Evasion of the Immune System by Pathogens lecture 15

Viral and Bacterial Evasion Strategies

Introduction

Previously, we examined immune responses against viruses and bacteria, focusing on how the immune system combats these pathogens. Now, we will explore the evasion strategies employed by viruses and bacteria to avoid immune attacks.

Learning Outcomes

Understand the strategies used by viruses and bacteria to evade attacks from the immune system.

Viral Evasion Strategies

Persistent Infections: Herpes Viruses

Herpes viruses are known for causing persistent infections. Examples include:

• Herpes simplex virus type 1: Causes cold sores.

• Herpes simplex virus type 2: Causes genital sores; infects approximately 70% of people.

• Varicella-zoster virus: Causes chickenpox (more common in children) and shingles (reactivation in adults, causing painful pox on the body).

• Epstein-Barr virus (EBV): Causes mononucleosis and is associated with Burkitt's lymphoma due to long-term colonization and mutations in B cells.

Other viruses like HIV and influenza also employ evasion strategies.

Evasion of Recognition

Viruses and bacteria evade immune attacks by avoiding recognition. The immune system differentiates between self and nonself to target foreign entities.

• Using Host Membrane: Many viruses, particularly enveloped viruses, use host cell membranes as they bud out. This incorporates human proteins, making it harder for toll-like receptors and other innate receptors to detect viral proteins.

Antigenic Variation

Viruses change their antigens to evade established immune responses. This is evident in influenza viruses, which require annual vaccinations due to their constantly changing antigens.

• Influenza Virus Structure: Influenza viruses have a small genome consisting of eight RNA fragments encoding 11 proteins. They utilize host cells for most functions.

• Types: Influenza is classified into types A, B, and C, with type A causing human infections.

• Virulence Factors: Hemagglutinin (H) and neuraminidase (N) are two major virulence factors on the virus surface that undergo frequent changes.

• Subtypes: Variations in H and N lead to different subtypes like H1N1 and H1N2.

• Antigenic Drift: Small variations due to mutations in the viral genome, resulting in minor changes in amino acids of virulence factors. Previous antibodies offer partial protection.

• Antigenic Shift: Large, abrupt changes occur when a host cell is infected with two different subtypes of a virus, leading to genetic material mixing and recombination. This results in new antigens that existing antibodies cannot recognize.

Antigenic drift and Antigen shift historical context

• Historical Context: Significant outbreaks of influenza include the Spanish flu (H1N1) and later outbreaks with different subtypes, although recent large-scale outbreaks have been less frequent.

Interference with Cytokine Production

Viruses interfere with cytokine production, particularly type I interferons, which are crucial for immune response.

• EBV Example: EBV produces a protein similar in function to interleukin-10 (IL-10), an inhibitory cytokine that suppresses immune responses.

• Cytokine Receptors: Viruses produce cytokine receptor-like molecules that bind to cytokines, preventing them from binding to actual cell surface receptors and exerting their biological effects.

• Inhibition of PKR Activation: Viruses like rotavirus and HIV inhibit the activation of PKR, a kinase involved in antiviral states.

Interference with the Complement System

Viruses interfere with the complement system to prevent cell lysis.

• CD59 Molecule: Viruses incorporate CD59, a molecule that prevents the formation of the membrane attack complex (MAC) by interfering with C9 polymerization.

Interference with Antigen Presentation

Viruses disrupt antigen presentation to hinder adaptive immune responses.

• Downregulation of MHC Class I Molecules: Viruses decrease MHC class I molecules to avoid killing by CD8+ T cells.

  • Adenovirus: Produces E1A protein, which inhibits transcription of MHC class I genes.

  • Cytomegalovirus (CMV): Dislocates the heavy chain of MHC class I molecules and targets them for degradation in the cytosol.

  • HIV: Produces NEF protein, which forces internalization of MHC class I molecules already on the cell surface.

• Interference with Peptide Loading: Some viruses interfere with the loading of peptides onto MHC class I molecules.

  • Adenovirus: E3 protein binds to MHC class I in the ER, preventing its movement to the Golgi apparatus.

  • Herpes Simplex Virus: ICP47 protein binds to TAP, inhibiting the transport of viral peptides into the ER.

Latency - ceasing replication until immunity wanes,

Viruses enter a state of latency to avoid immune detection and elimination, allowing viruses like Herpes Simplex Virus to remain dormant within host cells and reactivate later when the immune response is weakened. Examples include:

• Herpes Simplex Virus (HSV): During strong immune response, HSV travels along nerve fibers to the trigeminal ganglion, where it remains dormant. When the immune system weakens, the virus reactivates, traveling back to the mucosal surface, causing cold sores.

• Varicella-Zoster Virus: Moves to the dorsal root ganglion and reactivates as shingles when immunity declines.

• HIV: Directly attacks CD4+ T cells, impairing the immune system.

Bacterial Evasion Strategies

Evasion of Recognition

Bacteria employ various strategies to avoid recognition by the immune system.

• Coating with Human Proteins: Some bacteria coat themselves with human proteins to avoid detection. Treponema pallidum, the bacterium causing syphilis, coats itself with fibronectin, a human protein found in blood and body fluids.

• Enzyme Production: Staphylococcus aureus produces coagulase, an enzyme that converts fibrinogen into fibrin, forming a clot that protects the bacteria from immune cells. They also produce Protein A that binds to the Fc fragment of antibodies preventing the function of the antibodies in immune recognition.

• Protein Binding to Antibodies: Staphylococcus aureus produces protein A, and Streptococcus pyogenes produces protein G, both of which bind to the Fc fragment of antibodies, inhibiting their function. This mechanism is exploited in industry to purify immunoglobulins using protein A or protein G columns.

• Capsules: Capsules are large structures formed by various components. E. coli uses sialic acid in their capsules, and Streptococcus uses hyaluronic acid. These components are similar to those found in the human body, helping the bacteria evade immune detection.

• Capsule use of Sialic and Hyaluronic acid:

  • The E. coli capsule utilizes sialic acid.

  • Streptococcus incorporates hyaluronic acid to form their capules.

• Escape from Phagosomes: Listeria monocytogenes escapes from phagosomes to avoid fusion with lysosomes and subsequent killing.

Colonizing a Safe Location

Bacteria colonize areas where the immune system cannot function well to evade immune attacks.

• Examples: The gastrointestinal tract is one such area. Helicobacter pylori colonizes the stomach's mucosal surface for long periods.

• Abscess Formation: Bacteria may reside within abscesses, which lack blood circulation, preventing immune cells and factors from reaching them.

Evading Phagocytosis and Disruption

Bacteria avoid phagocytosis and disruption by various mechanisms.

• Capsules: As mentioned before, capsules help bacteria evade phagocytosis.

• Inhibition of Phagosome-Lysosome Fusion: Mycobacterium tuberculosis secretes substances that inhibit the fusion of phagosomes and lysosomes, preventing their destruction.

• Unique Structures: Mycobacterium tuberculosis has thick lipid layers that are resistant to enzymatic killing.

Destruction of the Immune System

Some bacteria and viruses destroy the immune system.

• Superantigens: Activate a large number of T cells, leading to excessive cytokine production that disrupts the immune system.

Antigenic Variation

Bacteria change their antigens to avoid immune recognition, similar to viruses.

• Salmonella typhimurium: Changes its flagellin antigens (proteins forming flagella) to evade immune targeting.

• Streptococcus pneumoniae: Has more than 100 types of capsules, making it difficult for antibodies to provide lasting protection against different strains.

Summary

Both bacteria and viruses use diverse mechanisms to evade the immune system, including:

• Evasion of recognition

• Antigenic variation

• Interference with immune signaling pathways

• Latency or persistence in protected sites