Lecture 14 Immunology of Viral Infections Lecture Notes

Immune Responses to Viral Infection

The general principles of immune responses to viral infections are similar to those for bacterial infections, but there are specific differences, especially in effector molecules.

Learning Outcomes

Key areas to focus on include the unique aspects of viral immune responses and the roles of different effector molecules. Common aspects can be described using the same general terms as with bacterial infections.

Viral Pathogens

Many viruses can cause human diseases. Examples include:

• Rhinovirus (common cold)

• Influenza (flu)

• Varicella-zoster virus (chickenpox)

• Herpes simplex virus (cold sores)

• HIV

• CMV

• EBV (kissing disease, or infectious mononucleosis)

• Gastroenteritis viruses

• Coronaviruses

Transmission of Viral Infection

Transmission methods vary depending on the virus:

• Gastrointestinal infections: contaminated food or water

• Respiratory infections: air, droplets, or aerosols (as highlighted during COVID discussions)

• Direct contact: e.g., EBV (saliva exchange)

• Direct blood introduction: e.g., HIV (shared needles among drug users)

• Insect vectors: e.g., dengue virus (mosquitoes)

Structure of Viruses

Viruses are divided into two main groups:

• Naked viruses: genetic material and capsid layer.

• Enveloped viruses: genetic material, capsid layer, and an additional membrane envelope on the surface.

Whether a virus is naked or enveloped affects immune responses and evasion strategies.

The genetic material can be either DNA or RNA, single-stranded or double-stranded.

• Retroviruses: carry single-stranded RNA, which is converted to DNA upon entering the host cell before insertion into the host genome.

• Herpesviruses: carry double-stranded DNA and often cause persistent infections. These viruses can remain in the body and replicate if the immune system weakens.

Viral Infection Process

Viruses must contact and enter host cells to replicate, unlike some bacteria that can multiply outside cells. Viral replication within host cells can cause damage, functional impairment, or lysis.

Some viruses can cause cellular transformation, leading to cancer. For example, EBV can stay in B cells and cause lymphoma by inducing mutations.

Example: HIV Infection

1. Attachment: The virus attaches to the host cell (e.g., HIV attaching to CD4 on T cells).

2. Fusion: The viral membrane fuses with the host cell membrane, releasing the viral genetic material.

3. Reverse Transcription: HIV uses reverse transcriptase to convert its RNA into DNA.

4. Integration: The viral DNA is inserted into the host cell's genome.

5. Replication: The host cell's machinery is used to produce viral RNA and proteins.

6. Assembly: New viral particles are assembled.

7. Release: The new viral particles are released from the cell, often taking part of the cell membrane with them.

Extracellular vs. Intracellular Viruses

Viruses exist in both extracellular and intracellular states:

• Intracellular: Viruses multiply inside host cells.

• Extracellular: After release from the host cell and before infecting another, viruses travel in body fluids and are considered extracellular pathogens during this stage.

Overview of Immune Response to Viral Infection

The immune response mirrors that of bacterial infections:

1. Innate immunity.

2. Adaptive immunity (if needed).

3. Elimination of the viral pathogen.

4. Establishment of immunological memory.

Innate Immunity

Innate receptors, such as Toll-like receptors (TLRs) like TLR3 and TLR7, are located inside cells to detect viruses. Other intracellular receptors include:

• RIG-I (retinoic acid-inducible gene I): Recognizes single-stranded RNA.

  • Eukaryotic (host) RNA has a 7-methylguanosine cap at the 5' end, whereas viral RNA does not, allowing innate receptors to distinguish between them.

• MDA5 (melanoma differentiation-associated protein 5): Recognizes double-stranded RNA.

Recognition of viruses by these receptors leads to the production of cytokines, especially interferons.

Toll-like receptor signaling results in the translocation of interferon regulatory factors (IRFs) to the nucleus, initiating the production of interferons like interferon-alpha and interferon-beta.

Interferons

Interferons are key cytokines in viral infection and are divided into two types:

• Type I: Interferon-alpha and interferon-beta, produced by many cells (immune and non-immune, such as fibroblasts and epithelial cells). They bind to the same receptor, which is ubiquitously expressed.

• Type II: Interferon-gamma, mainly produced by NK cells, CD4+ T cells, and CD8+ T cells.

Type I interferon production is strongly activated by viral infection.

Plasmacytoid Dendritic Cells (pDCs)

These cells, though rare, produce huge amounts of type I interferons upon detecting viruses. They express high levels of TLR7 and TLR9, which detect viruses.

Biological Effects of Type I Interferons

1. Induce an antiviral state in host cells.

2. Activate NK cells.

3. Increase expression of MHC class I molecules.

Induction of Antiviral State

Type I interferons induce the production of three main antiviral proteins:

1. Protein Kinase R (PKR): A kinase that phosphorylates eIF2 (eukaryotic initiation factor), reducing host protein translation and, consequently, viral protein synthesis.

2. Endoribonuclease (RNAse L): Activated by OAS (oligo adenylate synthetase), degrades viral RNA.

3. MX protein: A GTPase that inhibits viral transcription.

This process can also lead to apoptosis of infected cells.

Type II Interferon (Interferon-gamma)

Produced mainly by NK cells and T cells, interferon-gamma regulates both innate and adaptive immune responses by:

• Activating macrophages.

• Inducing MHC class II expression.

Natural Killer (NK) Cells

NK cells kill cells with less MHC class I and cells under stress, which secrete MIC A and MIC B (MHC class I-like molecules that activate NK cells). NK cells also produce interferon-gamma.

Macrophages

Macrophages perform phagocytosis to engulf viral particles or infected cells and produce cytokines.

Adaptive Immunity

Adaptive immunity involves B cells (producing antibodies) and T cells (activated subsets).

Antibodies

Antibodies cannot cross the cell membrane and do not directly affect intracellular pathogens. However, they are useful against viruses in the extracellular stage:

• Neutralize free viruses by blocking their entry into host cells.

• Activate complement, leading to lysis of viral envelopes.

• Target viral-infected cells by binding to viral antigens on the cell surface, activating complement or inducing ADCC (antibody-dependent cell-mediated cytotoxicity).

Antibodies are useful in protection when the virus is in extracellular space.

CD8+ T Cells

CD8+ T cells (cytotoxic T cells) play a crucial role in the response to viruses through:

• Killing viral-infected cells by releasing cytotoxic enzymes and molecules (perforin, granzymes, granulysin); perforin makes holes in the target cell membrane, facilitating the entry of granzymes, which induce apoptosis.

• Producing interferon-gamma and other cytokines such as TNF-alpha.

Cytotoxic T cells are more efficient in killing viral-infected cells than NK cells.

Memory cells are established as part of the adaptive response.

Complementary Activities of CD8+ T Cells and NK Cells

NK cells play an important role in the early stage of viral infection. Viruses often downregulate MHC class I molecules to evade cytotoxic T cells; however, NK cells can detect this decrease in MHC class I and kill the infected cells. This highlights their complementary actions.

Outcomes of Immune Response to Viral Infection

1. Successful elimination of the virus.

2. Host death (if the immune system fails).

3. Persistent infection: The virus remains in the body (e.g., EBV, herpes simplex virus) and can cause recurring episodes of infection.

   • This happens when virus stays and the immune system fights repeatedly.

Summary of Effector Mechanisms

The summary slide contains all the effector mechanisms used against viral and viral-infected cells.

This summarizes the lecture, highlighting key aspects specific to viral infection.