Microbial Immune Evasion Flashcards
What are virulence factors?
properties of the pathogen that allow it to successfully invade and cause disease in a host
Actions of virulence factors
·promote adherence/receptor binding and internalisation
·allow bacteria to colonise mucosal surfaces and promote adhesions
·promote tissue damage, for example the production of toxins and enzymes
·evade host defence mechanisms (innate & adaptive immunity)
Roles of complement (innate immunity)
- Induces inflammatory response
- Promotes chemotaxis (recruitment of neutrophils/macrophages to site of infection)
- Increases phagocytosis by opsonisation
- Increases vascular permeability
- Mast cell degranulation
- Lysis of cell membrane → killing pathogenic organism
How does the complement system (innate immunity) recognise pathogens?
A membrane attack complex assembles on the membrane and damages/kills the pathogens
Mechanisms by which BACTERIA evade complement (innate immunity)
Lipopolysaccharides & Capsules
-block the triggering of the complement-activating cascade.
Factor H Sequestration
-bacterial protein binds factor H, (negative regulator of complement cascade), and thus prevents complement activation on surface of bacteria
Non-Complement Fixing Immunoglobulin (e.g. IgA)
-bacteria can coat themselves when non-complement fixing immunoglobulins (antibodies) which complement can’t bind to, and thus these cannot undergo opsonisation by complement
Polysaccharide Capsules Block C3b
- C3b is a potent opsonin which binds to surfaces and allows opsonisation into macrophages
- polysaccharide capsules block this binding
Proteases Degrade Complement Proteins
- bacteria have proteases specific to degrade complement proteins such as C5a and C3a involved in inflammation
- inflammation is therefore minimised (favourable to microbe)
Other than complement, how else do bacteria evade innate immunity?
By evading phagocytosis by macrophages
Mechanisms by which BACTERIA evade phagocytosis (innate immunity)
Leukocidins (Staphylococci)
-toxins which damage cell membranes of macrophages
Produce Protein A (Staphylococci)
-protein A encodes mimics of the Fc receptor which binds Fc component of antibodies (IgG) the wrong way, blocking the antibody from having any effect and thus preventing opsonisation by a macrophage
Polysaccharide Capsules (meningococcus, Hib)
- block contact with macrophages, avoiding phagocytosis
- Intracellular pathogens also have mechanisms which evade phagocytosis
Mechanisms by which INTRACELLULAR BACTERIAL pathogens evade phagocytosis (innate immunity)
Promote their Own Uptake (Shigella & E.coli)
-secrete proteins into macrophage which act as receptors for the bacteria to be internalised
-via CR3 or mannose lectin receptors
Block Phagolysosome Fusion (Mycobacterium tuberculosis)
-once bacteria is in endosome of macrophage, it secretes proteins to block phagolysosome fusion and stops acidification of the early endosome to prevent progress to further steps
-bacteria replicates in high numbers in non-acidified vacuole, causing lysis of cell and infects other cells
Phagolysosome Escape (Listeria) -escape the phagolysosme and enter cytoplasm to replicate, escaping killing mechanisms of macrophage
Produce Catalases and Proteases
-neutralise reactive oxygen intermediates generated through phagolysosome fusion, resisting oxidative killing
Adaptive Immunity
immunity or resistance to a specific pathogen
Mechanisms by which pathogens evade adaptive immunity
1) Concealment of their Antigens
- hide inside cells
- reside in immunologically privileged sites (e.g. nerve cells)
- inhibit TAP protein, blocking presentation of antigens to MHC molecules
- surface uptake of host molecules
2) Immunosuppression
- downregulate MHC molecule expression in antigen presenting cells
- downregulate receptors on surface of cells
- inhibit apoptosis to replicate without cell death
- induce apoptosis to spread to other cells without inflammatory response
- disrupting cytokine balance
- produce IgA proteases which damage secretory IgA and degrade antibody defence mucosal surfaces, allowing pathogens to colonise mucosal surfaces
3) Antigenic Variation
4) Persistence/Latency/Reactivation
- e.g. Herpes virus remains latent in nerves and reactivated during immunocompromisation
-e.g. TB remains latent in innate macrophages deep inside granulomas for years until immune system wanes
What does Streptococcus pneumoniae cause?
Septicaemia, meningitis, pnuemonia, otitis media, osteomyelitis and other inflammatory processes
Pathogenic mechanisms of Streptococcus pneumoniae
COLONISATION
-Breathe organism in and it colonises nasopharynx via adhesion molecules
-Secrete IgA proteases which degrade immune antibodies at mucosal surfaces allowing colonisation
SURVIVAL & BY-PASSING DEFENCE MECHANISMS
-pathogen inhaled into lungs and overcomes surfactant molecules and mucus defence mechanisms by same secretion of IgA proteases, but also switching gene on for pneumolysin toxin
- pneumolysin toxin causes pores and lysis membranes of pneumocytes in the lungs
- pathogen also escapes phagocytosis because it has a polysaccharide capsule
- pathogen also has techoic acids that drive inflammation
DAMAGE
-pneumocytes are damaged and bacteria can create a niche environment for replication, causing inflammation resulting in lobar pneumonia
-spread from lobar pneumonia into the blood stream, causing septicaemia, osteomyelitis and meningitis
How is Streptococcus pneumoniae able to survive within a population?
It has multiple serotypes (antigenic diversity)
-slight changes in polysaccharide capsule structure
How do viruses evade immunity?
Latency (VZV, Herpes simplex)
- both remain latent in sensory neurones in dorsal root ganglion, considered immunologically privileged sites
- VZV reactivation causes shingles
- Herpes simplex virus I reactivation causes cold sores
Reducing Antigenic Presentation
-Herpes simplex binds TAP protein and blocks presentation of their antigens to MHC molecules
Reducing MCH Expression
-CMV can downregulate MHC expression
Mutation of Epitope
-viruses can escape both B cells (antibodies) and T cells (cytotoxic/CD8+ T cells) by undergoing rapid mutation
Phenotypic changes due to antigenic variation include…
Colony morphology changes Virulence factor changes Serotype Loose flagella Change surface sugars
Antigenic Variation
Successive expression of alternative forms of an antigen in a specific clone or its progeny (individual organism with a diverse antigenic nature on its surface) – e.g. Neisseria gonorrhoeae
- Phase Variation: ON/OFF expression/switching of an antigen at low frequency
- Occurs:
>During course of infection in an individual host
>During spread of microbe through a community
How does influenza virus evade immunity at a population level?
Influenza virus: Antigenic drift
- as the virus replicates itself, it accumulates mutations and therefore you get antigenic variants of those surface proteins (HA or NA)
- antibodies can no longer recognise these surface proteins
This is why we get continuous flu infections every year and why we have to have a flu vaccine every year. These cause epidemics.
Antigenic shift
This is a form of gene reassortment where two viruses infect a single cell and undergo recombination of the genome. These combinations of the genes have never been seen before by the human population for a few generations at least, meaning we don’t have an immune response against it. This virus will therefore spread and infect everyone, sustaining itself within the population. This is considered a pandemic. The host population is immunologically naïve and therefore the effects of virus infection are much more severe.
