V.
VIRUSES
Fundamental Statement for this Softchalk Lesson:
1. Innate immunity is an antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any microbe. This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.
2. Viral nucleic acids functions as a pathogen-associated molecular pattern (PAMP).
3. Binding of viral PAMPs to host cell pattern-recognition receptors (PRRs) triggers the synthesis and secretion of anti-viral cytokines called type-1 interferons. Type-I interferons are cytokines that have significant antiviral activity mediated through their ability to inhibit viral replication within infected cells, protect uninfected cells from infection, and stimulate antiviral immunity by cytotoxic T-lymphocytes (CTLs) and NK cells.
4. Adaptive (acquired) immunity refers to antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This is the immunity one develops throughout life.
5. An antigen is a molecular shape that reacts with antigen receptors on lymphocytes to initiate an adaptive immune response.
6. The actual portions or fragments of an antigen that react with antibodies and with receptors on B-lymphocytes and T-lymphocytes are called epitopes.
7. Opsonizing antibodies made against viral surface antigens can bind viruses to phagocytes for more efficient phagocytosis; antibodies made against viral surface proteins can block adsorption of viruses to host cell receptors.
8. Cell-mediated immunity involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigens. These defense cells help to remove infected cells and cancer cells displaying foreign epitopes.
9. One of the body's major defenses against viruses, intracellular bacteria, and cancers is the destruction of infected cells and tumor cells by cytotoxic T-lymphocytes or CTLs, effector cells derived from naïve T8-lymphocytes during cell-mediated immunity.
10. When the TCR and CD8 of the CTL binds to the MHC-I/epitope on the surface of the virus-infected cell or tumor cell, this triggers the release of cytotoxic perforins/granzymes/ granulysin granules from the CTL that lead to apoptosis, a programmed cell suicide of that cell to which the CTL has bound.
11. NK cells (Natural Killer cells) recognize infected cells displaying stress-induced proteins and not displaying MHC-I molecules and kill these cells by inducing apoptosis.
12. During apoptosis, the cell breaks into membrane-bound apoptotic fragments that are subsequently removed by macrophages.
LEARNING
OBJECTIVES FOR THIS SECTION
E.
VIRAL ACTIVATION OF IMMUNE RESPONSES
The body has two immune systems: the innate immune system and the adaptive immune system.
1. Innate immunity is an antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any microbe. This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.
2. Adaptive (acquired) immunity refers to antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This is the immunity one develops throughout life.
1. Viral Activation of Innate Immunity
In order to protect against infection, one of the things the body must initially do is detect the presence of microorganisms. The body does this by recognizing molecules unique to microorganisms that are not associated with human cells. These unique molecules are called pathogen-associated molecular patterns or PAMPs (def). For example, most viral genomes contain a high frequency of unmethylated cytosine-guanine dinucleotide sequences (a cytosine lacking a methyl or CH3 group and located adjacent to a guanine). Mammalian DNA has a low frequency of cytosine-guanine dinucleotides and most are methylated. In addition, most viruses produce unique double-stranded viral RNA, and some viruses produce uracil-rich single-stranded viral RNA during portions of their life cycle. These forms of viral nucleic acids are common PAMPs associated with viruses. These PAMPs bind to pattern-recognition receptors or PRRs (def) called toll-like receptors or TLRs found within the endosomes of phagocytic cells. Viral RNA can also bind to cytoplasmic PRRs called RIG-1 (retinoic acid-inducible gene-1)and MDR-5 (melanoma differentiation-associated gene-5).
Most of the PRRs that bind to viral components trigger the synthesis of cytokines (def) called Type-I interferons Type-I interferons (def). Interferons activate hundreds of genes that collectively are able to produce a variety of antiviral proteins interfering with every step in the viral life cycle and blocking viral replication. Interferons are ultimately able to:
1. Strengthen the cells outermost defenses to interfere with viral entry into the host cell.
2. Degrade mRNA to block transcription and curb protein synthesis within the host cell.
3. Block maturation of the viruses.
4. Block the release of mature viruses from infected cells.
5. Activate macrophages and NK-cells, as well as recruit B-lymphocytes and T-lymphocytes to the area for adaptibe immune responses against the virus and the viral-infected cells.
Most of the PRRs that bind to viral components trigger the synthesis of cytokines (def) called Type-I interferons (def) that block viral replication within infected host cells.
The TLRs for viral components are found in the membranes of the phagosomes used to degrade viruses during phagocytosis. As viruses are engulfed by phagocytes, the viral PAMPS bind to TLRs located within the phagolysosomes (endosomes) (def). The TLRs for viral components include:
1. TLR-3 binds double-stranded viral RNA;
2. TLR-7 binds uracil-rich single-stranded viral RNA such as in HIV;
3. TLR-8 binds single-stranded viral RNA;
4. TLR-9 binds unmethylated cytosine-guanine dinucleotide sequences (CpG DNA) found in bacterial and viral genomes.
5. RIG-1 (retinoic acid-inducible gene-1) and MDA-5 (melanoma differentiation-associated gene-5), are cytoplasmic sensors that both viral double-stranded and single-stranded RNA molecules produced in viral-infected cells.
2. Viral Activation of Adaptive Immunity
Proteins and glycoproteins associated with the viral envelope and/or the viral capsid function as antigens and initiate adaptive immunity. An antigen (def) is defined as a molecular shape that reacts with antibody molecules and with antigen receptors on lymphocytes. We recognize those molecular shapes as foreign or different from our body's molecular shapes because they fit specific antigen receptors on our B-lymphocytes> and T-lymphocytes, the cells that carry out adaptive immunity.
The actual portions or fragments of an antigen that react with antibodies and with receptors on B-lymphocytes (def) and T-lymphocytes (def) are called epitopes (def). An epitope is typically a group of 5-15 amino acids with a unique shape that makes up a portion of a protein antigen (see Fig. 1A), or 3-4 sugar residues branching off of a polysaccharide antigen (see Fig. 1B). A single microorganism has many hundreds of different shaped epitopes that our lymphocytes can recognize as foreign and mount an adaptive immune response against.The body recognizes an antigen as foreign when epitopes of that antigen bind to B-lymphocytes and T-lymphocytes by means of epitope-specific receptor molecules having a shape complementary to that of the epitope. The epitope receptor on the surface of a B-lymphocyte is called a B-cell receptor and is actually an antibody molecule. The receptor on a T-lymphocyte is called a T-cell receptor (TCR).
There are two major branches of the adaptive immune responses: humoral immunity and cell-mediated immunity.
1. Humoral immunity(def): Humoral immunity involves the production of antibody (def) molecules in response to an antigen and is mediated by B-lymphocytes. Through a variety of mechanisms, these antibodies are able to remove or neutralize microorganisms and their toxins after binding to their epitopes. For example, antibodies made against viral surface antigens can prevent viruses from adsorbing to host cell receptors thus blocking viral replication or function as opsonizing antibodies to attach viruses to phagocytes for enhanced attachment.
As will be seen in Unit 6, one of the major defenses against free viruses is the immune defenses' production of antibody molecules against the virus. The "tips" of the antibody (the Fab portion; (see Fig. 2) have shapes that have a complementary shape to portions of viral attachment proteins and glycoproteins called epitopes found on the viral surface. When antibodies react with these attachment proteins, they block viral adsorption to host cell receptors and, therefore, block viral replication.
In addition, antibodies such as IgG function as opsonins and bind viruses to phagocytes.
2. Cell-mediated immunity (def): Cell-mediated immunity involves the production of cytotoxic T-lymphocytes (def), activated macrophages (def), activated NK cells (def), and cytokines in response to an antigen and is mediated by T-lymphocytes. These defense cells help to remove infected cells and cancer cells displaying foreign epitopes. Virus-infected host cells naturally bind viral epitopes to a host molecule called MHC-I (def) and place the MHC-1 with bound viral epitope on the surface of the infected cell (see Fig. 3) where they can be recognized by CTLs having a T-cell receptors on its surface with a complementary shape.
In this way the CTL can kill the infected cell by apoptosis (def), a programmed cell suicide.
Another defense cell that is able to kill virus-infected cells is the NK cell (def). NK cells recognize infected cells displaying stressed-induced proteins and not displaying MHC-I molecules on their surface and kill these cells by inducing apoptosis (def) (see
Fig. 4).
MHC-I molecules are the molecules on host cells that display viral epitopes to cytotoxic T-lymphocytes (CTLs). Some viruses suppress the production of MHC molecules by host cells, preventing CTLs from recognizing the infected cell as foreign and killing it. NK cells, however, can recognize cells not displaying MHC-I and kill them anyway.
Gary E. Kaiser, Ph.D.
Professor of Microbiology
The Community College of Baltimore County, Catonsville Campus
This work is licensed under a Creative Commons Attribution 4.0 International License.
Based on a work The Grapes of Staph at https://cwoer.ccbcmd.edu/science/microbiology/index_gos.html.
Last updated: Feb., 2020
Please send comments and inquiries to Dr.
Gary Kaiser