Lecture 21; Immunity to infection part one Flashcards
Describe the inflammatory response to bacterial infections;
- Activation of mast cells (histamine and herapin)
- Activated Macrophages secrete pro-inflammatory cytokines
- Vasodilation and increased permeability of blood vessels (vascular leakage)
- Leukocyte extravasate from the blood an migrate to the site of injury/ infection
- Migration is guided by IL8 from macrophages
How do bacteria trigger inflammation?
PAMPs
What are some PAMPS specific to gram positive and negative bacteria?
- Lipopolysaccharide (LPS) – found on Gram-negative bacteria
* Lipoteichoic acid (LTA) – found on Gram-positive bacteria
What are some other bacterial PAMPS?
• Flagellin – protein part of bacterial flagellum
• Peptidoglycan – polymer of peptides and sugar forming
bacterial cell wall
• Bacterial DNA (unmethylated CpG dinucleotides)
What recognises PAMPs?
PRRs
What is central to the production of inflammatory cytokines?
NFkB transcription factor
What can inflammation against certain pathogens lead to?
Endotoxic shock or toxic shock
example:
Toxic shock syndrome toxin (TSST) produced by Staphylococcus aureus
How can bacterial inflammation lead to tissue damage?
Significant change in vascular permeability, loss of fluid into tissue, fall of blood pressure Symptoms include fever, circulatory collapse, diffuse intravascular coagulation, haemorrhagic necrosis, multiple organ failure
What are two examples of bacteria that can cause tissue damage?
Toxic Shock Syndrome (Streptococcus pyogenes
Staphylococcus aureus)
Meningococcal septicemia
What bacteria are phagocytosed what mediates this?
Highly specific interactions between the bacteria and phagocyte
i.e
C3b -> CR1
BML -> C1qR
Antibody -> Fc receptor
Lectins oligiosccharides
Describe how S.auereus can cause toxic shock syndrome;
LPS binds to CD14 on macrophage surface -> NFkB activation and proinflam cytokine secretion.
Bacterial super antigens i.e s aureus, bind MHC 2 on APC and T cell = proinflam cytokine secretion (LPS and Superantigens can act synergistically)
High levels of pro-inflam cyotkines can cause increased vascular permeability and loss of BP.
Additionally neutrophils release Platelet Activating Factor (PAF) which can cause aggregation and degranulation. Platelet + Fibrin deposition can lead to diffuse intravascular coagulation and hemorrhagic necrosis.
What are acute phase proteins?
They are proteins released from the liver heaptocytes in response to proinflam cytokines (IL1,6 and TNFa) and they bind to cell carbohydrates i.e MBL, Surfactants or phosphorylcholine (C-reactive protein).
These act as inflammation markers and can result in opsonin effect or compliment activation
Describe the immunity to gram positive EC bacteria
- Antibodies specific to bacteria
- Compliment components
- Proteases, nucleases, lipases
Describe the immunity to gram negative EC bacteria;
- Antibodies specific to bacteria
- Proteases, nucleases, lipases
No compliments as MAC cannot form due to the two layers of membrane
What are three mechanisms bacteria have developed to avoid compliment-mediated damage?
- Outer capsule or coat prevents complement activation
- Long side chains (O antigen) on bacterial LPS prevent binding of Cb3 to complement receptor
- Surface structures on microbe prevent attachment of lytic complex to membrane
What are mechanisms four to six that bacteria have developed to avoid compliment mediated damage?
- membrane-bound enzyme degrades fixed complement or cause it to be shed Pseudomonas elastase: cleaves C1q and IgG
- resistance of outer membrane
- Secretion of decoy proteins that bind complement
(SIC protein of S. pyogenes) or membrane vesicles
• Recruitment of factor H to prevent C3b deposition
Describe the respiratory burst of a phagocyte that kills bacteria;
- NADPH oxidase activation
- Transfer of electrons to oxygen producing superoxide, hydroxyl radicals and H2O2 (ROS)
- Myeloperoxidase produces hyperchlorite
The release of these ROS can kill bacteria.
The pathways are either peroxidase dependant or independant
What are three microbicidal mechanisms of phagocytes?
Respiratory burst
Nitric oxidase pathway
Antibodies
Describe the nitric oxidase pathway;
- iNOS is activated by IFN(g) or TNFa
- Convertes L-arginine+oxygen into citrulline and NO
NO is toxic
What are 3 ways that bacteria can escape from phagolysis;
- Outer capsule or coat prevents complement activation
- Long side chains on bacterial LPS prevent binding of CB3 to compliment receptor
- Escape form phagolysosome into cytosol (Mycobacterium, listeria)
What are some ways that bacteria can prevent the activation of killing mechanisms?
Release of factors that block killing mechanisms;
- Block lysosome fusion, inhibit proton pump
- Release of catalase
- Coats resistant to ROS
- Blocking IFNg signals
What can block bacterial toxins and examples;
High affinity IgA and IgG
i.e tetanus vaccine
How can the bacteria protect itself against antibodies?
- Hide intracellularly
- Antigenic variation ie capsule type, variable surface proteins
- Camo i.e Hyaluronic acid capsule, fibrin coat (host like coat)
- Ig proteases
- Rapid cell division
What are antibodies directed towards?
Everything
Metabolite chelating proteins LPS Flagella Bacterial toxins Immunorepellents etc
