10. Evasion of Immune Response

What are 5 strategies used to avoid phagocytosis?

- Killing/avoidance of phagocyte
- Interference w/ ciliary action
- Interfering w/ complement activation
- Production of iron-binding molecules
- Blocking interferons

What are 6 specific/direct ways bugs avoid phagocytosis?

- Toxin release to kill phagocyte (staph, strep, amoebae)
- Protein production that prevents interaction between opsonizing Ab and phagocyte (staph, protein C)
- Prevention of contact via capsule (strep pneumo, H flu, anthrax)
- Inhibition of phagolysosom

What bacteria prevent the triggering of oxidative burst?

Legionella

What bacteria abort normal phagosome maturation? What bacteria divert phagosome to another pathway (ER or Golgi)?

- MTB
- Chlamydia, legionella, brucella, toxo

What bacteria resist lysosomal degradation? What can't they resist?

- Coxiella burnetti, leishmania, and salmonella
- Can't survive activated macro

What bacteria can escape from phagosomes? What are they subject to after this?

- Listeria, shigella, rickettsia, trypanoma
- Subject to cytosolic MHC I pathway of Ag processing/presentation

What are some examples of viruses that can infect cells for a long time w/o affecting cell viability?

Rubella, hep, EBV.

What are the 2 general categories of persistent microbes? Give examples?

1. Continuous shedders:
- EBV into saliva
- Hep B into blood,
- Eggs of helminths into poop
2. Intermittent shedders:
- HSV
- Polio
- TB
- Typhoid
- Malaria

Compare viruses that carry out "hit and run" with those that don't.

Hit and run: Invasion followed by rapid shedding w/in days. Adaptive immunity not active. Body surface infections, rhinovirus, rotavirus.
Non Hit and Run: Evade lymphocytes via Ag concealment, Ag variation, immunosuppression.

How do viruses conceal antigens?

1. No antigen presentation on cell surface: Persistent latent infections like HSV in sensory neurons
2. Virus displays proteins on intracellular vacuoles, buds into vacuoles: HIV in macros and coronaviruses
3. Viral protein can combine w/ MHC I and preven

What are 6 ways that complement can be blocked?

1. Capsule can block complement activation
2. Steric hindrance: phagocyte can't get to C3b
3. Blocking proteins: MAC can't form pore
4. Degradation/cleavage of complement receptors
5.Regulation of complement activation
6. Blockage of convertases

What is listeria's mechanism of infection?

- Escapes vacuole, travels through cell on actin
- Easily travels to CNS and placenta
- From meat/cheese

Explain privileged sites.

Privileged:
- Skin, intestinal lumen, external secretions: Pathogens avoid circulating lymphocytes. Exposed to Ab and inflammatory factors though.
Very privileged:
- CNS, joints, testis, placenta: Low lymphocyte circulation and decreased access to Ab/comp

What are some specific mechanisms of privileged site infection?

- Sites created by infection itself: Hydatid cyst in liver/lung/brain from tapeworm Echinococcus granulosa. Worms survive, though Ab is in blood.
- Occupation of host DNA by retroviruses: Virus not recognized by immune cells.
- Egg/sperm DNA: Endogenous r

What is antigenic mimicry? Give example.

- Microbes mimic host antigens not recognized as foreign. Not protective for microbe.
- Cross rxn between group A beta-hemolytic strep and myocardium ==> autoimmune and antimocrobial response.

How do pathogens use host molecules to conceal themselves. Give example.

- Acquires surface coat of host glycolipids and HLA-1 and -2. Only happens w/ worms.
- Production of Fc receptors that bind Ab upside down (many viruses and bacteria)

What are 5 methods to avoid inducing an immune response or inducing a poor response (immune modulation)?

1. Embryonic infection
2. Production of large quantities of microbial Ag or Ag:Ab complexes
3. Exploiting gaps in immune repertoire
4. Upsetting antibody vs CMI resposne
5. Inducing responses that down-regulate/suppress protective immunity

Describe infections in early embryonic life.

- Hep B before immune system is developed, permanently have virus.
- May develop IgM Ab, but CMI is impaired ==> congenital infection

Describe the production of large quantities of Ag or Ag:Ab complexes.

- Results in immune tolerance
- Anergy develops, normal Ab made but CMI is deficient
- Coccidoides, cryptococcus

Describe "gaps in host" immune response?

Peptides to which host responds poorly are present

Describe unbalanced Th1 and Th2 response.

- IL-4 T cells are detected, but reduction of Th1
- Occurs in TB

Describe the induction of down-regulatory responses.

- Induction of Tregs by bacteria/helminths ==> IL-10
- Th1 cytokine response is downregulated

What are the 3 types of antigenic variation? Where does it occur?

- Mutation, recombination, gene switching
- Occurs in individual during infection and in community

Describe mutation.

- Small genetic changes in HA and NA (for flu) reduce effectiveness of B and T cell response ==> Ag drift (also in strep, staph, pneumo)

Describe recombination.

Exhange of genetic information ==> human and avian flu recombine to form new strain.

Describe gene switching.

- Expression of different surface glycoproteins that change expression w/ immune response
- Trypanosoma gambiense, borrelias, brucellas, gonorrhea (pilin expression)

What are mechanisms of immunosuppression?

- Temporary: HIV kills CD4 T cells
-
Infection of immune cells: T cells (HIV, measles), B cells (EBV), macrophages (HIV, CMV, leishmania), DC's (HIV)
- Release of immunosuppressive molecule: blocks complement/cytokines

What are specific examples of microbial immunomodulation?

- Staph: Superantigen polyclonal activation ==> kills immune cells, releases irrelevant Ab's
- Viruses: Code for fake molecules and fake receptors
- HSV glycoprotein C: Interferes w/ C3b
- EBV codes for IL-10 homologue ==> downregulates IL-12 response to

What are 4 ways viruses interfere w/ immune molecules?

- Downregulate MHC I expression ==> CTL's can't recognize: Adeno, herpes.
- Interfere w/ IFN's: Rota, adeno
- Induce apoptosis (esp after encountering macros): Yersinia (bacteria), measles
- Prevent apoptosis ==> persistent infection: HIV, HSV, EBV

What is apoptotic mechanism in yersinia?

- Caspase release ==> DNA breakdown, mitochondria switch off, membranes rearrange

What do N gonnorheoae, Strep. pneumo, and H flu do to interfere w/ immune response?

- Protease A cleavage of IgA

What do HSV, CMV, and VZV do to interfere w/ immune response?

- Produce Fc receptors that inhibit phagocytosis

What does psudomonas do to interfere w/ immune response?

- Produces elastase and inactivates C3b and C5a

What are 4 forms/states persistent infections can exist in?

Persist in...
- Blood / intestines: Hep B, schistomes
- Low infectious form: Adenoviruses in T&A's
- Metabolically altered state: TB
- Non-infectious, latent virus: HSV viral genome, not integrated into host DNA, remains circular and episomal

Review slide 37 of this lecture, timing/cycle of infections.

Review it