Lecture 20 - Vaccination and treatment of viral diseases Flashcards
Define intrinsic, innate, cellular and humoural immune responses.
Intrinsic immune response: Refers to the various defense mechanisms that individual cells possess to combat viral infections. These mechanisms include the production of antiviral proteins, RNA interference, and apoptosis.
Innate immune response: The first line of defense against viral infections, involving non-specific mechanisms such as the release of cytokines, activation of natural killer cells, and phagocytosis by macrophages.
Cellular immune response: Involves the activation of T lymphocytes (specifically cytotoxic T cells) to recognize and eliminate virus-infected cells. Cellular immunity is crucial for clearing viral infections and providing long-term immunity.
Humoral immune response: Involves the production of antibodies by B lymphocytes in response to viral antigens. Antibodies can neutralize viruses, opsonize them for phagocytosis, or activate the complement system to enhance viral clearance.
What evidence proves that vaccines are effective
Clinical trials: Vaccine candidates undergo rigorous testing in controlled clinical trials to assess their safety, immunogenicity, and efficacy.
Epidemiological studies: Observational studies compare disease incidence between vaccinated and unvaccinated populations to evaluate the impact of vaccination programs.
Surveillance data: Monitoring disease trends over time can reveal declines in disease incidence and outbreaks following widespread vaccination.
Give examples of diseases that have been effectively eradicated and those that have not.
Successfully eradicated: Smallpox is the only human disease that has been eradicated through vaccination efforts. Polio is close to eradication, with wild poliovirus transmission limited to a few countries.
Not eradicated: Diseases like measles, mumps, rubella, and influenza continue to circulate globally despite the availability of vaccines. Factors such as vaccine hesitancy, limited access to vaccines, and viral genetic variability contribute to the challenges of eradicating these diseases.
How was the polio vaccine designed
The polio vaccine can be either inactivated (IPV) or live attenuated (OPV).
IPV is made from killed poliovirus strains and is administered through injection. It induces humoral immunity.
OPV contains weakened (attenuated) poliovirus strains and is administered orally. It induces both humoral and cellular immunity.
What is vaccine derived poliovirus and how is it combated.
Vaccine-derived poliovirus can arise in under-vaccinated populations where the oral polio vaccine is used. The attenuated virus in the vaccine can regain virulence through mutations, leading to outbreaks.
Combating vaccine-derived poliovirus circulation involves strengthening routine immunization programs, conducting supplementary immunization campaigns, and introducing the inactivated polio vaccine (IPV) to reduce the risk of vaccine-derived strains.
What are some alternative approaches to vaccine design.
Virus-like particles (VLPs): Mimic the structure of viruses but lack genetic material, providing a safer vaccine option.
Recombinant vaccines: Engineered to express specific viral antigens, stimulating an immune response without the need for live virus.
Peptide cocktail vaccines: Contain multiple peptides representing different viral epitopes, designed to induce broad immune responses.
Give examples of antiviral drugs.
Acyclovir: Used to treat herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections by inhibiting viral DNA polymerase.
Ribavirin: Broad-spectrum antiviral used for hepatitis C virus (HCV), respiratory syncytial virus (RSV), and others, thought to inhibit viral RNA synthesis.
Zidovudine (AZT) and Tenofovir: Used to treat HIV by inhibiting viral reverse transcriptase and viral DNA synthesis.
Saquinavir: A protease inhibitor used in HIV treatment to block viral maturation by inhibiting viral protease activity.
Amantadine: Used to treat influenza A virus infections by blocking the M2 ion channel, preventing viral uncoating.
What are drug treatments for viruses that are not directly antiviral.
Some viral diseases, such as hepatitis B and C, may not have direct-acting antiviral drugs available. Instead, treatment focuses on managing symptoms, reducing complications, and supporting the immune response. For example, interferon therapy is used for hepatitis B and C infections to boost the immune response against the virus.
How does intrinsic immunity work.
Intrinsic immunity refers to the natural defence mechanisms present within cells to combat viral infections. One such mechanism is the RNA interference (RNAi) pathway, which plays a crucial role in insect cells’ antiviral response.
1. Recognition of dsRNA: During viral infection, cytoplasmic double-stranded RNA (dsRNA) is produced as a byproduct of viral replication. This dsRNA is recognized by an enzyme called Dicer2.
2. Cleavage of dsRNA: Upon recognition, Dicer2 cleaves the dsRNA into smaller fragments known as dsRNA oligonucleotides.
3. Formation of RNA-induced Silencing Complex (RISC): These dsRNA fragments then associate with a protein called Argonaut, forming a complex. This complex unwinds the dsRNA, and one of the strands is selected as the guide strand.
4. Loading of Guide Strand into RISC: The guide strand, selected from the dsRNA fragment, is loaded into the RNA-induced silencing complex (RISC). RISC now carries the guide strand, which is complementary to viral mRNA sequences.
5. Targeting Viral mRNA: RISC, armed with the guide strand, searches for viral mRNA molecules. When it encounters viral mRNA that is complementary to the guide strand, RISC binds to it.
6. Cleavage of Viral mRNA: Once bound to the viral mRNA, RISC induces cleavage of the mRNA strand. This cleavage is mediated by the Argonaut protein within the RISC complex.
7. Inactivation of Viral mRNA: Cleavage of the viral mRNA prevents it from being translated into viral proteins. As a result, the virus’s ability to replicate and propagate within the host cell is inhibited, contributing to the cell’s defence against viral infection.
What are PAMPs
- Infection Sensing: When a pathogen infects a cell, it releases molecules called Pathogen-Associated Molecular Patterns (PAMPs). These PAMPs are recognized by Pattern Recognition Receptors (PRRs) present in various cellular compartments such as the plasma membrane, endosomes, and cytoplasm. For virus infections, significant PRRs include Toll-like receptors (TLRs) such as TLR2, TLR3, TLR4, TLR7/8, TLR9, as well as cytoplasmic receptors like RIG-I and Mda5. Different viruses are recognized by different combinations of these receptors.
- Activation of PRRs: When a PRR recognizes a PAMP, it initiates a signalling cascade within the cell. This cascade involves the recruitment of specific adaptor molecules and leads to the activation of downstream signalling pathways.
- Phosphorylation of IRF3/7 and IkB: One of the outcomes of the signalling cascade is the phosphorylation of specific proteins such as Interferon Regulatory Factor 3 (IRF3), IRF7, and Inhibitor of kappa B (IkB). Phosphorylation is a chemical modification that alters the activity of these proteins.
- Transcription Factor Activation: Phosphorylated IRF3/7 proteins form homo- or hetero-dimers (meaning they pair up either with identical copies of themselves or with each other) in the cytoplasm. These dimers then translocate to the nucleus and bind to specific DNA sequences called promoters. These promoters are regulatory regions of genes, including the one controlling the expression of the Interferon-beta (IFNβ) gene.
- Activation of NFkB: Phosphorylation of IkB leads to its degradation via ubiquitin-mediated proteolysis. This degradation frees another transcription factor called Nuclear Factor kappa B (NFkB), allowing it to translocate to the nucleus.
- Gene Expression: Once in the nucleus, the dimers of phosphorylated IRF3/7, along with NFkB and other transcription factors such as ATF/c-jun, bind to the promoters of target genes, including the IFNβ gene. This binding activates the transcription (copying) of the gene into mRNA, which is then translated into the Interferon-beta protein.
Interferon Signalling: Interferon-beta is a crucial signalling molecule that helps to alert neighbouring cells of the presence of a viral infection. It triggers the expression of various antiviral genes and proteins, helping to establish an antiviral state in the surrounding cells, thus limiting the spread of the virus.
What are interferon and induction of interferon-stimulated genes.
Interferons are signalling proteins produced by cells in response to viral infections or other immune stimuli.
* IFNα or IFNβ binds to its specific receptor located on the plasma membrane of target cells.
* Upon binding, the receptor undergoes conformational changes, leading to the activation of receptor-associated tyrosine kinases.
* The activated tyrosine kinases phosphorylate Signal Transducer and Activator of Transcription 1 (STAT1) and STAT2 proteins present in the cytoplasm.
* Phosphorylated STAT1 and STAT2 proteins form a heterodimeric complex.
* The STAT1/2 heterodimer translocates into the nucleus.
* Once in the nucleus, the STAT1/2 heterodimer binds to Interferon Regulatory Factor 9 (IRF9), forming a complex known as Interferon-Stimulated Gene Factor 3 (ISGF3).
* The ISGF3 complex binds to specific DNA sequences called promoters located on the genes of Interferon-Stimulated Genes (ISGs).
* Binding of ISGF3 to the promoters of ISGs stimulates the transcription (copying) of these genes into mRNA.
* The transcribed mRNA molecules are then translated into proteins known as Interferon-Stimulated Proteins (ISPs) or Interferon-Stimulated Genes (ISGs).
ISGs play crucial roles in the cell’s antiviral defence mechanisms and immune modulation.
They can inhibit viral replication, modulate immune responses, and promote the clearance of infected cells.
Discuss antibodies.
Antibodies, also known as immunoglobulins (Ig), are Y-shaped proteins produced by the immune system in response to the presence of foreign substances called antigens. Here’s a summary of their structure:
1. Overall Structure: Antibodies are composed of four polypeptide chains - two identical heavy chains and two identical light chains - arranged in a Y-shaped structure.
2. Variable and Constant Regions: Each antibody chain consists of variable (V) and constant (C) regions. The variable regions, located at the tips of the Y-shaped structure, contain antigen-binding sites that recognize and bind to specific antigens.
3. Antigen-Binding Sites: These are the regions at the tips of the antibody molecule formed by the variable regions of the heavy and light chains. They exhibit high specificity for antigens through complementary interactions.
4. Heavy and Light Chains: Antibody chains are linked by disulfide bonds. Heavy chains are longer and contain multiple domains, while light chains are shorter. Both heavy and light chains contribute to the antigen-binding site.
5. Constant Regions: The constant regions are responsible for determining the antibody’s class or isotype (e.g., IgG, IgM, IgA, IgD, IgE). They also mediate effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement activation.
6. Fc Region: The stem of the Y-shaped antibody, formed by the constant regions of the heavy chains, is known as the Fc region. It interacts with various immune cells and molecules, mediating functions such as opsonization, neutralization, and activation of the complement system.
Flexibility: Antibodies possess flexibility due to hinge regions between the Fab (fragment antigen-binding) and Fc regions. This flexibility allows them to bind to antigens with different spatial orientations and to engage in various effector functions.
Describe T cell activation
- Infected Cell Presentation: An infected cell presents a short peptide antigen derived from a virus on its surface. This peptide is presented in a complex with Major Histocompatibility Complex (MHC) class I molecules.
- T Cell Recognition: A specific type of T cell, called a cytotoxic T cell (CTL), possesses a T cell receptor (TCR) that can recognize and bind to the virus peptide antigen presented by the MHC class I molecule on the infected cell’s surface. The TCR’s recognition is assisted by the CD8 co-receptor molecule associated with the T cell surface.
- Activation of CTL: Binding of the TCR and CD8 to the virus peptide-MHC class I complex triggers signalling cascades within the cytotoxic T cell, leading to its activation.
Killing of Infected Cell: Once activated, the cytotoxic T cell becomes capable of exerting its cytotoxic function. It releases cytotoxic molecules such as perforin and granzymes, which induce apoptosis (programmed cell death) in the infected cell. This eliminates the infected cell, preventing the spread of the virus.
