4.7 - Immune Evasion Flashcards
1
Q
Staphylococcus aureus
A
- gram positive bacteria that is commensal and lives harmlessly in nose of 30% of humans
- opportunistic pathogen that can cause minor skin infections to severe/life-threatening diseases
- diseases caused by S. aureus are divided into two groups:
- localised pyogenic (pus-producing) diseases characterised by tissue destruction mediated by hydrolytic enzymes and cytotoxins
- diseases mediated by toxins that function as superantigens producing systemic diseases
2
Q
Properties of Staphylococcus aureus
A
- ability to grow aerobically and anaerobically over a wide range of temperatures, and in the presence of a high concentration of salt (bacteria is a common cause of food poisoning)
- polysaccharide capsule that protects bacteria from phagocytosis
- cell surface proteins (protein A, clumping factor proteins) that mediate adherence of bacteria to host tissues
- catalase protects them from peroxides produced by neutrophils and macrophages
- coagulase converts fibrinogen into fibrin that forms clots and can protect S. aureus from phagocytosis
- contain hydrolytic enzymes and cytotoxins: lipases, nucleases and hyaluronidase that cause tissue destruction; cytotoxins (alpha, beta, delta, gamma, leucocidin) that lyse erythrocytes, neutrophils, macrophages etc
- toxins: enterotoxins (heat-stable and acid-resistant toxins responsible for food poisoning), exfoliative toxins A and B (which cause the superficial layers of skin to peel off - scalded skin syndrome), and toxic shock syndrome toxin (heat and protease-resistant toxin that mediates multiorgan pathology)
3
Q
Streptococcus pyogenes
A
- gram positive bacterium
- can live harmlessly in the throat of humans
- opportunistic pathogen - can cause a range of diseases including pharyngitis (Strep throat), skin infections, scarlet fever and sepsis
- evolved many sophisticated mechanisms to evade neutrophils
4
Q
Pathogen diversity
A
- huge diversity in bacterial microbes
- immune responses developed mechanisms to detect this diverse range of bacteria
- bacteria often share common features - detected by immune response e.g. LPS in gram-negative bacteria, LTA in gram-positive bacteria, flagella on certain bacteria
- some microbes have evolved mechanisms which enhance survival in their host
- these immune evasion mechanisms contribute to bacterial pathogenesis
5
Q
The role of the innate immune system
A
- first line of defence against pathogens
- very efficient and detecting and killing invading microbes
- includes neutrophils, basophils, eosinophils, dendritic cells and macrophages
6
Q
Neutrophils - key points
A
- most abundant leucocyte (50-70%) in blood
- recruited to areas of infection
- detect microbes
- perform effector functions –> kill microbes
- considered ‘simple’ immune cells
- neutrophil responses must be balanced to prevent infection, but also prevent damage (inflammation) to the host
7
Q
How do neutrophils work?
A
- microbes enter the body and become opsonised with antibodies and complement
- results in production of gradient of C3a and C5a (complement components) as well as bacterial proteins and peptides
- C3a and C5a bind to their receptors (C3aR and C5aR respectively) on endothelial cells, which causes endothelial cells to express ICAM on their surface –> neutrophil recruitment
- when neutrophils contact endothelial cells they detect this increase in ICAM and adhere to ICAM receptors, roll along the surface of endothelium, then transmigrate across the endothelial layer
- they become primed by gradient of C3a and C5a / bacterial proteins and peptides
- migrate towards complement components and bacterial proteins (where microbes are) via chemotaxis
- become activated and perform effector functions –> can be phagocytosis (ingestion and killing pathogens within phagosome by antimicrobial molecules) or degranulation (reactive O2 species or antimicrobial molecules produced)
- neutrophils also recruit other immune cells (part of inflammatory response)
8
Q
Bacterial evasion of antibody opsonisation
A
- bacteria express surface and secreted proteins that interfere with innate immune responses
What is antibody opsonisation?
- antibodies bind bacterial antigens allowing:
- deposition of complement in the classical complement pathway
- neutrophils and other phagocytes the ability to detect invading microbes
- bacteria have evolved many mechanisms to evade antibody opsonisation
9
Q
Capsule expression - evading antibody opsonisation
A
- bacteria can express a capsule on their surface –> helps hide antigenic structures that can be detected by innate and adaptive components e.g. complement and antibodies
- done by S. aureus along with E.coli, S. pyogenes, S. pneumonia, S. agalactiae, Pseudomonas aeruginosa
- MAIN FUNCTION - HIDE ANTIGENS
10
Q
Binding of surface proteins to Fc region of antibodies - evading antibody opsonisation
A
- S. aureus protein A (Spa) and M surface proteins bind antibodies via their Fc region not their Fab region
- this prevents normal opsonisation (prevents deposition of complement onto bacterial surface via classical complement pathway) = neutrophils cannot detect S. aureus or S. pyogenes
- other bacteria express surface proteins that bind to antibodies including Streptococcus dysgalactiae (protein G binds IgG), Peptostreptococcus magnus (protein L binds IgG) and Streptococcus agalactiae (beta protein binds IgA)
- MAIN FUNCTION - DISRUPT FUNCTION
11
Q
Expressing SSL10 - evading antibody opsonisation
A
- SSL10 is a secreted protein that binds to Fc region of IgG antibodies that opsonise S. aureus and prevents Fc receptors on neutrophils from detecting these IgG receptors on S. aureus surface
- also prevents deposition of complement via classical complement pathway
- another protein called Sak also does this
- MAIN FUNCTION - PREVENT DETECTION
12
Q
Proteases that cleave antibodies - evading antibody opsonisation
A
- proteases cleave / modify antibodies into non-functional forms (e.g. S. pyogenes expresses IdeS protease which cleaves IgG antibodies at the hinge region = reduced classical complement response)
- prevents normal opsonisation and therefore neutrophils cannot detect S. pyogenes
- MAIN FUNCTION - DEGRADE ANTIBODIES
13
Q
Antigenic variation - evading antibody opsonisation
A
- switching proteins/capsules on surface of bacteria means antibodies that recognise first surface structure are unable to recognise them now
- e.g. N. gonorrhoeae expresses Opa protein –> different antigenic variations
- MAIN FUNCTION - MODIFY ANTIGENICITY
14
Q
Bacterial evasion of complement activation
A
- complement system is composed of a large number of proteins that react with one another to opsonise pathogens or to directly kill them by membrane attack complex (MAC)
- the key step of the process is deposition of C3b onto surface of microbe which can be detected by complement receptors expressed on neutrophils/phagocytes which can phagocytose the microbe
- key steps of complement cascade:
- initiation
- formation of C3 convertase
- formation of C5 convertase
- MAC formation
15
Q
What are the three initiation pathways that result in the formation of C3 convertase? (complement cascade)
A
- classical pathway - antibodies bind to antigens resulting in complex C1qrs forming which activate the C3 convertase, C4bC2b
- lectin / MBL pathway - MBL (mannose binding lectin made in liver) is able to detect and bind carbohydrates or sugars on surface of microbes and form a complex with MASP –> generation of C4bC2b
- alternative pathway - C3b is sporadically deposited onto surface of microbe, recruitment of additional factor B –> C3bBb (C3 convertase)
- both C3 convertases produce more C3b when factor B and C3 work together, resulting in formation of C5 convertase C3bBbC3b which degrades C5 –> C5a and C5b
- deposition of C5b on microbial surface –> recruits C6, C7, C8 and C9 which form MAC
