How microbes avoid phagocytosis and killing Flashcards
what are the Microbe survival strategies
Strategy 1: Avoid being phagocytosed
Strategy 2: Subvert phagocytosis (escape from phagosome or avoid being killed)
how do microbes Avoid Phagocytosis?
– Inhibit phagocyte recruitment
– Kill phagocytes
– Resist phagocytosis
how do microbes Inhibit phagocyte recruitment?
Directly inhibiting motility and chemotaxis eg. Bordetella pertussis produces toxins 1. Adenylate cyclase » Increases cyclic AMP in neutrophils » Leads to cell paralysis 2. Pertussis toxin » Impairs migration of monocytes
how does Chlamydia inhibit phagocytes?
produce LPS with very low inflammatory activity to reduce phagocyte chemotaxis/activation
how do microbes kill phagocytes?
– release Leukocidins (exotoxins) kill neutrophils and macrophages
e.g. highly invasive bacteria Pseudomonas, staphylococci,
how does Streptococcus pyogenes kill leukocytes
- by secreting leukocidins
- Subunits oligomerize within the leukocyte membrane
- Pore formation kills leukocytes
how do bacteria use the capsule in Resisting phagocytosis?
• Loose unstructured network of polymers on bacterial surface
• Polysaccharide mainly
• Antiphagocytic
• Decreased cell lysis by complement components
• Less complement C3b and C5b formation
• Some capsules mimic host polysaccharides
LPS is believed to be resistant to complement, acting in a similar manner to a capsule
how does Opsonisation can overcome the advantages of capsule?
appearance of antibodies allows clearance of Streptococcus pneumoniae
give an example of how Microbes avoid opsonization by antibodies?
Staphylococci
– Express bacterial surface protein, protein A (protein G)
– Binds to IgG molecules by the wrong end (Fc region)
– Cannot act as opsonins because Fc region not free to bind to Fc receptors on phagocytic cells
what is Avoidance of complement opsonisation?
- Non-opsonic phagocytosis
Direct recognition and uptake by phagocytes - Opsonic phagocytosis
Phagocytosis of particles labeled with antibodies/complement
• Complement (C3b)
• Collectins (SP-A, SP-D)
• Antibodies
what does Deposition of C3b cause?
- Inflammation
- Phagocytosis
- Bacterial killing
why are Human cells not opsonized
Factor H prevents opsonization of sialic acid-containing surfaces
how does Neisseria avoid complement opsonisation?
- modifies its LPS with sialic acid
how does M protein of Streptococcus pyogenes help the organism to resist phagocytosis?
–Binds H factor in serum (prevents complement opsonisation)
–Also binds fibrinogen (prevents phagocytosis)
how do Yersinia YOPs (Yersinia Outer Proteins) block complement?
- block host cell actin polymersiation, preventing uptake of bacteria
- YOPs are secreted into the host cells (Type III secretion)
how does Subversion of Phagocytosis occur?
- Escape into the cytoplasm
- Survival inside phagocytes
- Inhibition of lysosome and phagosome fusion
- Resistance to lysosomal contents
- Inhibition of phagocyte oxidative pathway
give an example of a bacteria that can Escape into the cytoplasm
Rickettsia (Rocky Mountain Spotted Fever) crosses membrane of phagosome to enter cytoplasm
– Since lysosomes do not secrete contents into cytoplasm, organism is safe
– Possess surface-bound phospholipase, which may weaken membrane
Why block phagosome maturation?
• Limit hydrolytic capacity (ie addition of enzymes)
• Restrictinterfacebetweenpathogenandantigen processing/presentation
• Provide time for bacterial maturation/differentiation
Examples:
– Mycobacterium tuberculosis
what is Mycobacterium tuberculosis?
Causes 2 million deaths each year
One third of world population is infected
how is Mycobacterial phagosome maturation arrested
- Lacks H-ATPase pump
- Fails to fully acidify
- Retain TACO (coronin)
- Lacks many proteins found in normal phagolysosome
what is TACO?
Newly formed phagosome is coated with a protein called “TACO” (tryptophan-aspartate-containing coat protein), also called “Coronin”
how does TACO prevent maturation?
- must be removed before phagosome can fuse with a lysosome.
- Mycobacteria prevent TACO coat being removed, thus fusion is blocked
- Macrophages with TACO gene knocked out rapidly kill mycobacteria by phagosome-lysosome fusion
how does TACO modulate the vacuole?
- Mycobacteria cause TACO to be retained, so the phagosome can’t fuse with the lysosome
- Incontrast, M.bovis vacuole fuses with lysosome in TACO -ve macrophages
what is Mycobacterial Mannosylated Lipoarabinomannan (ManLam)?
- Component of the bacterial cell wall
- Also used by M.tuberculosis to block phagosome / lysosome fusion
- ManLam interferes with acquisition of lysosome, inhibits signalling pathway
how are microbes Resistant to lysosomal contents?
- microbes produce high-affinity binding proteins, siderophores that allow them to acquire iron sequestered by the host protein lactoferrin
• Some microbes are resistant to cationic peptides
what are Innate human ‘peptide antibiotics?
Cationic antimicrobial peptides = CAMPs
name two CAMPs
- a-Defensin hNP-1 (Granulocytes, Macrophages, Paneth cells, T cells)
- -Defensin hBD1 (Epithelia, skin)
give evidence that Host defence factors are ‘positive by nature’ - Bacteria are ‘negative by nature’
1. Antimicrobial host factors are Positively charged • Antimicrobial peptides •Lysozyme 2. Bacterial cell envelope components are Negatively charged: • Peptidoglycan • Teichoicacids • Phospholipids • Lipid A, LPS,...
give 2 negatively charged bacterial cell envelope
Gram-positive bacteria (Staphylococcus aureus)
Gram-negative bacteria (Shigella flexneri)
how is Staph. aureus resistant to defensins
- introduction of positive charges into the cell wall
- incorporation of D-ala into techie acids
what are the Bacterial CAMP resistance mechanisms?
- Cleavage of CAMP PgtE protease: Salmonella, Escherichia
- Anti-CAMP Staphylokinase: Staphylococcus
- Extrusion of CAMP MtrCDE efflux pump: Neisseria
- Repulsion of CAMP
- Modification of teich. acids and lipids:
Staphylococcus, Listeria, Streptococcus, …
- Modification of lipid A:Salmonella, Pseudomonas
example of Survival inside phagocytes
Resistance to lysosomal enzymes—survive in phagolysosome (pH as low as 4)
Leishmania spp. (protozoa)—resistance may be due to:
– Resistant cell surfaces
– Secretion of enzyme inhibitors
how does Inhibition of phagocyte’s oxidative pathway protect microbe?
Legionella pneumophila (Legionnaire’s disease) Inhibits oxygen consumption in neutrophils Reduces respiratory burst for killing microbes
how do microbes become Resistance to Reactive oxygen and nitrogen intermediates
- ROI detoxifiers, ROI scavengers
Staphylococci—produce catalase, which degrades hydrogen peroxide
• RNI : ROI detoxifiers interfere with RNI
what are the Antibody effects?
- Rickettsia coated with antibody can’t pass through membrane into cytoplasm
• Antibodies don’t always prevent entry into cells, but can inhibit subsequent effects
• Antibodies against Legionella prevent inhibition of phagolysosomal fusion
name the Bacterial strategies to avoid being phagocytosed
- Capsule- Haemophilus influenzar
- Slime- Pseudomonas aeruginosa
- IgG improperly bound- Staphylococcus aureus
- Inhibition of chemotaxis- Bordetella pertussis
- Escape from phagosome- Shigella flexneri
name the Bacterial strategies to avoid killing by phagocytes
- Alter phagosome maturation / lysosome fusion- Mycobacterium tuberculosis
- Resistance to oxidative killing- Mycobacterium tuberculosis
- Resistance to non-oxidative killing- Escherichia coli
- Failure of respiratory burst- Mycobacterium tuberculosis
- Inhibits macrophage activation- Mycobacterium leprae
- Kills macrophages- Yersinia enterocolitica
- Inhibition of antigen presentation- Mycobacterium tuberculosis
