Parasite Survival Strategies and Persistent Infections

Question 1

What are different strategies used to avoid the innate immune response?

Answer 1

Antiphagocytic strategies
Interfering with ciliary action
Interfering with complement alternative pathway
Producing iron-binding molecules
Blocker interferons

Question 2

What are antiphagocytic strategies?

Answer 2

Toxins (kill phagocytes)
Prevention of opsonization
Prevention of contact (production of capsule)
Inhibition of phagolysosome fusion (key step in order to kill pathogens)
Escape from phagolysosome into the cytoplasm and replicate
Resistance to killing via the production of antioxidants (resistant to ROS

Question 3

How does interfering with ciliary action prevent innate immune response?

Answer 3

Cilia prevent attachment of pathogens to the epithelium

Bordetella pertussis produces a toxin that paralyzes the action of cilia

Question 4

How does interfering with the complement alternative pathway avoid an innate immune response?

Answer 4

The outer surface (e.g., capsule) prevents either C activation or it can prevent access to fixed C3b
Bacterial membrane can be resistant to MAC format (divert attachment)
Membrane bound enzymes can degrade fixed complement or cause it to be shed
Complement inhibitors can be attached to the surface
Direct inhibition of C3 and C5 convertases blocks complement activation

Question 5

How does producing iron-binding molecules prevent innate immune response?

Answer 5

Pathogens, such as Neisseria spp. can produce proteins such as transferrin which can bind iron tighter than our own iron-binding proteins

Question 6

How does blocking interferons prevent innate immune response?

Answer 6

The host cell responds to dsDNA/RNA from infecting microbes by producing INF
Some virus are poor inducers of INF (e.g., Hep B) or produce molecules that block the action of INF in cells (e.g., HIV)

Question 7

What makes avoiding the adaptive immune response different form avoiding the innate immune response?

Answer 7

The strategies involved are more sophisticated because lymphocytes are programmed to recognize virtually any shape (B cells) or amino acid sequence (T cells). B cells recognize the polysaccharides of capsules causing formation of antibodies and opsonization and phagocytosis. Intracellular microbes can resist destruction in macrophages but their peptides can be presented via MHC molecules to T cells, causing cytotoxic action

Question 8

What are some viral survival strategies?

Answer 8

Viruses are very good at avoid immune defences because they are intracellular. Their invasion is often silent (no toxin formation, lack of extensive cell destruction)
Virus latency is another survival strategy

Question 9

What are some evasion strategies (strategies to avoid adaptive immune response)

Answer 9

Hit and run
Concealment of antigens
Antigenic variation
Immunosuppression

Question 10

Describe the hit and run evasion strategy

Answer 10

The microbe invades, multiplies and sheds within a few days. This is not enough time to mount an immune response.
Infections of the body surfaces (rhinoviruses, rotaviruses) come into this category

Question 11

Describe the concealment of antigens evasion strategy

Answer 11

Pathogens can hide in host cells, in sites that are not exposed to circulating pathogens
There is also molecular mimicry, as well as covering microbial surfaces with host proteins

Question 12

MHC molecules can act as ‘informants’ if there is an intracellular pathogen. How can viruses avoid antigen display?

Answer 12

HIV display its proteins on the surface of vacuoles instead of the cell surface
Some adenoviruses combine with class I MHC molecules and prevents their passage to the cell surface so that infected cells are not recognized by cytotoxic T cells

Question 13

Where do antigens hide if they want to avoid circulating lymphocytes?

Answer 13

The skin (warts), the intestinal tract, various secretions (IgA binds and reduces infectious potential but does not kill them), CNS, joints, testes, placenta. Activation of the inflammatory response causes lymphocytes and antibodies to be rapidly delivered

Question 14

What is the most privileged site for evasion?

Answer 14

The host DNA, which is occupied by retroviruses. Retroviral RNA is transcribed into DNA (reverse transcription) which becomes integrated into the host DNA. As long as viral products are not expressed, it will remain undetected indefinitely (e.g., HIV)

Question 15

What is molecular mimicry?

Answer 15

Some pathogens have antigens that are similar to antigens of the host. The consequence is the generation of antibodies that start targeting the host tissue (e.g., endocarditis: M-protein from streptococcus resembles proteins of the heart tissue

Question 16

Does molecular mimicry offer an advantage to the pathogen?

Answer 16

Not really. The body will be weakened but the pathogen doesn’t directly gain anything

Question 17

How is covering microbial surfaces with host molecules an evasion strategy?

Answer 17

The best studied example is of protein A of Staphylococcus aureus. S. aureus’s A-protein has a high affinity for the constant region of antibodies and the result is that the antibody can’t activate the immune system

Question 18

What is antigenic variation?

Answer 18

Some pathogens can change their cell surface antigens to escape the immune system, as it cannot recognize the pathogen. This can happen throughout the same infection of a single host, from infection to infection of the same host or from host to host. Example: it’s very rare to se the same flu virus every year

Question 19

What are the three molecular mechanisms of antigenic variation?

Answer 19

Mutation
Recombination
Gene switching

Question 20

Describe the mutation strategy of antigenic variation

Answer 20

E.g., influenza virus:
Genes encoding hemagglutinin and neuraminidase undergo mutation
This leads to antigen changes that make them unrecognizable by B and T memory cells from previous influenza infections
This is known as antigenic drift (small changes to amino acid sequence).
It also occurs in other organisms (e.g., rhinovirus, enterovirus)

Question 21

Describe the recombination strategy of antigenic variation

Answer 21

A sudden dramatic change in the surface antigen can occur when genetic material between two different viruses. Example: human and avian strains of influenza A recombine giving rise to a completely new virus not experienced in the present population, causing a pandemic (e.g., H1N1)

Question 22

Describe the gene switching strategy of antigenic variation through the example African trypanosome

Answer 22

African trypanosome have genes for 1000 different surface molecules and it can switch 1 gene for the next so that the surface antigens change weekly
Trypanosome persists as the immune system is always playing catchup

Question 23

Describe the gene switching strategy of antigenic variation through the example Neisseria gonorrhoea

Answer 23

Neisseria gonorrhoea changes bacterial surface properties as infection proceeds
Initially, it expresses pili and outer membrane proteins allowing attachment to urethral epithelial cells
Once established, it may switch off so not sticky for phagocytes
As it moves through the population, genetic rearrangement of piling genes allows people to be reinfected with gonorrhoea multiple times

Question 24

What is immunosuppression?

Answer 24

There are some pathogens that infect immune cells
Measles infects T cells
EBV infects B cells
HIV infects T cells, macrophages, dendritic cells

Question 25

How do some pathogens interfere with the immune response

Answer 25

Adenovirus and herpesvirus reduce MHC-1 expression, so that cytotoxic T cells fail to recognize these cells
N. gonorrhoea and S. pneumoniae liberate a protease that cleaves IgA

Question 26

What are superantigens?

Answer 26

Some organisms produce superantigens which produce an immune response that is much bigger than required, causing the host to produce cytokines that results in damage to the host cells and defences are compromised

Question 27

How do microbes persist?

Answer 27

Some persist as a continuously infectious form (e.g., Hep B virus in the blood)
Some persist as low infectivity (e.g., adenovirus in the tonsils and adenoids)
Some persist as non-infectious forms (latent virus, HSV; the viral DNA persists for life in the host nerves)

Question 28

What are latent infections important?

Answer 28

Some infections can become reactivated under different signals
There is an association with chronic infection (e.g., HIV can lead to AIDS)
There is an association with cancer (e.g., HBV can lead to liver cancer)
They enable the persistence of the infection within the community

Question 29

What causes reactivation of a latent infection?

Answer 29

It typically happens in immunocompromised patients (disease, cancer, tissue transplant, elderly, pregnancy, too much sunlight, fever, a hormonal shift, drinking too much coffee, stress)
Stage A: Stimulus (HSV: sunlight, fever, hormonal shift, drinking too much coffee, stress)
Stage B: Spread and replication (HSV: it travels via sensory axon to the skin/mucosal surface and causes infection of the epithelial cells and forms virus rich vesicles aka cold sores. The infection is arrested by the immune system (sometimes before a lesion is even formed)