L18 Immune system in action Flashcards
Mechanisms to evade the immune response
Alter their structure/surface to hide from
host sensors e.g: altering the structure of their coating. Most can alter host defense mechanisms: * Inhibit cellular pathways e.g: proteins that translocate in cell and block production of inflammatory mediators?
* Damage/degrade host receptors
* Kill immune cells
* Also often activate and benefit from
inflammation
»Mediated by VIRULENCE FACTORS - proteins present only in pathogens.
Extracellular bacteria
colonise the surface of barrier tissue
(gastrointestinal tract, respiratory
tract, skin) e.g: ecoli colonises the gut and causes diarrhoea
✓ Tissue spaces
✓ Blood - where they replicate efficiently
Immunity to extracellular bacteria
- Epithelial barriers - physical barrier so help of innate with adaptive
- Antimicrobial peptides
- Complement
- Phagocytosis (macrophages, neutrophils)
- Neutrophil extracellular traps (NETs)
- Innate sensing and inflammation
- Antibodies
Need mechanisms to work together
Avoidance of antibodies: by pathogens to hide from detection through:
Antigenic variation: have diff mutations at the surface to not be recognised
Diff pillin cobmbinations to form pilli= difficult for antibodies to recognise them
Neisseria meningitidis
E. Coli
* Phase variation: change structure of lipopolysaccharides (LPS). downregulate the expression of proteins-phase variation.
Neisseria meningitidis
* Direct degradation of Ab (IgA protease)
Neisseria meningitidis
H. influenzae
Streptococcus pneumoniae
Disruption of epithelial barriers: first line of defense against pathogens.
Epithelial barriers are first line of defense and
first obstacle for pathogens which have
evolved mechanisms for
* Direct destruction of tight junctions
(Enteropathogenic E.coli - EPEC)
* Induction of inflammation
Targeting of complement
- Mimicking host proteins - CD59-like (negative regulator of complement, prevent mac assembly), B burgdorferi, hijacks negative regulator. ?
- Hijacking negative regulators – Factor H - Neisseria meningitidis
- Secretion of proteases – C3/C5 cleavage, P aeruginosa
- Secretion of evasion molecules - C3/C5 inhibition, S aureus
Neutrophil extracellular traps: use dna as a trap to trap extracellular bacteria and digest bacteria through enzymes
NETs
* Regulated explosion of
neutrophils
* DNA coated with histones and
chromatin>TRAP
* Enzymes/antimicrobial proteins:
neutrophil elastase
myeloperoxidase» KILL
inhibition of release e.g: induction of host IL-10, degradation e.g: nucleases, resistance e.g: encapsulation, resistance proteins e.g: M1. all done by diff bacteria.
To dna trap or inhibit enzymes
Nets more efficient against single bacteria, forming colony makes it harder for nets to attack.
phagocytosis?
Phagocytosis
* Phagocytosis (macrophages/neutrophils)
>’Cell eating’ of large particles
> actin driven process
* Enhanced by opsonisation – Antibodies,
Complement
* Phagosome fuses with lysosome to form
phagolysosome where bacteria are killed
Evasion by extracellular pathogens
* Inhibition of phagocytosis
- Blocking actin polymerization
Yersinia, EPEC, Pseudomonas: have evolved inhibitors of actin pol
* Hiding from Complement or Antibodies by expressing sugary coat: Capsule
Prevention of killing
- Inhibition of ROS
- Staph (Catalase)
* Direct killing of innate immune cells
> regulated activation of apoptosis: EPEC,
Yersinia
> toxins: Staph
Inflammatory signalling bridges innate and adaptive immunities
Innate Immune Sensing and Pathogen Evasion
Innate Immune Sensing:
The innate immune system relies on Pattern Recognition Receptors (PRRs) to detect conserved microbial components known as Pathogen-Associated Molecular Patterns (PAMPs).
PAMPs are critical for the survival of pathogens in the host and are not present in host cells, making them key targets for immune detection.
Mechanisms of PRR Detection:
PRRs initiate immune responses by recognizing PAMPs, leading to the upregulation of pro-inflammatory cytokines, which:
Recruit and activate other immune cells.
Trigger signaling cascades to control infections.
Pathogen Evasion Strategies:
Pathogens have evolved mechanisms to evade detection and block immune responses, such as:
Blocking PRR activity (e.g., receptor inhibition).
Inhibiting kinase signaling pathways downstream of PRRs.
Preventing the activation or nuclear entry of transcription factors needed for inflammatory responses.
Blocking or degrading inflammatory mediators.
Interferons (IFNs):
Interferons are critical for protecting tissues from infection by inducing an antiviral state and enhancing immune responses.
They are produced in response to PRR activation and trigger the expression of interferon-stimulated genes (ISGs) that inhibit pathogen replication.
Pathogen Strategies to Evade IFN Responses:
Pathogens, such as Francisella, can evade inflammatory signaling by:
Modifying PAMPs to avoid detection by PRRs.
Blocking various components of inflammatory signaling, including:
Receptors: Preventing PAMP recognition.
Signaling Components: Inhibiting downstream pathways.
Transcription Factors: Blocking their activation or nuclear translocation.
Inflammatory Mediators: Inducing degradation or inhibition to suppress the immune response.
Impact of Evasion Strategies:
By disrupting these key processes, pathogens can avoid immune detection and enhance their survival within the host.
Immune evasion- intracellular bacteria
- Invade non phagocytic cells
- Replicate in epithelial cells
- Many replicate in macrophages
Innate immunity to intracellular bacteria - Autophagy: macrophages or epithelial cells degrade intracellular pthogens.
- Innate sensing (intracellular/cytosolic
sensors) of pamps? - Cell death
Cells can induce:
>Apoptosis
>Necroptosis
>Pyroptosis - Inflammasome
> inflammatory cell death
Can alter phagolysosomal compartment to make it hospitable for bacteria.
Can interfere with ros and ph. Make phagolysosome a vacuole. Some pathogens want to be in cytosol e.g: in epithelial cells.
* Inhibition of phagolysosome formation (Mtb,
Salmonella)
* Resistance to degradation in phagolysosome
(Mtb, Salmonella, Legionella)
* Phagosome escape (Listeria, Shigella)
* Block autophagy (Mtb, Shigella)
* Block cell death (Shigella, Yersinia)
* Inhibition of innate sensing (almost all
viruses and bacteria)
Immunity to viral infection
Inteferon prod by innate immune system. Interferon stimulated gene block viral replication. NK cells kill virus infected cells. Adaptive immunity: B cells produce antibodies that neutralise virus. CD8+ kill infected cells.
Immune evasion:
Inhibition of IFN induction or signaling
(SARS-CoV2) all of them can do this:
Block: signalling pathways of making inteferons and isg? Search this part up
- Inhibition of inflammatory signaling
- Production of immunosuppressive
products, vIL-10 (Epstein-Barr)
- Antigenic variation (Influenza)
- Inhibition of MHC pathway
(Cytomegalovirus, herpes simplex)
- Infection/death of immune cells (HIV)
yersina example ***
T3SS- or injectisome
chatgpt: A major virulence determinant conserved among many virulent bacteria.
Found in pathogens such as Salmonella, Shigella, Yersinia, Pseudomonas, E. coli, Bordetella, Vibrio, and various plant pathogens.
Functions as a ‘molecular needle’ that injects effector proteins (virulence factors) directly into the host cell.
These effector proteins manipulate the host cell’s processes to benefit the pathogen, such as:
Subverting immune responses.
Altering the cytoskeleton for bacterial invasion or survival.
Promoting intracellular replication and spread.
Enteropathogenic Yersinia (enterolitica, pseudoTB) lifecycle
- Invades the gut epithelium
- Taken up by macrophages and
migrate to the lymph nodes, liver - Induce apoptosis (death) in
macrophages - Uses effectors of T3SS to
- Block phagocytosis by macrophages
- Block innate signaling and cytokine
expression - Manipulate cell death and inflammation
Yop
Effectors
Invasin
Migration to
MLN, liver
Apoptosis of
macrophages
Inhibition of inflammatory genes
Inhibition of phagocytosisInflammatory
genes
Invasion of epithelial cells
Yersinia vs man: phagocytosis
Phagocytosis driven by actin- actin activated by strong gtpases in the rho family.
* Activated by Rho GTPases
* Lead to bacterial death
- Yersinia is an extracellular pathogen
- Blocks its phagocytosis
- Through inhibition of Rho GTPases
No phagocyotsis, no actin, pathogen survives.
