killing intracellular pathogens L23 Flashcards
what is the benefit of being an intracellular pathogen?
can hide from immune effector mechanisms like antibodies, complement proteins etc
have ready supply of resources from cell like nutrients and cellular machinery to hijack
hitch a ride around the host to transport and spread infection
intracellular microbes in phagocytes
phagocytosed microbes that survive within phagolysosomes or microbes that escaped it and now in cytoplasm
mycobacteria, fungi or protozoa
intracellular microbes in nonphagocytic cells
viruses, rickettsia, bacterial, protozoa
advantage of infecting immune cells
for immune evasion - to manipulate immune pathways easier if inside them
immune cells migrate readily around host so are perfect transporters to spread infection
macrophages are trying to eat them already to evade killing mechanisms
detection of intracellular microbes
via intracellular PRR to detect these intracellular pathogens
- endosomes = TLRs
- cytosol have NOD-like receptors - NOD1 NOD2 to recognise bacteria, Rig-like receptors RIG-1 to recognise viral RNA
evasion of phagocytosis 1
does this by avodiing killing mechanisms
- prevent formation of phagolyosome
- inactivates ROS and RNS
- disrupts phagosomes membrane to escape into the cytoplasm
- prevent lysosome fusion
evasion of phagocytosis 2
escaping the phagosome
breaking out and living and replicating in the cytosol by using LLO to disrupt phagosome membrane or use host actin to move within and between cells like an actin rocket
anti-viral state
viral infection stimulates type 1 interferons IFN-A IFNB
induce an anti-viral state where cells protect them from being infected
type 1 IFN functions
inhibition of viral gene expression, viral RNA degradation or autophagy (eating own organelles)
induces apoptosis, alters cell response from TNF-A being pro-inflammatory to apoptosis
promote T cell and NK cell activation, increase cytotoxicity of CTL and NK, promote Th1 differentiation and upregulates MHC 1
NK cells kill infected cells
targeting cells infected with bacteria, viruses and protozoa, and tumour cells
need IFN-Y from Th1 and CTL for full activation
IFN-Y activate macrophages is secreted by NK cells
necrosis
uncontrolled cell death due to mechanical damage or microbe bursting cell
cell ruptures and releases contents
highly inflammatory
apoptosis
programmed cell death
fragmentation of DNA, membrane blebbing
aopototic cells cleared by phagocytosis
non-inflammatory
NK cell activation
express a range of activating and inhibitory receptors
inhibitory receptors recognise ligands on healthy cells like MHC 1
activating receptors recognise ligands on infected or injured cells
activation depends on balance of activating and inhibitory signals received
NK infected cells activation
either inhibitory receptors not engaged, pathogen causing MHC down regulation or/and, cells express stress molecules that engage the activating receptors
Th1 (CD4) and CTL (CD8) cooperate to kill
Th1 produce IFN-Y to activate macrophages, NK and CTL
CTL identify and kill infected cells
Th1 cells enhance CD8 activation
Th cells produce cytokines IL-2 and IFN-Y to stimulate differentiation CTLs
and enhance ability to APCs to stimulate CTL differentiation
CTL recognise intracellular Ag presented by MHC 1
this is a precise way of identifying infected cells
more specific than NK cells
CTL/NK cell killing mechanism
perforins - create pore in infected cells membrane
granzymes - enter via pore and induce apoptosis
targets cells expressing Fas
CTL/NK express FAS ligand (Fasl) activating Fas
Fas activation signals apoptosis
CTL activation - cross presentation
This helps activate CD8 T cells even when DC isn’t infected itself
allows immune system to launch CTL response to virus or tumours that don’t infect APC directly
enables DC to present external antigens on MHC 1 to activate CTLS
viral evasion of CTL and NK cells
viruses disrupt MHC 1 Ag presentation is essential for evasion
this is why NK cells detect MHC 1 down regulation to combat this
Ab neutralisation
Ab can target intracellular pathogens during extracellular stages like moving between cells
preventing further infection
