Immune Response to Intracellular Pathogens

Question 1

Pros and Cons of intracellular pathogenesis (for the pathogen)

Answer 1

Pros:

• accessing a protected environment
• Protection from immune response
• Protection from bacterial competitors
• nutrient rich environment

Cons:

• overcoming host barriers
• resisting innate and adaptive immune response
• adapting to life in a hostile environment

Question 2

Obligate Intracellular pathogens

Answer 2

• All viruses (must have a lifecycle stage as an intracellular pathogen)
• Chylamydia Spp
• Mycobacterium Spp: TB/leprosy
• Rickettsia spp: Typhus

Question 3

Facultative Intracellular pathogens

Answer 3

Salmonella spp: typhoid/gastroenteritis
Legionella pneumophilia: Legionnaires
Shigella spp: Dysentery
Yersinia spp: Plague

Question 4

Mycobacterium tuberculosis (Mtb)

Risk factors

Answer 4

Kills 1.5million a year. Multiple risk factors:

• Spread in congregate settings like prisons
• Infection depending on overall health/immune status:
  > poverty and unemployment
  > Homelessness
  > Alcoholism/drug abuse: health repressors
  > HIV co-infection
  > Steroid immunosuppression
• genetic predispositions (e.g. polymorphisms)

Question 5

Pulmonary tuberculosis

Answer 5

Symptoms: Cough, night sweats, weight loss

Diagnosis: Sputum smear/culture (<50% paucibacillary)

Pathology: Caseating (cheese-like) granulomas in lungs, extreme tissue necrosis, cavitation

Death: Cachexia (patients degrading own organs for energy), Respiratory failure (damaged lungs) and massive haemoptysis (coughing blood)

Question 6

Probability of Pulmonary tb infection

Answer 6

70% with no infection
- adequate immune response

30% with infection
- inadequate immunity

Question 7

Mtb infecting resident lung phagocytes

Answer 7

1) Mtb’s Fibronectin Attachment Protein (FAP) binds to phagocyte’s surface receptors (mannose, CD14 and CR3) to trigger its phagocytosis (at cholesterol rich regions of plasma membrane)
2) Mtb arrests phagosome maturation at an early stage to avoid the antimicrobial phagolysosome developing:
- SapM hydrolyses PIP3 to inhibit maturation
- Phosphatidylinositide mannoside promotes fusion of early endosomes with Mtb

Evidence of arrest: Rab5 present but unable to recruit other proteins onto phagosome membrane

Question 8

Activation of the innate immune system

Answer 8

Antigen Presenting Cells (APCs) express toll-like receptors (TLRs) to detect bacterial PAMPs

• produce pro-inflammatory cytokines
• Activates Vitamin D pathway to produce antibacterial peptide Cathelicidin

Question 9

Macrophage upregulation from TLRs activation

Answer 9

TLRs:
MHCI/MHCII, CD40/B7, TNF/IFNg receptors, Fas receptors (apoptosis regulators)

Cytokines:
IL-12, TNF (Tumour Necrosis Factor), IL-1 and IL-18

Antimicrobial functions:
Toxic oxygen radicals, toxic nitrogen radicals, lysosomal enzymes, number of granules

Question 10

Recruiting Natural Killer (NK) to site of infection

Answer 10

Done by releasing cytokines to act as messenger molecules (e.g. IL-12 acting as a ‘homing beacon’)
- NKs also enhance macrophage antimicrobial activity through IFNg release

                       IL-12

                     IFNg

Question 11

Difference in infecting macrophage vs infecting DCs

Answer 11

Different responses as a result of their different MHC properties:
TB infection in DCs is less success successful as the TB is less effective in blocking endosomal maturation. Also being mobile allows the DCs to trigger adaptive immune responses
- TB infection in macrophage = less destroyed TB and increased infection (macrophage restricted to local area)

Question 12

2 Types of Adaptive Immune System

Answer 12

1) Humoral immunity
- Target parasites, extracellular bacteria, fungi and bacterial toxins
- Helper T cells activate B cells to produce antibodies

2) Cellular immunity
- Target intracellular bacteria, viruses and viral proteins
- Helper T cells (CD4) activate cytotoxic T cells (CD8) to lyse infected cells

Question 13

T helper cells

Answer 13

Use different signalling molecules to conduct specific responses
- e.g. IL-2 and other cytokines activate CD8 T cells

At site of infection specific signals determine Th differentiation:

• IFNg + IL-12 = Th1 (attacks intracellular)
• IL=4 = Th2 (attacks extracellular)

Question 14

How different Th differentiation impacts response to infection

Answer 14

e. g. Mycobacterium leprae infection:
- Th2 = Lepromatous leprocy (unable to remove foreign mycobacteria)
- Th1 = Tuberculoid Leprosy (normal T cell response)

Question 15

Role of CD4 cells in Mtb infection

Answer 15

Th1 cells release activating signals (CD40 ligand and IFNg) for all arms of immune response:
- Activating macrophages and CD8 cells

Last resort: form a granuloma

Question 16

Granuloma formation in Mtb infection

Answer 16

Organised aggregates of T cells surround the foci of infected tissues to limit further dissemination of Mtb
- no more pathology: can remain for life, constantly being renewed and maintained

Reactivating Mtb through use of immunosuppressants:

• Immunosuppressants inactivating the TNFa signal that normally maintains the granuloma wall
• Common practice now to have chest X-ray before prescribing anti-TNFa treatment