Bacterial Pathogenesis and Immune Evasion Flashcards
What is balanced pathogenicity?
Balance between properties of the microbe and properties of the host (pathogenic mechanisms and defensive mechanisms)
What are some pathogenic mechanisms?
Adhesins
Toxins
Capsule
What are some defensive mechanisms?
Natural barriers
Defensive cells
Complement
Immune response
What do virulence factors do?
Promote colonisation and adhesion
Evade host defences
Promote tissue damage
What are some virulence factors?
Adherence factors
Invasion factors
Capsules
Endotoxins
Exotoxins
Siderophores
What do adherence factors do?
Colonise mucosal sites by using pili to adhere to cells
What are invasion factors?
Surface components and secreted effector proteins
What are capsules?
Polysaccharides
Protect from opsonisation and phagocytosis
Describe endotoxins
Lipopolysaccharide on gram negatives
Lipoteichoic acids on gram positives
Cause fever, changes in BP, inflammation, lethal shock
What are exotoxins?
Protein toxins and enzymes produced and/or secreted
What are siderophores?
Iron-binding factors to compete with the host for iron haemoglobin, transferrin and lactoferrin
What are the types of pathologic effects of infection?
Direct
Via innate immune mechanisms
Via adaptive immune mechanisms (hypersensitivity)
Describe the pathogenesis and defence to Bordetella pertussis (whooping cough)
Pathogenesis - numerous toxins, non-invasive
Defence - mucosal and systemic antibody to toxins and adhesins
Describe the pathogenesis and defence to Vibrio cholerae
Pathogenesis - non-invasive enteritis
Defence - neutralising and adhesion Abs, antitoxin Abs
Describe pathogenesis and defence to Neisseria meningitidis
Pathogenesis - nasopharynx carriage; bacteriaemia, meningitis, endotoxaemia
Defence - killed by lytic, opsonised by Ab then phagocytosed and killed
Describe the pathogenesis and defence to Staphylococcus aureus
Pathogenesis - locally invasive and toxins
Defence - Opsonised by Ab and complement, killed by phagocytes
Describe the pathogenesis and defence to Mycobacterium tuberculosis
Pathogenesis - invasive, immunopathology granuloma
Defence - macrophage activation by cytokines from T cells
Describe the pathogenesis and defence to Streptococcus pneumoniae
Pathogenesis - inflammatory, toxin causes damage, carriage invasion
Defence - muco-ciliary clearance, splenic filtration, complement activation, Ab opsonisation
What are the stages of infection?
Acquisition
Colonisation - adherence
Penetration
Multiplication and spread
Immune avoidance
Damage
Transmission
Resolution
What are the mechanisms of microbial interactions with immunity?
Extracellular - pneumolysin, superantigens, toxins
Capsule - inhibition C3b and Ig deposition, -ve phagocytosis
Surface structures - protein A, M protein, LPS
Direct secretion of effector proteins into cells - type 3 secretion systems
Intracellular survival mechanisms
What are some receptors for adhesins?
Glycolipids
Glycoproteins
Transmembrane proteins
Mucins
Give examples of bacterial adhesins
Fimbriae/pili
Capsular polysaccharides
LPS
Lipoteichoic acid
Outer membrane proteins
Flagella
Curli - Salmonella, bind to fibronectin and laminin
Describe adherence in E coli
P fimbriae bind P blood group on uroepithelial cells
Describe adherence in Neisseria gonorrhoeae
Pili attach to mucosal cells
Non-piliated mutants are less pathogenic
Describe adherence in Vibrio cholerae
Fimbriae bind intestinal epithelial cell receptors
Describe adherence in Strep pyogenes
Lipoteichoic acid binds to epithelial cell
What is the function of M protein in Streptococcus pyogenes?
Acts as adhesin and structural component of cell wall
Describe Neisseria-host interactions
Pili allow anchorage to epithelial cells
Tight adherence maintained by Opa proteins
Invasion and transcytosis
Formation of granulocyte
Invasion and intracellular accommodation
Formation of monocyte
Systemic infection of endothelial cells
Describe promoted phagocytosis as a host-pathogen interaction
Some pathogens allow themselves to be phagocytosed instead of evading phagocytosis as the next step in their pathogenicity is after being phagocytosed
They manipulate the phagocyte such that they do not get killed when they are engulfed
e.g. Streptococcus pyogenes
What can E. coli manipulate host cells to do?
Form attachments pedestals for them to adhere to
Describe attachment and pedestal formation by EPEC
Bundle forming pili (bfp) mediate the initial attachments to the microvilli of the host cell
Type 3 secretion systems are activated
Bacterial translocation intimin receptor (Tir) is secreted and injected onto host cell and binds to intimin
Loss of microvilli
Actin rearrangements lead to formation of pedestal
Describe what is meant by attaching and effacing lesion
Microvillus elongation
Effacement of apical membrane - destruction of microvilli
Pedestal formation
Where is E. coli commensal?
The gut
What can E. coli cause?
Diarrhoea
Dystentery
Haemolytic uraemic syndrome (HUS)
Urinary tract and kidney infections
Septicaemia
Pneumonia and meningitis
What are virulence factors of E. coli?
Toxins
Adhesins
Invasins
Describe ETEC infection
Traveller’s diarrhoea
Secretory
No inflammation
No structural changes
Toxins = LT and ST cGMP at membrane
Describe EPEC infection
Diarrhoea
Attaching and effacing lesions
Describe EIEC infection
Dysentery
Specific serotypes
Describe EHEC infection
O157:H7
Verotoxin (Shiga-like toxin)
Intense inflammation
HUS
Dysentery (not so invasive)
Attaching and effacing lesions
Describe the role of Tir in type 3 secretion systems
Release of Tir from bacteria when bfp facilitates attachment to host
Tir is then phosphorylated and is injected into the host membrane
Allows binding of intimin (adhesin protein)
Activation of cytoskeletal rearrangements and pedestal formation
Describe the molecular structure of a type 3 secretion system
Pore complex - YopBD, LcrV
Needle - YscF
Basal body - Ysc secretory proteins
What are YOPS?
YOPS - Yersinia outer membrane proteins
Bacterium Yersinisa pestis secretes YOPS into macrophage and PMNs
Each YOP has different effects
What effects does YopE have?
Actin rearrangement via GTPases
Cell rounding
Anti-phagocytic
What effects does YopH have?
YopH is a tyrosine phosphatase
Negative phagocytosis - YopH blocks ability of cell to undergo phagocytosis
What effects does YopJ/P have?
Blocks TNF and MAP kinase release
Induces apoptosis
What effects does YopA/O have?
A serine protease so will breakdown several proteins
What effects does YopT have?
Actin rearrangement
What are molecular syringes?
Gram negative bacteria that inject effectors into a host cell
Give some examples of molecular syringes
Salmonella gut epithelium invasion
Modification macrophage phagosome
Yersinia inhibition neutrophil and macrophage function
Shigella macrophage invasion and escape from phagosome
Cell-to-cell spread
EHEC and EPEC adhesion to gut epithelium
Legionella inhibition phagolysosomal fusion
Why is site of infection of intracellular pathogens commonly the macrophage?
It is the first cell to encounter the pathogen
It can subvert bacterial recognition and phagocytic pathways to encourage infection
What are some examples of intracellular pathogens?
M. tuberculosis
Listeria monocytogenes - gram positive
Legionella pneumophila - gram negative
Leishmania - protozoa
Histoplasma capsulatum - fungi
Salmonella typhi - gram negative
Francisella tularensis - gram negative
Coxiella burnettii - ricketsia
How do bacteria interfere with cellular functions?
Adhesion to receptors e.g. adhesins and integrins
Manipulation of cytoskeleton by invasive and non-invasive organisms, pedestal formation by E. coli
Manipulation of cytoskeleton for movement of intracellular organism e.g. Shigella
Endosomal trafficking e.g. M. tuberculosis
Manipulation of lysosomal function e.g. S. typhi
Escape from phagosome e.g. Legionella
-ve protein synthesis e.g. diphtheria
Membrane disruption
Pore forming toxins
Blocking of phagocytosis e.g. Yersinia
How does staphylococci prevent phagocytosis?
Produces leucocidins that kill the cell
Have protein A on their surface which binds Abs the wrong way round (binds Fc portion of IgG) preventing opsonisation
Expression of Fc receptors similar to protein A
What is the purpose of capsules on bacteria?
Block phagocytosis
e.g. meningococci, Haemophilus influenzae
How do intracellular pathogens cause infection?
Promote uptake via CR, Fc receptors
Prepares cell for invasion by class 3 secretion e.g. Shigella
Prevents phagosome-lysosome fusion e.g. M.tb
escape P-L to cytoplasm e.g. Listeria
Resist oxidative killing by producing catalase/peroxidases that block MHC, IFN receptors and TNF release
Describe listeria cell-cell invasion
Listeria phagocytosed and endosome formation
Listeriolysin (intracellular pore forming toxin) released from endosome into cytoplasm
Other effector proteins released that take control of actin filament formation inside cell
Actin re-arrangement allows transport of bacteria through the cell and from one cell to another
What are the roles of complement?
Induces inflammatory response
Promotes chemotaxis
Increases phagocytosis by opsonisation
Increases vascular permeability
Mast cell degranulation
Lysis of cell membranes
Activates macrophages (C3a)
Removal of immune complexes
How do bacteria avoid complement?
Surface components of bacterial polysaccharide capsules are poor activators of complement
Long side chains (O antigens) fix C3b and prevent access to the membrane
Capsules rich in sialic acid promote interaction with H and I factors hat promote MAC dissociation e.g. Group B Streps, N. meningitidis, E coli K1
Outer layer of G-ve bacteria can rapidly shed C5b-C9 MAC
C3a and C5a proteases
Coat themselves with non-complement fixing IgA
Describe the importance of opsonisation
Uncoated by Abs, bacteria are phagocytosed poorly
When coated with Ab, adherence to phagocytosis is enhanced
Give examples of opsonins
IgG1 and 3
IgM
C3b
CRP
What are the phagocyte receptors?
Fc
CR3
Name some bacteria that have capsules
Neisseria meningitidis
Haemophilus influenzae
Streptococcus pneumoniae (G+ve)
E. coli K1
What does presence of a sialic acid or hyaluronic acid capsule result in?
Decreased complement binding/activation
Decreased opsonisation
Decreased phagocytosis
How can the host’s immune defences cause damage?
Overactivity of immune defences e.g. with endotoxins produced by G-ve bacteria
Types of hypersensitivity e.g. type 4 hypersensitivity granuloma in TB
Cross-reaction with host e.g. Strep pyogenes in Rheumatic fever
Describe how S. aureus stimulates IL8
Surface protein A binds epithelial TNF-a receptor (TNFR1)
Stimulates proinflammatory signalling
Induces IL8 secretion
Increased neutrophil recruitment
Necrotising destructive pneumonia
S. aureus stimulation of IL8 is detrimental to the host
Describe cross reactivity in Strep pyogenes infection
Abs against strep antigens are produced - group A carbohydrate and M protein
These Abs cross-react with antigens of the host
Binding of Ab to host Ag activates complement and leads to inflammatory responses and hypersensitivity reactions
What are some sites of cross reactivity in Strep pyogenes infection?
Myocardium - rheumatic heart disease
Synovium - reactive arthritis
Brain - Sydenhams chorea
Kidney - post-streptococcal acute glomerulonephritis
