Immunity-L4- Intracellular Bacteria: Macrophages and Bacterial Evasion mechanisms-Innate

why would bacteria want to be phagocytose? example!

survive inside host cells to evade extracellular immune defences like AMPs, complements, antibodies

• TB- mycobacterium tuberculosis

how do intracellular bacteria survive killing mechanisms? 4

1. stop phagosome maturation- stop endosome from interacting with lysosome

2. counteract the killing mechanism of ie resisting V-ATPases and ROS/NRS

3. escape the phagosome

4. inducing cell death

how does TB inhibit phagosome maturation? why does this happen?

Mycobacterium Tuberculosis

1. freezes the process at early endosome stage

2. stops calcium signalling and stops recruitment of EEA1 and V-ATPases

3. uses lipoarabinomannan- waxy and stops calcium cytosol concentration increase

allows for extra time to replicate, avoids exposure to AMPs, and increases bacteria load to transmit

what bacteria evades pphagolyososme maturation? experimental

S. pyogenes

• EEA1 is expressed but disappeared after 1 hour

• LAMP1 appears later- indicates later endosome but later- delays

why do intracellular bacteria still reproduce even when they ARE exposed to AMPs?

to transmit to new hosts and rapid growth of S.pyogenes can increase bacterial numbers(4 fold in 1 hour). delaying growth buys TIME

how do TB survive acidic conditions in the phagolyososme?

• have a thick waxy cell wall that resists the low PH

• have genes encoding enzymes to maintain the protective layer

how do intracellular bacteria- S.aureus inhibit ROS/RNS? examples

1. s. aureus- express staphyloxantin, a golden pigment that absorbs excess energy of ROS and neutralises ROS

• others can interfere with the assembly of NADPH oxidase

how do intracellular bacteria escape the phagosome? what else does it do? examples

listera monocytogenes

• produces listeriolysin O which forms pores

• active in acidic pH in the phagosome

• once phagosome membrane is perforated, enters the cytoplasm and replicates

also hijacks cytoskeleton and expresses ActA and mimics WASP for actin polymerisation to allow. it to move across the cell to spread to adjacent cells

why do intracellular bacteria modulate host cell responses? (4)

1. to survive inside the phagocytes for longer

2. to control inflammation to avoid necrosis

3. to continue intracellular replication(in some)

4. some induce to reduce phagocyte numbers and evade killing

how does S.aureus modulate neutrophil death?

produces PVL toxin

• low concentration induces apoptosis and is controlled

• high concentration induces inflammatory necrosis

how can bacteria exploit efferocytosis? and why?

• tag live neutrophils with “eat me” signals and bacteria survive inside the macrophage and is now hidden or can escape the neutrophil after to replicate

discuss S.aureus intracellular and extracellular strategies

.aureus extracellular strategies:

1.     Protein A: inhibits C1q by making Ab bind backwards to the C1q and no complement is made

2.     Staphylococcus complement inhibitor stops the cleavage of C3 by C3 convertase and so no opsonin’s, MAC etc is made

3.     Reduces surface charge to avoid AMPs: LTA modified by D alanine and Phospholipids modified to L lysine to make it more positive and repel AMPs

 

S.aureus intracellular strategies

1.     staphyloxanthin- gold pigment produced to absorb the ROS and make it more neutral and less acidic

2.     PVL- to encourage neutrophil death with “eat me” signals to induce apoptosis or necrosis to reduce phagocyte numbers

 

TB intracellular stregies

1. inhibit maturation of phagosome- at endosome by secreting lipoarabinomannan- inhibits calcium in the cytosol needed for maturation- no EE1 and V-ATPases

2. counteracts acidic environment- thick, waxy wall resists low pH with genes for this

3. resistance to ROS/RNS- enzymes to neutralise ROS/RNS