Immune evasion Flashcards
What is immune evasion? (4)
Evolution between host and pathogen has been/is an arms race
Both deploy sophisticated mechanisms to eliminate and evade killing
Great way to study important immune mechanisms
Ultimately allow logical therapeutic targeting
What are the different evasion and subversion mechanisms (7)
Antigenic variation
Host deletion
Molecular mimicry
Resistance to killing
Immune skewing/subversion
Immune “hiding”
Biofilms?
What is antigenic variation in bacteria? (3)
Alteration of surface antigens
Bacterial serotypes
Phase variation (switching on/off various genes) of mycoplama
What is antigenic variation in viruses? (3)
Influenza virus - antigenic drift and shift
HIV - high mutation rate of reverse transcriptase and rapid replication rate
SARS-COV2 - slower rate of mutation than HIV/Flu
What is evasion through hiding (1)
Pathogens may reside in various compartments to hide from immune system
Give examples of bacteria and how they hide (5)
Plasmodium falciparum invades red blood cells (lack almost all immune receptors)
P. Falciparum uses PfEMP1 to sequester erythrocytes in post venule capillaries (anatomical seclusion)
Anaplasma phagocytophilum resides in neutrophil intracellular vacuoles
More detail msp proteins/p44 antiapoptosis
Mycobacteria tuberculosis reside in macrophage phagosome
Listeria monocytogenes escape in to cytoplasm
What is evasion by molecular mimicry (3)
Many pathogens (especially viruses) encode host homologues to subvert immune response - bacteria/viruses produce molecules that look similar to human proteins and stop it from working
What is evasion through host deletion (2)
A number of pathogens eliminate host immune cells in order to survive
Superantigens cause polyclonal T cell activation and subsequent apoptosis - completely immunosuppressed
Give examples of induction of immunosuppression (5)
Bacillus anthracis toxins (lethal toxin) is a metalloprotease specific to MAP kinase kinase - Resulting in apoptosis of infected macrophages and dysfunction DC maturation
HIV Viral cytotoxicity kills infected cells
Depletion of CD4 cells results in immunosuppression
(both antibody and cytotoxic response)
Measles virus-induced immunopathology
DCs actively inhibit CD4 T cell proliferation via Lack of CD40 or kill
tumour necrosis factor-related apoptosis- inducing ligand (TRAIL)
Memory T cell response is severely reduced
Give some examples of different ways bacteria are resistance to killing Anti-killing mechanisms (3)
Change charge on surface membrane so antimicrobial peptides no longer bind
Have catalase
Proteases - prevent production of oxidase
What advantages do pathogens have in the molecular arms race? (1)
Low stringency replication and rapid life cycles give many pathogens an evolutionary advantage
What advantages do hosts have in the molecular arms race? (5)
However complex metazoan manage to keep pace
Redundancy (MHC polymorphism (>500 for some MHCI gene),
multiple immune mechanisms)
PRR tend to evolve against essential components
Adaptive immune response allows real time molecular evolution
Larger genome
What is the struggle for Fe2+? (4)
All organisms require Fe2+ for growth
Macrophages reduce Fe2+ concentration
Bacteria evolve receptors that bind to siderophores
Macrophage evolves Lipocalin
Describe the pathogen–host evolution and counter evolution of T cell killing (4)
Viruses down-regulated MHC molecule that prevent T cell cloning
NK cells recognise lack of MHC cells and kill the viral infected cell
Viruses have evolved due to molecular mimicry - developed MHC 1-like molecule so NK cells can no longer recognise
NK cells got a receptor that binds specifically to fake MHC molecule
Describe phagosome maturation (3)
Live inside cell - get taken up inside phagosome
Phagosme matures to have different types of surface proteins on vacuole
Fusion with other endosome and lysosomes which change condition inside the vacuole and kill the bacteria
What does phagosome maturation involve (4)
Membrane recruitment
Vesicle tethering and fusion (Rab5a, SNARE proteins)
Acidification
Hydrolyase activation
How does Mtb affect phagosome maturation (2)
Mtb expression profile is dramatically altered after uptake
Gene expression profile is actively switched on after uptake, and acidification
Describe Mtb evasion mechanisms (5)
Mtb is phagocytosed via CR3 uptake but phagosomes fail to mature
Rab5a effectors (EEA1, hVPS34) impaired. No PI(3)P generation
LAM (cell wall component) is actively shed, inhibits
↑ Ca2+, Mtb also inhibits sphingosine kinase prevents
↑ Ca2+ from ER. SapM hydrolyses PI(3)P
Depletion of PI(3)P from early phagosome prevents transition to late and phagolysomal stages
How is Mtb killed? (4)
IFN-gamma treat macrophages induce autophagy which sequesters arrested phagosome controlling Mtb
Innocuous cytosolic proteins are engulf by autophagocytic vacuoles and converted into potent antimicrobial peptides
Evading IFN-gamma mediated killing (3)
Constant activation leads to downregualtion of receptors which leads to down regulation of antigen presentation by MHC - less killing
Prolonged TLR stimulation results in inhibition of MHCII expression
Inhibits through this - mycobacterial agonists of Toll-like receptor 2
How does IL-1beta allow macrophages to kill Mtb (4)
IL-1beta restores PI(3)P and allows continued phagosome maturation
Mtb secrets ZmpA- metalloprotease that prevent inflammasome activation
The inflammasome is a multiprotein complex that ultimately activates IL- beta and IL-18
How does Mtb skew immune response? (3)
Mtb induces host Arginase 1:
Up regulation of Arg 1 (via TLR) – MyD88 pathway
↓ NO production, skew towards a less microbicidal macrophage
(alternatively activated macrophage)
Evasion of killing-Listeria (7)
5 minutes post phagocytosis Listeria secrets the cholesterol-dependent cytolysin Listeriolysin O (LLO)
LLO is activated by low pH and phagosomal enzyme (GILT) prevents lysing plasma membrane
After proliferation Listeria is able to spread from cell-cell
ActA is similar to host WASP protein (interacts with Arp2/3)
Listeria proteins induce actin comet tails to spread from cell to cell (push from one cytoplasm to another)
Avoids extracellular milieu ie antibodies, complement, other opsonins
What is autophagy? (3)
Phagocytosis in cytosol
Synthesis of double membrane in cytosol and engulf and destroy different types of bacteria
The Type III secretion system (3)
“Injectisome”
Multiprotein complex that can deliver effector proteins across eukaryotic cell membranes
