses A primary infection in a nonimmune, susceptible host is countered first by the nonspecific defense mechanisms see Ch.
Specific Defenses Antibody The events that lead to a specific immune response begin almost immediately after exposure and result in the production of antiviral antibody and cell-mediated immunity in 3 to 10 days. Cell-Mediated Immunity Cell-mediated immunity is essential in recovery from and control of viral infections, especially infections involving oncogenic viruses or viruses that spread directly from cell to contiguous cell.
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Verh Dtsch Ges Pathol. Innate immune defenses exhibit circadian rhythmicity and differential temporal sensitivity to a bacterial endotoxin in Nile tilapia Oreochromis niloticus. Fish Shellfish Immunol.
Epub Jun J Virol. Epub Feb Methods Mol Med. Recent Activity. Clear Turn Off Turn On. Immune Defenses - Medical Microbiology.
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Mast Cells. A pair of closely related drugs, chloroquine and hydroxychloroquine, have gotten tons of press but, so far, mostly disappointing results in clinical trials for treating COVID Some researchers advocate using hydroxychloroquine, with the caveat that use should be early in the course of the disease.
In a lab dish, these drugs diffuse into cells, where they diminish acidity in endosomes and prevent it from building up in lysosomes. The virus remains locked in a prison of its own device. But only further clinical trials will tell how much that matters. SARS-CoV-2 has entered the cell, either by fusion or by riding in like a Lilliputian aquanaut, stealthily stowed inside an endosome.
It must replicate itself in entirety and in bulk, with each copy constituting the potential seed of a new viral particle.
To do both things, the virus needs a special kind of polymerase. Every living cell, including each of ours, uses polymerases to copy its DNA-based genome and to transcribe its contents the genes into RNA-based instructions that ribosomes can read. Our cells never need to do this, and they lack polymerases that can.
Fortunately for the virus, there can be as many as 10 million ribosomes in a single cell. Once made, the viral polymerase cranks out not only multiple copies of the full-length viral genome — replication — but also individual viral genes or groups of them.
These snippets can clamber aboard ribosomes and command them to produce the entire repertoire of all the proteins needed to assemble numerous new viral offspring. These newly created proteins include, notably, more polymerase molecules. Each copy of the SARS-CoV-2 genome can be fed repeatedly through prolific polymerase molecules, generating myriad faithful reproductions of the initial strand.
Well, mostly faithful. So the copies of the initial strand — and their copies — are at risk of being riddled with copying errors, aka mutations. It chops out the wrongly inserted chemical component and gives the polymerase another, generally successful, stab at inserting the proper chemical unit into the growing RNA sequence. Initially developed for treating Ebola virus infection, it belongs to a class of drugs that work by posing as legitimate chemical building blocks of a DNA or RNA sequence.
These poseurs get themselves stitched into the nascent strand and gum things up so badly that the polymerase stalls out or produces a defective product. Some intact viral genome copies still manage to be made, escape from the cell, and infect other cells — mission accomplished. Using remdesivir in combination with some still-sought, as yet undiscovered drug that could block the proofreader might be a more surefire strategy than using remdesivir alone, Shafer said.
In addition to replicating its full-length genome, the virus has to make lots of proteins.
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