NK Cell Function and Antiviral Defense

Immune Response to Infectious Diseases - Viruses

• Viruses are composed of DNA or RNA, a protein shell (capsid), and sometimes an outer lipid membrane (called a virion).
• Viruses depend on host cells to replicate.
• Viruses bind to specific receptors on the surface of target cells to invade them.
• Viruses replicate inside the host cell via budding or cell lysis.
• Viruses can spread to neighboring cells through intercellular junctions.
• Outside of a host cell, viruses are metabolically inactive.
• A virus's protein coat or capsid encloses either DNA or RNA that codes for viral elements.

Learning Objectives

• Describe how the immune system recognises and responds to viral pathogens.
• Identify various strategies employed by viral pathogens to evade detection and elimination by the immune system.

Viruses - Typical Life Cycle

• The diagram displays the steps of a virus's development within a host cell.
• The stages encompass virus entry, replication, and release in order.

Viruses Structure and Function

• Upon contacting a cell, the virus uses surface molecules to inject its genetic material.
• The infected cell then produces viral proteins and genetic material instead of its usual products.
• The viral life cycle within the cell is characterized by two phases: the lysogenic and the lytic phases.

Lytic vs. Lysogenic Cycle

• The lytic cycle is where the phage DNA enters the host cell, replicated, and the host cell lyses or breaks open to release new phages.
• The lysogenic cycle is where the phage DNA integrates into the host cell's DNA. The phage DNA is replicated as the host cell divides, without the host cell being harmed or destroyed.

Immune Response

• The immune system uses different mechanisms to defend against viruses.
• Interferons limit viral infections.
• Antibodies target viruses in the extracellular phase.
• Natural Killer cells respond in the intracellular phase.
• Cytotoxic T cells also respond in the intracellular phase.

Response to Viral Infection

• NK cells and interferons are crucial in the initial (innate) immune response to a viral infection.
• Lymphocytes and antibodies play a critical role in the subsequent (adaptive) stages of immune response and memory formation.

Interferons

• Interferons α and β are essential for an early response to viral infections (innate immunity).
• Interferon-γ is produced by immune cells (NK, Th1, and Tc cells) and is part of both innate and adaptive responses.
• Interferon-γ is an effector molecule for innate and adaptive immunity.

Interferons in viral infection and antiviral immunity

• Three types of interferons (α, β, and γ) are produced by various immune cells, particularly activated T cells and NK cells.
• Interferons α and β are important in controlling viral replication by influencing cellular processes.
• Interferons promote specific immune responses and enhance the expression of major histocompatibility complex class I molecules on infected cells.

Natural Killer (NK) Cells

• NK cells have preformed granules containing perforins and granzymes to destroy target cells.
• They act through invariant receptors, considered a function of innate cell-mediated immunity.
• NK cells recognize and kill infected or cancerous cells.
• IL-12 and interferon-γ enhance NK cell activity.
• NK cells produce interferon-γ and contribute to Th1 cell development.

NK Cell Receptors

• Activating receptors trigger NK cell killing of target cells by releasing IFN-γ.
• Activating receptors recognize Fc regions of Immunoglobulins (e.g. IgG).
• Inhibitory receptors bind to MHC class I proteins and class 1b proteins preventing NK cell killing.

NK Cell Receptors (continued)

• Two receptor families exist: Killer cell Immunoglobulin-like Receptors (KIRs) and Killer Lectin-like Receptors (KLRs).
• KIRs recognize classical HLA class I molecules.
• KLRs bind HLA-E and other class Ib molecules.
• Activating receptors bind to stress, infection, or malignant transformation-induced molecules (MICA, MICB, etc.)

NK Cell Receptors (continued)

• NK cell triggering of IgG and IgG3 via FcyRIII triggers granule release.
• This process is called antibody-dependent cellular cytotoxicity (ADCC).

Humoral Antibodies

• Antibodies neutralize viruses and prevent infection (e.g., IgM, IgG, IgA).
• IgM and IgG activate the complement system and lead to virus destruction.
• IgG coats viruses (opsonization) facilitating phagocytosis.
• Antibodies bind to viral antigens on infected cells, activating NK cells (ADCC).
• IgE is involved in expelling viruses through smooth muscle contraction.

Cell-Mediated Antiviral Mechanisms

• Antibodies contain viral spread, but do not eliminate the virus after infection occurs.
• Cell-mediated immunity is crucial for eliminating the virus.
• CD8+ T cells and CD4+ T1 cells (or CD4+ T cells) are the main components of cell-mediated antiviral defenses.

Tc Cells

• Tc cells recognize cytosolic pathogens using MHC class I.
• Tc cells induce apoptosis (programmed cell death) in target cells through granzymes and perforins.
• Tc cells play an essential role in the adaptive immune response to viral infections.

Cell-Mediated Antiviral Mechanisms (continued)

• Activated Th1 cells produce cytokines (e.g., IL-2).
• These cytokines assist in CTL recruitment/activation and activate NK cells.
• IFN-γ directly induces an antiviral state in cells.
• TNF activates NK cells.

Other Lymphocytes

• This section illustrates relationships between different lymphocytes (T, B, NK) and their functions.

Evasion of Immune Detection

• Viruses can modify capsid proteins (antigenic drift) to avoid antibody recognition.
• Viruses can rapidly change surface proteins, causing outbreaks (antigenic shift).
• Viral envelopes may mask viral antigens, offering camouflage.
• Viral latency (e.g., Varicella-zoster virus) can hide the virus from the immune system.
• Viruses can cause immunosuppression to evade the immune system's response.

Influenza Virus - Properties

• Influenza virions are spherical or ovoid, ~90-100 nm in diameter.
• Virions have an outer envelope with two proteins: hemagglutinin (HA) and neuraminidase (NA).
• The nucleocapsid is surrounded by a matrix protein.
• Influenza contains 8 strands of single-stranded RNA.

Influenza Virus - Types

• Influenza viruses are classified into types A, B, and C based on differences in nucleoprotein and matrix proteins.
• Antigenic changes in HA and NA drive influenza variability and create distinct strains.
• Antigenic drift refers to smaller changes in these proteins over time, leading to variant strains.
• Antigenic shift refers to major, abrupt changes in these proteins.

Influenza Virus - Symptoms

• Common influenza symptoms include fever, muscle aches and pain, headache, fatigue, dry cough, sore throat, and runny nose.

Influenza Virus - Host Response

• The body produces antibodies specific to the HA molecule during infection.
• Serum antibodies defend against reinfection by the same strain.
• Cytotoxic T lymphocytes (CTLs) also play a role in the immune response to influenza.

Summary

• The immune system uses sophisticated methods to identify and fight viral pathogens.
• Viruses have developed strategies to evade the immune system.

This quiz explores the essential roles of interferons in antiviral defense and the mechanisms by which NK cells are activated. It covers the receptors involved in NK cell activity, the effects of inhibitory receptors, and the specific binding of NK cell receptors to HLA Class I molecules. Test your understanding of these critical immune responses.