Immune Evasion

Question 1

Describe the respiratory system’s barrier to infection.

Answer 1

• Respiratory pathogens need to cross a well-protected and robust mucosal layer.
• Respiratory epithelium has evolved to prevent microbes from entering the submucosal spaces.
• Goblet cells produce mucous.
• Cilia move mucous outwards, trapping and ejecting potential pathogens.
• True respiratory pathogens have evolved counter characteristics to breach the mucosal layer.

Question 2

Describe the normal course of infection.

Answer 2

• Infective agent crosses anatomical barrier - either by specialised receptors or through a breach.
• Triggers an innate immune response.
• Innate immune cells then induce adaptive responses and most often infection is controlled.
• True pathogens often have developed ways to avoid and overcome innate and adaptive responses - evade the immune response and spread.

Question 3

What are the defining features of a true pathogen?

Answer 3

• Avoid immune destruction by innate and adaptive immunity long enough to replicate and spread to new host.
• Different pathogens adopt different strategies - at one extreme some pathogens cause acute disease, replicate and spread quickly before they are cleared by the host or kill the host - right through to the other extreme where some pathogens can survive over long periods causing chronic infections.

Question 4

What is co-evolution?

Answer 4

• Hosts and pathogens co-evolve over time - sometimes millions of years to e.g. enter intact barriers (pathogen), develop new barriers (host).
• Different pathogens adopt different strategies to overcome host defences.
• The anti-immune systems developed by pathogens can be as sophisticated as the host immune systems to control them.

Question 5

What are the classes of microrganisms responsible for life-threatening infections?

Answer 5

• Pathogenic:
  
  • Viruses
  • Extracellular and intracellular bacteria
  • Intracellular and extracellular protozoa (parasites)
• Note: some helminths (multicellular parasites) and fungi can cause disease but are rarely life-threatening.

Question 6

What is antigenic variation?

Answer 6

• A characteristic of many different pathogens.
• The adaptive immune system mounts an antibody response, the pathogen numbers decline.
• The pathogen then alters surface antigens and the immune system needs to begin all over again - the virus then gains ground.

Question 7

Describe how RNA viruses, such as influenza, replicate.

Answer 7

• RNA viruses, such as influenza, require host RNA polymerase to replicate.
• Unlike host DNA polymerase, RNA polymerase will not proof-read the nascent strand.
• Therefore, new viral RNA genomes have a higher mutation rate than DNA viruses.
• RNA viruses are more likely to mutate and evade host immunity through antigenic drift.

Question 8

What is antigenic drift?

Answer 8

• Viral particle with SNP mutation can infect formerly immune host but mutation involves only one locus therefore only partial evasion and mild disease.

Question 9

What is antigenic shift?

Answer 9

• Recombination - a rare event. 2 viruses infect the same host (normally bird or pig) at the same time and their genomes recombine.
• A new virus genotype emerges and poses a threat, including to the human population.

Question 10

Describe some of the diverse mechanisms evolved by DNA viruses (e.g. Herpes (H) and Pox (P) viruses) to evade or subvert the host immune system.

Answer 10

These are large DNA viruses and >50% of their genome can code for immune evasion genes.

Question 11

What are viral immunoevasins?

Answer 11

• Viral encoded proteins that prevent infected host cells from presenting viral peptides in MHC class I molecules to CD8⁺T cells.
• CD8⁺T cells are cytotoxic T cells that primarily recognise and kill viral infected cells by recognising virus particles presented in MHC class I molecules.

Question 12

What are latent viruses?

Give examples.

Answer 12

• Viruses which presist in the host by not replicating - laying dormant.
• Herpes simplex - recurrent cold sores.
• Herpes zoster (varicella zoster) - chicken pox / shingles.
• Human papilloma virus (HPV) - cervical cancer
• HIV - AIDS

Question 13

Describe how the herpes simplex virus persists and reinfects (latency).

Answer 13

• Initial infection in the skin is cleared by the host immune system.
• Residual infection persists in the nuclei of sensory neurons serving the infected tissue.
• The virus transcribes a small part of the genome that codes for LAT protein that suppresses the lytic cycle.
• LAT also interferes with host cell apoptosis, prolonging the life of the infected cell.
• When the virus is re-activated by environmental factors or other host conditions, viral particles travel back along the neurons to the tissue and cause repeat infections (e.g. cold sores on the lips).

Question 14

Which type of immune response is typically elicited by extracelular bacteria?

Answer 14

Extracellular bacteria typically elicit an ILC type 3 immune response - T_H17 and neutrophil.

Question 15

What is intracellular bacterial clearance?

Answer 15

• Macrophages phagocytose bacteria that have breached barriers.
• The phagosome fuses with the lysosome and the bacterium is normally degraded.

Question 16

What is immune evasion of intracellular pathogenic bacteria?

Answer 16

• Intracellular bacterial pathogens have developed mechanisms to survive inside cells, mainly macrophages.

Question 17

Describe the invasion of myobacterium tuberculosis.

Answer 17

• M. tuberculosis is phagocytosed by macrophages BUT M.tb prevents fusion of phagosome and lysosome and is therefore protected.
• This is followed by granuloma formation.

Question 18

Describe what happens after M. tb enters a macrophage by phagocytosis.

Answer 18

• M. tb resists the effects of macrophage activation.
• M. tb is only partially eliminated by a type 1 immune response (ILC type 1, T_H1 CD4⁺T lymphocytes and cytotoxic CD8⁺T cells).
• A chronic low level infection develops requiring T_H1 to keep infection from spreading.
• A localised inflammatory response develops and a granuloma forms.
• The granuloma consists of a central core of infected macrophages - with fused multinucleated giant cells and surrounded by large macrophages called epithelioid cells - the core can become necrotic.
• The core is surrounded by T cells, mostly CD4⁺T_H cells.
• What drives this formation and how it breaks down is largely unknown.

Question 19

How can protozoa evade the immune system?

Give examples.

Answer 19

• Plasmodium and Trypanosoma species can escape the immune system by antigenic variation.
• In trypanosome the surface is covered with variant surface antigens (VSA).
  
  • Approximately 1000 VSA genes but only one gene in a specific expression site, telomeric active site, is actively transcribed and that will be the VSA type.
  • If the host has made specific antibodies to the active VSA then another gene will be translocated to a telomeric active site.
  • A new VSA is expressed and the host immunity needs to start all over again.

Question 20

List 4 mechanisms used by viruses to overcome the host immune system.

Answer 20

• Inhibition of humoral immunity.
• Inhibition of inflammatory response.
• Blocking of antigen processing and presentation.
• Immunosuppression of host.