Control of infection by the innate immune system

Question 1

What is an adaptor protein?

Answer 1

It is a scaffolding protein which helps initiate downstream intracellular signalling. For example, for TLRs, it’s MyD88 which supports activation of NF-kB and AP-1 or IRFs.

Question 2

TLRs

Answer 2

Different TLRs recognise different things but their downstream signalling is the same.

Question 3

What mutation in MyD88 leads to?

Answer 3

Patients with mutation in MyD88 cannot initiate immune responses by either TLRs. So they cannot use TLRs for recognition of pathogens and they usually die very early due to strong bacterial infections.

Question 4

CLRs

Answer 4

C-type lectin receptors:
- Large family of receptors
- Important for both immunity and physiological responses
- important for anti-fungal immunity
- Many signals through similar intracellular signalling pathways using CARD9 as an adapter protein
- Examples: Dectin-1, Dectin-2

Question 5

Do PRRs work together?

Answer 5

Yes, pathogens often engage multiple receptors, some will recognise lipids, some proteins, etc., at the same time. You get a lot of intracellular signalling. Different receptors can switch each other on and off.

Question 6

NF-kB

Answer 6

• Transcription factor
• The master regulator of immune responses
• Activated by TLRs, NLRs, RLRs
• Drives expression of different cytokines and chemokines

Question 7

What are different types of fungal spores?

Answer 7

• Resting fungal spore: is not a threat, weakly engages TLR2, does not express many antigens on the surface, does not activate NF-kB, does not lead to release of cytokines.
• Germinating fungal spore: is potentially invasive, expresses more antigens on the surface, engages multiple PRRs (TLR2, Dectin-1), triggers activation of NF-kB and production of cytokines.

Question 8

Tissue resident macrophages

Answer 8

They reside in different organs and tissues, they have different functions depending on which organ they are in, and they have different names e.g. microglia in the brain. They arise during embryogenesis from embryonic precursors from yolk sack or fetal liver and are not replenished by the bone marrow, they support the development of the organs they are found in. They are one of the first ones to recognise pathogens or damage as they are already there, and they activate the immune response.

Question 9

Where tissue-resident macrophages come from?

Answer 9

They are mostly made during embryonic development in yolk sack and fetal liver, they dont come from bone marrow and are not replenished by bone marrow. They are very long lived and depending on the organ, there is some turnover from monocytes. For example, in the spleen and intestines they are replenished in certain level by monocytes but for example brain-resident macrophages are not really replenished and can stay there for many years since birth. When doing bone marrow transplant you need to think if there is issue with microglia the BM transplant most likely will not fix it as they are not replaced by monocytes.

Question 10

What happens with patients who have leukocyte adhesion deficiency?

Answer 10

Immune cells cannot get from the blood into the site of infection.

Question 11

How can neutrophils kill yeast cells or worms which are much bigger than neutrophils

Answer 11

NETosis

Question 12

What is NETosis?

Answer 12

Neutrophils flip themselves inside-out and form “nets”. These nets can stick to the pathogen and stop it from moving. Nets are also full of toxic molecules and enzymes which damage the cell wall and membranes to break the pathogen. They form nets by:
- nuclear membrane break down
- chromatin decondensation
- membrane rupture

Question 13

M1 macrophages

Answer 13

• Pro-inflammatory, antimicrobial
• Differentiation into M1 macrophages is directed by Th1 cells and TNF and IFN-y
• They produce a lot of toxic enzymes
• They use oxygen and nitrogen-based killing
• Antigen presentation
• Use glycolysis

Question 14

M2 macrophages

Answer 14

• Tissue repair properties
• IL-4 and IL-13 promote differentiation into M2 macrophages
• Promote angiogenesis and matrix synthesis
• Use mitochondrial metabolism
  Macrophages can change from M1 to M2 and other way around depending on the cytokine environment.

Question 15

What is the problem with fungal infections?

Answer 15

• we have only 3 classes of drugs to treat fungi
• we don’t have vaccines against fungi
• Fungi are increasing resistance against the drugs we have
• Drugs against fungi can give a lot side effects because fungi are very similar to us and cause toxicity problems

Question 16

Candida auris

Answer 16

• Fungus which is resistant to antifungal drugs
• It can survive in high temperatures, up to 42 degrees, which could be caused by global warming and they are adapting to higher temperatures
• It spreads (usually fungus don’t spread from person to person but this fungus can) it is visible in hospitals and care homes